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  • 1.
    Björklund, Peyman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Svedlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    The internally truncated LRP5 receptor presents a therapeutic target in breast cancer2009In: PloS one, ISSN 1932-6203, Vol. 4, no 1, p. e4243-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Breast cancer is a common malignant disease, which may be caused by a number of genes deregulated by genomic or epigenomic events. Deregulated WNT/beta-catenin signaling with accumulation of beta-catenin is common in breast tumors, but mutations in WNT signaling pathway components have been rare. An aberrantly spliced internally truncated LRP5 receptor (LRP5Delta666-809, LRP5Delta) was shown recently to be resistant to DKK1 inhibition, and was required for beta-catenin accumulation in hyperparathyroid tumors and parathyroid tumor growth. METHODOLOGY/PRINCIPAL FINDINGS: Here we show, by reverse transcription PCR and Western blot analysis, that LRP5Delta is frequently expressed in breast tumors of different cancer stage (58-100%), including carcinoma in situ and metastatic carcinoma. LRP5Delta was required in MCF7 breast cancer cells for the non-phosphorylated active beta-catenin level, transcription activity of beta-catenin, cell growth in vitro, and breast tumor growth in a xenograft SCID mouse model. WNT3 ligand, but not WNT1 and WNT3A augmented the endogenous beta-catenin activity of MCF7 cells in a DKK1-insensitive manner. Furthermore, an anti-LRP5 antibody attenuated beta-catenin activity, inhibited cell growth, and induced apoptosis in LRP5Delta-positive MCF7 and T-47D breast cancer cells, but not in control cells. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the LRP5Delta receptor is strongly implicated in mammary gland tumorigenesis and that its aberrant expression present an early event during disease progression. LRP5 antibody therapy may have a significant role in the treatment of breast cancer.

  • 2.
    Bolin, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Wikström, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Wiberg-Itzel, Eva
    Department of Clinical Science and Education, Section of Obstetrics and Gynecology, Karolinska Institute, Södersjukhuset, Stockholm, Sweden.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ringvall, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sundström-Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Axelsson, Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i D län (CKFD).
    Thilaganathan, Basky
    Division of Clinical Development Sciences, Department of Obstetrics and Gynecology, St George’s University of London, England.
    Åkerud, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Prediction of Preeclampsia by Combining Serum Histidine-Rich Glycoprotein and Uterine Artery Doppler2012In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 25, no 12, p. 1305-1310Article in journal (Refereed)
    Abstract [en]

    Background

    Preeclampsia is associated with both maternal and perinatal morbidity and mortality. Histidine-rich glycoprotein (HRG) is a protein interacting with angiogenesis, coagulation, and inflammatory responses, processes known to be altered in preeclamptic pregnancies. Significantly lower levels of HRG have been demonstrated as early as in the first trimester in women later developing preeclampsia compared with normal pregnancies. The aim of this study was to investigate whether the combination of HRG and uterine artery Doppler ultrasonography can be used as a predictor of preeclampsia.

    Methods

    A total of 175 women were randomly selected from a case-control study; 86 women had an uncomplicated pregnancy and 89 women later developed preeclampsia. Blood samples and pulsatility index (PI) were obtained from both cases and controls in gestational week 14.

    Results

    HRG levels were significantly lower in women who developed preterm preeclampsia compared with controls, but not for women developing preeclampsia in general. PI was significantly higher in the preeclampsia group compared with controls, especially in preterm preeclampsia. The combination of HRG and PI revealed a sensitivity of 91% and a specificity of 62% for preterm preeclampsia.

    Conclusions

    The combination of HRG and uterine artery Doppler may predict preterm preeclampsia in early pregnancy.

  • 3.
    Cedervall, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tumor-Induced Local and Systemic Impact on Blood Vessel Function2015In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, article id 418290Article, review/survey (Refereed)
    Abstract [en]

    Endothelial dysfunction plays a role in several processes that contribute to cancer-associated mortality. The vessel wall serves as a barrier for metastatic tumor cells, and the integrity and activation status of the endothelium serves as an important defense mechanism against metastasis. In addition, leukocytes, such as cytotoxic T-cells, have to travel across the vessel wall to enter the tumor tissue where they contribute to killing of cancer cells. Tumor cells can alter the characteristics of the endothelium by recruitment of leukocytes such as neutrophils andmacrophages, which further stimulate inflammation and promote tumorigenesis. Recent findings also suggest that leukocyte-mediated effects on vascular function are not limited to the primary tumor or tissues that represent metastatic sites. Peripheral organs, such as kidney and heart, also display impaired vascular function in tumor-bearing individuals, potentially contributing to organ failure. Here, we discuss how vascular function is altered in malignant tissue and distant organs in individuals with cancer and how leukocytes function as potent mediators of these tumor-induced effects.

  • 4.
    Cedervall, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tumor-induced neutrophil extracellular traps-drivers of systemic inflammation and vascular dysfunction2016In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 5, no 3, article id e1098803Article in journal (Other academic)
    Abstract [en]

    Neutrophil extracellular traps (NETs) are part of the innate immune defense against microbes, but their contribution to several non-infectious inflammatory conditions has recently been unraveled. We demonstrate that NETs accumulate in the peripheral circulation in tumor-bearing mice, causing systemic inflammation and vascular dysfuntion in organs not affected by tumor cells.

  • 5.
    Cedervall, Jessica
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dragomir, Anca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Saupe, Falk
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Yanyu
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ärnlöv, Johan
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Divis Family Med, Huddinge, Sweden.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Olsson, Anna-Karin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice.2017In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 6, no 8, article id e1320009Article in journal (Refereed)
    Abstract [en]

    Renal insufficiency is a frequent cancer-associated problem affecting more than half of all cancer patients at the time of diagnosis. To minimize nephrotoxic effects the dosage of anticancer drugs are reduced in these patients, leading to sub-optimal treatment efficacy. Despite the severity of this cancer-associated pathology, the molecular mechanisms, as well as therapeutic options, are still largely lacking. We here show that formation of intravascular tumor-induced neutrophil extracellular traps (NETs) is a cause of kidney injury in tumor-bearing mice. Analysis of clinical biomarkers for kidney function revealed impaired creatinine clearance and elevated total protein levels in urine from tumor-bearing mice. Electron microscopy analysis of the kidneys from mice with cancer showed reversible pathological signs such as mesangial hypercellularity, while permanent damage such as fibrosis or necrosis was not observed. Removal of NETs by treatment with DNase I, or pharmacological inhibition of the enzyme peptidylarginine deiminase 4 (PAD4), was sufficient to restore renal function in mice with cancer. Tumor-induced systemic inflammation and impaired perfusion of peripheral vessels could be reverted by the PAD4 inhibitor. In conclusion, the current study identifies NETosis as a previously unknown cause of cancer-associated renal dysfunction and describes a novel promising approach to prevent renal failure in individuals with cancer.

  • 6.
    Cedervall, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hamidi, Anahita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Platelets, NETs and cancer2018In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 164, p. S148-S152Article in journal (Refereed)
    Abstract [en]

    In addition to the central role of platelets in hemostasis, they contribute to pathological conditions such as inflammation and tumor progression. Aberrant expression and/or exposure of pro-coagulant factors in the tumor microenvironment induce platelet activation and subsequent release of growth factors from platelet granules. Cancer patients are commonly affected by thrombotic events, as a result of tumor-induced platelet activation. A novel player potentially contributing to cancer-associated thrombosis is the formation of neutrophil extracellular traps (NETs). NETs are composed of externalized DNA of nuclear or mitochondrial origin, bound to histones and granular proteases such as neutrophil elastase (NE) and myeloperoxidase (MPO). These extracellular traps help neutrophils to catch and kill pathogens such as bacteria, virus and fungi. It is now clear that NETs form also under conditions of sterile inflammation such as cancer and autoimmunity and can promote thrombosis. Recent data show that platelets play a key role in determining when and where NETs should form. This review will highlight our current insight in the role of platelets as regulators of NET formation, both during infection and sterile inflammation.

  • 7.
    Cedervall, Jessica
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Yanyu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Huang, Hua
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Zhang, Lei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Femel, Julia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Olsson, Anna-Karin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Neutrophil Extracellular Traps Accumulate in Peripheral Blood Vessels and Compromise Organ Function in Tumor-Bearing Animals2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 13, p. 2653-2662Article in journal (Refereed)
    Abstract [en]

    Cancer produces a variety of collateral effects in patients beyond the malignancy itself, including threats to distal organ functions. However, the basis for such effects, associated with either primary or metastatic tumors, are generally poorly understood. In this study, we show how heart and kidney vascular function is impaired by neutrophils that accumulate in those tissues as a result of tumor formation in two different transgenic mouse models of cancer (RIP1-Tag2 model of insulinoma and MMTV-PyMT model of breast cancer). Neutrophil depletion by systemic administration of an anti-Gr1 antibody improved vascular perfusion and prevented vascular leakage in kidney vessels. We also observed the accumulation of platelet-neutrophil complexes, a signature of neutrophil extracellular traps (NET), in the kidneys of tumor-bearing mice that were completely absent from healthy nontumor-bearing littermates. NET accumulation in the vasculature was associated with upregulation of the proinflammatory adhesion molecules ICAM-1, VCAM-1, and E-selectin, as well as the proinflammatory cytokines IL1 beta, IL6, and the chemokine CXCL1. Administering DNase I to dissolve NETs, which have a high DNA content, restored perfusion in the kidney and heart to levels seen in nontumor-bearing mice, and also prevented vessel leakage in the blood vasculature of these organs. Taken together, our findings strongly suggest that NETs mediate the negative collateral effects of tumors on distal organs, acting to impair vascular function, and to heighten inflammation at these sites.

  • 8.
    Cedervall, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Yanyu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ringvall, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Thulin, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Jahnen-Dechent, Willi
    Biointerface Laboratory, Department of Biomedical Engineering, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    HRG regulates tumor progression, epithelial to mesenchymal transition and metastasis via platelet-induced signaling in the pre-tumorigenic microenvironment2013In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 16, no 4, p. 889-902Article in journal (Refereed)
    Abstract [en]

    Mice lacking histidine-rich glycoprotein (HRG) display an accelerated angiogenic switch and larger tumors-a phenotype caused by enhanced platelet activation in the HRG-deficient mice. Here we show that platelets induce molecular changes in the pre-tumorigenic environment in HRG-deficient mice, promoting cell survival, angiogenesis and epithelial-to-mesenchymal transition (EMT) and that these effects involved signaling via TBK1, Akt2 and PDGFR beta. These early events subsequently translate into an enhanced rate of spontaneous metastasis to distant organs in mice lacking HRG. Later in tumor development characteristic features of pathological angiogenesis, such as decreased perfusion and pericyte coverage, are more pronounced in HRG-deficient mice. At this stage, platelets are essential to support the larger tumor volumes formed in mice lacking HRG by keeping their tumor vasculature sufficiently functional. We conclude that HRG-deficiency promotes tumor progression via enhanced platelet activity and that platelets play a dual role in this process. During early stages of transformation, activated platelets promote tumor cell survival, the angiogenic switch and invasiveness. In the more progressed tumor, platelets support the enhanced pathological angiogenesis and hence increased tumor growth seen in the absence of HRG. Altogether, our findings strengthen the notion of HRG as a potent tumor suppressor, with capacity to attenuate the angiogenic switch, tumor growth, EMT and subsequent metastatic spread, by regulating platelet activity.

  • 9.
    Dimberg, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rylova, Svetlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dieterich, Lothar C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Schiller, Petter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wikner, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bohman, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lukinius, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wawrousek, Eric F
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    alphaB-crystallin promotes tumor angiogenesis by increasing vascular survival during tube morphogenesis2008In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 111, no 4, p. 2015-2023Article in journal (Refereed)
    Abstract [en]

    Selective targeting of endothelial cells in tumor vessels requires delineation of key molecular events in formation and survival of blood vessels within the tumor microenvironment. To this end, proteins transiently up-regulated during vessel morphogenesis were screened for their potential as targets in antiangiogenic tumor therapy. The molecular chaperone alpha B-crystallin was identified as specifically induced with regard to expression level, modification by serine phosphorylation, and subcellular localization during tubular morphogenesis of endothelial cells. Small interfering RNA-mediated knockdown of alpha B-crystallin expression did not affect endothelial proliferation but led to attenuated tubular morphogenesis, early activation of proapoptotic caspase-3, and increased apoptosis. alpha B-crystallin was expressed in a subset of human tumor vessels but not in normal capillaries. Tumors grown in alpha B-crystallin(-/-) mice were significantly less vascularized than wild-type tumors and displayed increased areas of apoptosis/necrosis. Importantly, tumor vessels in alpha B-crystallin(-/-) mice were leaky and showed signs of caspase-3 activation and extensive apoptosis. Ultrastructural analyses showed defective vessels partially devoid of endothelial lining. These data strongly implicate alpha B-crystallin as an important regulator of tubular morphogenesis and survival of endothelial cell during tumor angiogenesis. Hereby we identify the small heat shock protein family as a novel class of anglogenic modulators.

  • 10.
    Dixelius, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Thulin, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lee, Chunsik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Johansson, Irja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Minimal active domain and mechanism of action of the angiogenesis inhibitor histidine-rich glycoprotein2006In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 66, no 4, p. 2089-97Article in journal (Refereed)
    Abstract [en]

    Histidine-rich glycoprotein (HRGP) is an abundant heparin-binding plasma protein that efficiently arrests growth and vascularization of mouse tumor models. We have shown that the antiangiogenic effect of HRGP is dependent on its histidine/proline-rich domain, which needs to be released from the mother protein to exert its effects. Here we identify a 35-amino-acid peptide, HRGP330, derived from the histidine/proline-rich domain as endowed with antiangiogenic properties in vitro and in vivo. The mechanism of action of HRGP330 involves subversion of focal adhesion function by disruption of integrin-linked kinase (ILK) and focal adhesion kinase (FAK) functions, inhibition of vascular endothelial growth factor (VEGF)-induced tyrosine phosphorylation of the FAK substrate alpha-actinin, and, as a consequence, an arrest in endothelial cell motility. The disturbed focal adhesion function is reflected in the ability of HRGP as well as of HRGP330 to prevent endothelial cell adhesion to vitronectin in a manner involving alpha(v)beta3 integrin. In conclusion, HRGP330, which we define as the minimal antiangiogenic domain of HRGP, exerts its effects through signal transduction targeting focal adhesions, thereby interrupting VEGF-induced endothelial cell motility.

  • 11.
    Femel, Julia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Huijbers, Elisabeth JM
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Saupe, Falk
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cedervall, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zhang, Lei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Roswall, Pernilla
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Olofsson, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Pietras, Kristian
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Therapeutic vaccination against fibronectin ED-A attenuates progression of metastatic breast cancer.2014In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 5, no 23, p. 12418-12427Article in journal (Refereed)
    Abstract [en]

    Therapeutic vaccination targeting self-molecules is an attractive alternative to monoclonal antibody-based therapies for cancer and various inflammatory diseases. However, development of cancer vaccines targeting self-molecules has proven difficult. One complicating factor is that tumor cells have developed strategies to escape recognition by the immune system. Antigens specifically expressed by the tumor vasculature can therefore provide alternative targets. The alternatively spliced extra domain-A and B (ED-A and ED-B) of fibronectin are expressed during vasculogenesis in the embryo, but essentially undetectable under normal conditions in the adult. However, these domains are re-expressed during tumor angiogenesis and matrix remodeling, which renders them highly interesting for targeted cancer therapies. Using the MMTV-PyMT transgenic model of metastatic mammary carcinoma, we show that tumor burden can be significantly decreased by immunization against ED-A in a therapeutic setting. Furthermore, we found that in mice carrying anti-ED-A antibodies the number of metastases was reduced. ED-A immunization increased infiltration of macrophages and compromised tumor blood vessel function. These findings implicate an attack of the tumor vasculature by the immune system, through a polyclonal antibody response. We conclude that tumor vascular antigens are promising candidates for development of therapeutic vaccines targeting growth of primary tumors as well as disseminated disease.

  • 12. Fischer, Silvia
    et al.
    Gesierich, Sabine
    Griemert, Barbara
    Schaenzer, Anne
    Acker, Till
    Augustin, Hellmut G.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Preissner, Klaus T.
    Extracellular RNA Liberates Tumor Necrosis Factor-alpha to Promote Tumor Cell Trafficking and Progression2013In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 73, no 16, p. 5080-5089Article in journal (Refereed)
    Abstract [en]

    Extracellular RNA (eRNA) released from injured cells promotes tissue permeability, thrombosis, and inflammation in vitro and in vivo, and RNase1 pretreatment can reduce all these effects. In this study, we investigated the role of the eRNA/RNase1 system in tumor progression and metastasis. Under quiescent and stimulatory conditions, tumor cells released much higher levels of endogenous extracellular RNA (eRNA) than nontumor cells. In glioblastomas, eRNA was detected at higher levels in tumors than nontumor tissue. eRNA induced tumor cells to adhere to and migrate through human cerebral microvascular endothelial cells (HCMEC/D3), in a manner requiring activation of VEGF signaling. In addition, eRNA liberated TNF-alpha from macrophages in a manner requiring activation of the TNF-alpha-converting enzyme TACE. Accordingly, supernatants derived from eRNA-treated macrophages enhanced tumor cell adhesion to HCMEC/D3. TNF-alpha release evoked by eRNA relied upon signaling activation of mitogen-activated protein kinases and the NF-kappa B pathway. In subcutaneous xenograft models of human cancer, administration of RNase1 but not DNase decreased tumor volume and weight. Taken together, these results suggest that eRNA released from tumor cells has the capacity to promote tumor cell invasion through endothelial barriers by both direct and indirect mechanisms, including through a mechanism involving TNF-alpha release from tumor-infiltrating monocytes/macrophages. Our findings establish a crucial role for eRNA in driving tumor progression, and they suggest applications for extracellular RNase1 as an antiinvasive regimen for cancer treatment. 

  • 13.
    Huijbers, Elisabeth J M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Femel, Julia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Björkelund, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The non-toxic and biodegradable adjuvant Montanide ISA 720/CpG can replace Freund's in a cancer vaccine targeting ED-B-a prerequisite for clinical development2012In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 30, no 2, p. 225-230Article in journal (Refereed)
    Abstract [en]

    We have recently shown that immunization against the extra domain-B (ED-B) of fibronectin, using Freund's adjuvant, reduces tumor growth in mice by 70%. In the present study we compare the immune response generated against ED-B using the non-toxic and biodegradable adjuvant Montanide ISA 720/CpG with the response elicited by Freund's adjuvant. Montanide ISA 720/CpG induced anti-ED-B antibodies with higher avidity and less variable levels between individuals than Freund's. Moreover, the duration of the immune response was longer and the generation of anti-ED-B antibodies in naïve mice was faster, when Montanide ISA 720/CpG was used. We conclude that it is possible to replace the mineral oil based adjuvant Freund's with an adjuvant acceptable for human use, which is a prerequisite for transfer of the ED-B vaccine to the clinic.

  • 14.
    Huijbers, Elisabeth J. M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ringvall, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Femel, Julia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kalamajski, Sebastian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lukinius, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Åbrink, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Vaccination against the extra domain-B of fibronectin as a novel tumor therapy2010In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, ISSN 20634349, Vol. 24, no 11, p. 4535-4544Article in journal (Refereed)
    Abstract [en]

    Monoclonal antibody-based therapies have made an important contribution to current treatment strategies for cancer and autoimmune disease. However, the cost for these new drugs puts a significant strain on the health-care economy, resulting in limited availability for patients. Therapeutic vaccination, defined as induction of immunity against a disease-related self-molecule, is therefore an attractive alternative. To analyze the potential of such an approach, we have developed a vaccine against the extra domain-B (ED-B) of fibronectin. This 91-aa domain, inserted by alternative splicing, is expressed during vasculogenesis in the embryo, but essentially undetectable under normal conditions in the adult. However, ED-B is highly expressed around angiogenic vasculature, such as in tumorigenesis. Here, we demonstrate that it is possible to break self-tolerance and induce a strong antibody response against ED-B by vaccination. Nineteen of 20 vaccinated mice responded with production of anti-ED-B antibodies and displayed a 70% reduction in tumor size compared to those lacking anti-ED-B antibodies. Analysis of the tumor tissue revealed that immunization against ED-B induced several changes, consistent with an attack by the immune system. These data show that tumor vascular antigens are highly interesting candidates for development of therapeutic vaccines targeting solid tumors.

  • 15.
    Kärrlander, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lindberg, Nanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Olofsson, Tommie
    Rättsmedicinalverket, Avdelningen för rättsmedicin, Uppsala.
    Kastemar, Marianne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Histidine-rich glycoprotein can prevent development of mouse experimental glioblastoma2009In: PLoS ONE, ISSN 1932-6203, Vol. 4, no 12, p. e8536-Article in journal (Refereed)
    Abstract [en]

    Extensive angiogenesis, formation of new capillaries from pre-existing blood vessels, is an important feature of malignant glioma. Several antiangiogenic drugs targeting vascular endothelial growth factor (VEGF) or its receptors are currently in clinical trials as therapy for high-grade glioma and bevacizumab was recently approved by the FDA for treatment of recurrent glioblastoma. However, the modest efficacy of these drugs and emerging problems with anti-VEGF treatment resistance welcome the development of alternative antiangiogenic therapies. One potential candidate is histidine-rich glycoprotein (HRG), a plasma protein with antiangiogenic properties that can inhibit endothelial cell adhesion and migration. We have used the RCAS/TV-A mouse model for gliomas to investigate the effect of HRG on brain tumor development. Tumors were induced with platelet-derived growth factor-B (PDGF-B), in the presence or absence of HRG. We found that HRG had little effect on tumor incidence but could significantly inhibit the development of malignant glioma and completely prevent the occurrence of grade IV tumors (glioblastoma).

     

  • 16.
    Kårehed, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Wikström, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Åkerud, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Fibrinogen and histidine-rich glycoprotein in early-onset preeclampsia2010In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 89, no 1, p. 131-139Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To determine whether plasma levels of fibrinogen and the placental tissue distributions of fibrinogen and histidine-rich glycoprotein (HRG) differ between early- and late-onset preeclampsia. DESIGN: The study comprised 18 women with early-onset (gestational weeks 24-32) and 19 women with late-onset (gestational weeks 35-42) preeclampsia. As controls concerning the plasma levels of fibrinogen, we used samples from non-pregnant fertile women, healthy pregnant women at gestational weeks 24-32 and healthy pregnant women at gestational weeks 35-42. Placental samples from women with healthy pregnancies at gestational weeks 35-42 served as controls in the immunohistochemical staining. SETTING: Uppsala University Hospital, Uppsala. METHODS: Plasma fibrinogen levels were analyzed and the placental tissue expression of fibrinogen and HRG determined by immunohistochemistry. RESULTS: Plasma level of fibrinogen was increased in early-onset, but not late-onset, preeclampsia. Levels of fibrinogen were significantly lower, and that of HRG significantly higher, in placentas from women with early-onset preeclampsia as compared with control placentas (p = 0.01 and 0.001). CONCLUSIONS: HRG and fibrinogen might be involved in the hypercoagulability and the angiogenic imbalance seen in early-onset preeclampsia.

  • 17.
    Larsson (Åkerud), Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Histidine-rich glycoprotein2002Patent (Other (popular science, discussion, etc.))
  • 18.
    Lee, Chunsik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dixelius, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Thulin, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kawamura, Harukiyo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Signal transduction in endothelial cells by the angiogenesis inhibitor histidine-rich glycoprotein targets focal adhesions2006In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 312, no 13, p. 2547-2556Article in journal (Refereed)
    Abstract [en]

    Histidine-rich glycoprotein (HRGP) is an abundant heparin-binding plasma protein. We have shown that a fragment released from the central histidine/proline-rich (His/Pro-rich) domain of HRGP blocks endothelial cell migration in vitro and vascularization and growth of murine fibrosarcoma in vivo. The minimal active HRGP domain exerting the anti-angiogenic effect was recently narrowed down to a 35 amino acid peptide, HRGP330, derived from the His/Pro-rich domain of HRGP. By use of a signal transduction antibody array representing 400 different signal transduction molecules, we now show that HRGP and the synthetic peptide HRGP330 specifically induce tyrosine phosphorylation of focal adhesion kinase and its downstream substrate paxillin in endothelial cells. HRGP/HRGP330 treatment of endothelial cells induced disruption of actin stress fibers, a process reversed by treatment of cells with the FAK inhibitor geldanamycin. In addition, VEGF-mediated endothelial cell tubular morphogenesis in a three-dimensional collagen matrix was inhibited by HRGP and HRGP330. In contrast, VEGF-induced proliferation was not affected by HRGP or HRGP330, demonstrating the central role of cell migration during tube formation. In conclusion, our data show that HRGP targets focal adhesions in endothelial cells, thereby disrupting the cytoskeletal organization and the ability of endothelial cells to assemble into vessel structures.

  • 19.
    Lee, Chunsik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Thulin, Åsa
    Johansson, Irja
    Jahnen-Dechent, Willi
    Claesson-Welsh, Lena
    Regulation of tumor-associated macrophage infiltration, VEGF and MMP production, by the angiogenesis inhibitor histidine-rich glycoprotein.Manuscript (Other academic)
  • 20. Leifler, Karin Söderlund
    et al.
    Svensson, Susanne
    Abrahamsson, Annelie
    Bendrik, Christina
    Robertson, Jennifer
    Gauldie, Jack
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dabrosin, Charlotta
    Inflammation induced by mmp-9 enhances tumor regression of experimental breast cancer2013In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 190, no 8, p. 4420-4430Article in journal (Refereed)
    Abstract [en]

    Matrix metalloproteinases (MMPs) have been suggested as therapeutic targets in cancer treatment, but broad-spectrum MMP inhibitors have failed in clinical trials. Recent data suggest that several MMPs including MMP-9 exert both pro- and antitumorigenic properties. This is also the case of the natural inhibitors of MMPs, tissue inhibitor of metalloproteinases (TIMPs). The inhibitor of MMP-9 is TIMP-1, and high levels of this enzyme have been associated with decreased survival in breast cancer. Inflammation is one hallmark of cancer progression, and MMPs/TIMPs may be involved in the local immune regulation. We investigated the role of MMP-9/TIMP-1 in regulating innate antitumor immunity in breast cancer. Breast cancers were established in nude mice and treated with intratumoral injections of adenoviruses carrying the human TIMP-1 or MMP-9 gene (AdMMP-9). In vivo microdialysis for sampling of cancer cell-derived (human) and stroma-derived (murine) proteins, immunostainings, as well as cell cultures were performed. We report a dose-dependent decrease of tumor growth and angiogenesis after AdMMP-9 treatment. In addition to increased generation of endostatin, AdMMP-9 promoted an antitumor immune response by inducing massive neutrophil infiltration. Neutrophil depletion prior to gene transfer abolished the therapeutic effects of AdMMP-9. Additionally, AdMMP-9 activated tumor-infiltrating macrophages into a tumor-inhibiting phenotype both in vivo and in vitro. AdMMP-9 also inhibited tumor growth in immune-competent mice bearing breast cancers. Adenoviruses carrying the human TIMP-1 gene had no effect on tumor growth or the immune response. Our novel data identify MMP-9 as a potent player in modulating the innate immune response into antitumor activities.

  • 21.
    Macarak, Edward J.
    et al.
    Thomas Jefferson Univ, Sidney Kimmel Med Coll, Joan & Joel Rosenbloom Res Ctr Fibrot Dis, Philadelphia, PA 19107 USA;Thomas Jefferson Univ, Sidney Kimmel Med Coll, Dept Dermatol & Cutaneous Biol, Philadelphia, PA 19107 USA.
    Lotto, Christine E.
    Thomas Jefferson Univ, Sidney Kimmel Med Coll, Joan & Joel Rosenbloom Res Ctr Fibrot Dis, Philadelphia, PA 19107 USA;Thomas Jefferson Univ, Sidney Kimmel Med Coll, Dept Dermatol & Cutaneous Biol, Philadelphia, PA 19107 USA;Thomas Jefferson Univ, Sidney Kimmel Med Coll, Dept Surg, Philadelphia, PA 19107 USA.
    Koganti, Deepika
    Thomas Jefferson Univ, Sidney Kimmel Med Coll, Joan & Joel Rosenbloom Res Ctr Fibrot Dis, Philadelphia, PA 19107 USA;Thomas Jefferson Univ, Sidney Kimmel Med Coll, Dept Dermatol & Cutaneous Biol, Philadelphia, PA 19107 USA;Thomas Jefferson Univ, Sidney Kimmel Med Coll, Dept Surg, Philadelphia, PA 19107 USA.
    Jin, Xiaoling
    Thomas Jefferson Univ, Sidney Kimmel Med Coll, Joan & Joel Rosenbloom Res Ctr Fibrot Dis, Philadelphia, PA 19107 USA;Thomas Jefferson Univ, Sidney Kimmel Med Coll, Dept Dermatol & Cutaneous Biol, Philadelphia, PA 19107 USA.
    Wermuth, Peter J.
    Thomas Jefferson Univ, Sidney Kimmel Med Coll, Joan & Joel Rosenbloom Res Ctr Fibrot Dis, Philadelphia, PA 19107 USA;Thomas Jefferson Univ, Sidney Kimmel Med Coll, Dept Dermatol & Cutaneous Biol, Philadelphia, PA 19107 USA.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Montgomery, Matthew
    Thomas Jefferson Univ, Sidney Kimmel Med Coll, Joan & Joel Rosenbloom Res Ctr Fibrot Dis, Philadelphia, PA 19107 USA;Thomas Jefferson Univ, Sidney Kimmel Med Coll, Dept Dermatol & Cutaneous Biol, Philadelphia, PA 19107 USA.
    Rosenbloom, Joel
    Thomas Jefferson Univ, Sidney Kimmel Med Coll, Joan & Joel Rosenbloom Res Ctr Fibrot Dis, Philadelphia, PA 19107 USA;Thomas Jefferson Univ, Sidney Kimmel Med Coll, Dept Dermatol & Cutaneous Biol, Philadelphia, PA 19107 USA.
    Trametinib prevents mesothelial-mesenchymal transition and ameliorates abdominal adhesion formation2018In: Journal of Surgical Research, ISSN 0022-4804, E-ISSN 1095-8673, Vol. 227, p. 198-210Article in journal (Refereed)
    Abstract [en]

    Background: Intra-abdominal adhesions are a major cause of morbidity after abdominal or gynecologic surgery. However, knowledge about the pathogenic mechanism(s) is limited, and there are no effective treatments. Here, we investigated a mouse model of bowel adhesion formation and the effect(s) of an Federal Drug Administration-approved drug (trametinib) in preventing adhesion formation. Materials and methods: C57BL/6 mice were used to develop a consistent model of intra-abdominal adhesion formation by gentle cecal abrasion with mortality rates of <10%. Adhesion formation was analyzed histologically and immunochemically to characterize the expression of pro-fibrotic marker proteins seen in pathologic scaring and included alpha smooth muscle actin (alpha SMA) and fibronectin EDA (FNEDA) which arises from alternative splicing of the fibronectin messenger RNA resulting in different protein isoforms. Trichrome staining assessed collagen deposition. Quantitative polymerase chain reaction analysis of RNA isolated from adhesions by laser capture microscopy was carried out to assess pro-fibrotic gene expression. To block adhesion formation, trametinib was administered via a subcutaneous osmotic pump. Results: Adhesions were seen as early as post-operative day 1 with extensive adhesions being formed and vascularized by day 5. The expression of the FNEDA isoform occurred first with subsequent expression of alpha SMA and collagen. The drug trametinib was chosen for in vivo studies because it effectively blocked the mesothelial to mesenchymal transition of rat mesothelium. Trametinib, at the highest dose used (3 mg/kg/d), prevented adhesion formation while at lower doses, adhesions were usually limited, as evidenced by the presence of FNEDA isoform but not alpha SMA. Conclusions: Cecal abrasion in mice is a reliable model to study abdominal adhesions, which can be ameliorated using the MEK1/2 inhibitor trametinib. While blocking adhesion formation at the cell and molecular levels, trametinib, at the therapeutic doses utilized, did not impair the wound healing at the laparotomy site. 

  • 22.
    Nowak-Sliwinska, Patrycja
    et al.
    Univ Lausanne, Univ Geneva, Fac Sci, Mol Pharmacol Grp,Sch Pharmaceut Sci,CMU, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland;Univ Geneva, Translat Res Ctr Oncohaematol, Geneva, Switzerland.
    Alitalo, Kari
    Univ Helsinki, Wihuri Res Inst & Translat Canc Biol Program, Helsinki, Finland.
    Allen, Elizabeth
    Katholieke Univ Leuven, Dept Oncol, Lab Tumor Microenvironm & Therapeut Resistance, VIB Ctr Canc Biol, Louvain, Belgium.
    Anisimov, Andrey
    Univ Helsinki, Wihuri Res Inst & Translat Canc Biol Program, Helsinki, Finland.
    Aplin, Alfred C.
    Univ Washington, Dept Pathol, Seattle, WA 98195 USA.
    Auerbach, Robert
    Univ Wisconsin, Madison, WI USA.
    Augustin, Hellmut G.
    Heidelberg Univ, Med Fac Mannheim, European Ctr Angiosci, Heidelberg, Germany;German Canc Res Ctr, Div Vasc Oncol & Metastasis Res, Heidelberg, Germany;German Canc Consortium, Heidelberg, Germany.
    Bates, David O.
    Univ Nottingham, Sch Med, Div Canc & Stem Cells, Nottingham, England.
    van Beijnum, Judy R.
    Vrije Univ Amsterdam, Dept Med Oncol, Canc Ctr Amsterdam, Angiogenesis Lab,Med Ctr, Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands.
    Bender, R. Hugh F.
    Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92717 USA.
    Bergers, Gabriele
    Katholieke Univ Leuven, Dept Oncol, Lab Tumor Microenvironm & Therapeut Resistance, VIB Ctr Canc Biol, Louvain, Belgium;Univ Calif San Francisco, Dept Neurol Surg, Brain Tumor Res Ctr,Dept Neurol Surg, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA.
    Bikfalvi, Andreas
    Univ Bordeaux, Angiogenesis & Tumor Microenvironm Lab, INSERM, U1029, Pessac, France.
    Bischoff, Joyce
    Harvard Med Sch, Boston Childrens Hosp, Vasc Biol Program, Boston, MA USA;Harvard Med Sch, Boston Childrens Hosp, Dept Surg, Boston, MA USA.
    Boeck, Barbara C.
    Heidelberg Univ, Med Fac Mannheim, European Ctr Angiosci, Heidelberg, Germany;German Canc Res Ctr, Div Vasc Oncol & Metastasis Res, Heidelberg, Germany;German Canc Consortium, Heidelberg, Germany.
    Brooks, Peter C.
    Maine Med Ctr Res Inst, Ctr Mol Med, Scarborough, ME USA.
    Bussolino, Federico
    Univ Torino, Dept Oncol, Turin, Italy;Candiolo Canc Inst FPO IRCCS, I-10060 Candiolo, Italy.
    Cakir, Bertan
    Harvard Med Sch, Boston Childrens Hosp, Dept Ophthalmol, Boston, MA USA.
    Carmeliet, Peter
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Leuven, Belgium;Katholieke Univ Leuven, Leuven Canc Inst LKI, Leuven, Belgium;VIB, Ctr Canc Biol, Lab Angiogenesis & Vasc Metab, Leuven, Belgium.
    Castranova, Daniel
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, NIH, Bethesda, MD USA.
    Cimpean, Anca M.
    Victor Babes Univ Med & Pharm, Dept Microscop Morphol Histol, Angiogenesis Res Ctr, Timisoara, Romania.
    Cleaver, Ondine
    Univ Texas Southwestern Med Ctr Dallas, Dept Mol Biol, Ctr Regenerat Sci & Med, Dallas, TX 75390 USA.
    Coukos, George
    Univ Lausanne, Ludwig Inst Canc Res, Dept Oncol, Lausanne, Switzerland.
    Davis, George E.
    Univ Missouri, Sch Med, Dept Med Pharmacol & Physiol, Columbia, MO USA;Dalton Cardiovasc Ctr, Columbia, MO USA.
    De Palma, Michele
    Swiss Fed Inst Technol, Sch Life Sci, Lausanne, Switzerland.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Dings, Ruud P. M.
    Univ Arkansas Med Sci, Dept Radiat Oncol, Little Rock, AR 72205 USA.
    Djonov, Valentin
    Univ Bern, Inst Anat, Bern, Switzerland.
    Dudley, Andrew C.
    Univ Virginia, Dept Microbiol Immunol & Canc Biol, Charlottesville, VA USA;Univ Virginia, Emily Cour Canc Ctr, Charlottesville, VA USA.
    Dufton, Neil P.
    Imperial Coll London, Vasc Sci, Imperial Ctr Translat & Expt Med, Natl Heart & Lung Inst, London, England.
    Fendt, Sarah-Maria
    VIB Ctr Canc Biol, Lab Cellular Metab & Metab Regulat, Leuven, Belgium;Katholieke Univ Leuven, Lab Cellular Metab & Metab Regulat, Dept Oncol, Leuven, Belgium;Leuven Canc Inst, Leuven, Belgium.
    Ferrara, Napoleone
    Univ Calif San Diego, La Jolla, CA 92093 USA.
    Fruttiger, Marcus
    UCL, Inst Ophthalmol, London, England.
    Fukumura, Dai
    Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, Boston, MA 02114 USA;Harvard Med Sch, Boston, MA 02114 USA.
    Ghesquiere, Bart
    VIB, VIB Ctr Canc Biol, Metabol Expertise Ctr, Leuven, Belgium;Katholieke Univ Leuven, Dept Oncol, Metabol Expertise Ctr, Leuven, Belgium.
    Gong, Yan
    Harvard Med Sch, Boston Childrens Hosp, Dept Ophthalmol, Boston, MA USA.
    Griffin, Robert J.
    Univ Arkansas Med Sci, Dept Radiat Oncol, Little Rock, AR 72205 USA.
    Harris, Adrian L.
    Univ Oxford, John Radcliffe Hosp, Mol Oncol Labs, Weatherall Inst Mol Med,Dept Oncol, Oxford, England.
    Hughes, Christopher C. W.
    Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92717 USA.
    Hultgren, Nan W.
    Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92717 USA.
    Iruela-Arispe, M. Luisa
    Univ Calif Los Angeles, MCDB, Los Angeles, CA USA.
    Irving, Melita
    Univ Lausanne, Ludwig Inst Canc Res, Dept Oncol, Lausanne, Switzerland.
    Jain, Rakesh K.
    Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, Boston, MA 02114 USA;Harvard Med Sch, Boston, MA 02114 USA.
    Kalluri, Raghu
    Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Metastasis Res Ctr, Houston, TX 77030 USA.
    Kalucka, Joanna
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Leuven, Belgium;Katholieke Univ Leuven, Leuven Canc Inst LKI, Leuven, Belgium;VIB, Ctr Canc Biol, Lab Angiogenesis & Vasc Metab, Leuven, Belgium.
    Kerbel, Robert S.
    Univ Toronto, Dept Med Biophys, Sunnybrook Res Inst, Biol Sci Platform, Toronto, ON, Canada.
    Kitajewski, Jan
    Univ Illinois, Dept Physiol & Biophys, Chicago, IL 60680 USA.
    Klaassen, Ingeborg
    Univ Amsterdam, Ocular Angiogenesis Grp, Dept Ophthalmol, Acad Med Ctr, Amsterdam, Netherlands;Univ Amsterdam, Ocular Angiogenesis Grp, Dept Med Biol, Acad Med Ctr, Amsterdam, Netherlands.
    Kleinmann, Hynda K.
    George Washington Univ, Sch Med, Washington, DC USA.
    Koolwijk, Pieter
    Univ Lausanne, Dept Ophthalmol, Jules Gonin Eye Hosp, Fdn Asile Aveugles, Lausanne, Switzerland.
    Kuczynski, Elisabeth
    Univ Toronto, Dept Med Biophys, Sunnybrook Res Inst, Biol Sci Platform, Toronto, ON, Canada.
    Kwak, Brenda R.
    Univ Geneva, Dept Pathol & Immunol, Geneva, Switzerland.
    Marien, Koen
    HistoGeneX, Antwerp, Belgium.
    Melero-Martin, Juan M.
    Harvard Med Sch, Boston Childrens Hosp, Dept Cardiac Surg, Boston, MA USA.
    Munn, Lance L.
    Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, Boston, MA 02114 USA;Harvard Med Sch, Boston, MA 02114 USA.
    Nicosia, Roberto F.
    Univ Washington, Dept Pathol, Seattle, WA 98195 USA;VA Puget Sound Hlth Care Syst, Pathol & Lab Med Serv, Seattle, WA USA.
    Noel, Agnes
    Univ Liege, Lab Tumor & Dev Biol, GIGA Canc, Liege, Belgium.
    Nurro, Jussi
    Univ Eastern Finland, Dept Biotechnol & Mol Med, Kuopio, Finland.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Petrova, Tatiana V.
    Ludwig Inst Canc Res Lausanne, Dept Oncol UNIL CHUV, Lausanne, Switzerland.
    Pietras, Kristian
    Dept Lab Med, Div Translat Canc Res, Lund, Sweden.
    Pili, Roberto
    Indiana Univ, Simon Canc Ctr, Genitourinary Program, Indianapolis, IN 46204 USA.
    Pollard, Jeffrey W.
    Univ Edinburgh, Med Res Council, Ctr Reprod Hlth, Coll Med & Vet Med, Edinburgh, Midlothian, Scotland.
    Post, Mark J.
    Maastricht Univ, Dept Physiol, Maastricht, Netherlands.
    Quax, Paul H. A.
    LUMC, Einthoven Lab Expt Vasc Med, Dept Surg, Leiden, Netherlands.
    Rabinovich, Gabriel A.
    Consejo Nacl Invest Cient & Tecn, Natl Council Sci & Tech Invest, Lab Immunopathol, Inst Biol & Expt Med, Buenos Aires, DF, Argentina.
    Raica, Marius
    Victor Babes Univ Med & Pharm, Dept Microscop Morphol Histol, Angiogenesis Res Ctr, Timisoara, Romania.
    Randi, Anna M.
    Imperial Coll London, Vasc Sci, Imperial Ctr Translat & Expt Med, Natl Heart & Lung Inst, London, England.
    Ribatti, Domenico
    Univ Bari, Med Sch, Dept Basic Med Sci Neurosci & Sensory Organs, Bari, Italy;Natl Canc Inst Giovanni Paolo II, Bari, Italy.
    Ruegg, Curzio
    Univ Fribourg, Dept Oncol Microbiol & Immunol, Fac Sci & Med, Fribourg, Switzerland.
    Schlingemann, Reinier O.
    Univ Amsterdam, Ocular Angiogenesis Grp, Dept Ophthalmol, Acad Med Ctr, Amsterdam, Netherlands;Univ Amsterdam, Ocular Angiogenesis Grp, Dept Med Biol, Acad Med Ctr, Amsterdam, Netherlands;Univ Lausanne, Dept Ophthalmol, Jules Gonin Eye Hosp, Fdn Asile Aveugles, Lausanne, Switzerland.
    Schulte-Merker, Stefan
    WWU, Inst Cardiovasc Organogenesis & Regenerat, Fac Med, Munster, Germany.
    Smith, Lois E. H.
    Harvard Med Sch, Boston Childrens Hosp, Dept Ophthalmol, Boston, MA USA.
    Song, Jonathan W.
    Ohio State Univ, Dept Mech & Aerosp Engn, Columbus, OH 43210 USA;Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA.
    Stacker, Steven A.
    Univ Melbourne, Tumour Angiogenesis & Microenvironm Program, Peter MacCallum Canc Ctr & Sir Peter MacCallum, Dept Oncol, Melbourne, Vic, Australia.
    Stalin, Jimmy
    WWU, Inst Cardiovasc Organogenesis & Regenerat, Fac Med, Munster, Germany.
    Stratman, Amber N.
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, NIH, Bethesda, MD USA.
    Van de Velde, Maureen
    Univ Liege, Lab Tumor & Dev Biol, GIGA Canc, Liege, Belgium.
    van Hinsbergh, Victor W. M.
    Univ Lausanne, Dept Ophthalmol, Jules Gonin Eye Hosp, Fdn Asile Aveugles, Lausanne, Switzerland.
    Vermeulen, Peter B.
    HistoGeneX, Antwerp, Belgium;Sint Augustinus & Univ Antwerp, Translat Canc Res Unit, GZA Hosp, Antwerp, Belgium.
    Waltenberger, Johannes
    Univ Munster, Med Fac, Albert Schweitzer Campus 1, Munster, Germany.
    Weinstein, Brant M.
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, NIH, Bethesda, MD USA.
    Xin, Hong
    Univ Calif San Diego, La Jolla, CA 92093 USA.
    Yetkin-Arik, Bahar
    Univ Amsterdam, Ocular Angiogenesis Grp, Dept Ophthalmol, Acad Med Ctr, Amsterdam, Netherlands;Univ Amsterdam, Ocular Angiogenesis Grp, Dept Med Biol, Acad Med Ctr, Amsterdam, Netherlands.
    Yla-Herttuala, Seppo
    Univ Eastern Finland, Dept Biotechnol & Mol Med, Kuopio, Finland.
    Yoder, Mervin C.
    Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA.
    Griffioen, Arjan W.
    Vrije Univ Amsterdam, Dept Med Oncol, Canc Ctr Amsterdam, Angiogenesis Lab,Med Ctr, Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands.
    Consensus guidelines for the use and interpretation of angiogenesis assays2018In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 21, no 3, p. 425-532Article, review/survey (Refereed)
    Abstract [en]

    The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference.

  • 23.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Therapeutic vaccination targeting the tumour vasculature2014In: Biochemical Society Transactions, ISSN 0300-5127, E-ISSN 1470-8752, Vol. 42, p. 1653-1657Article in journal (Refereed)
    Abstract [en]

    Therapeutic vaccination targeting self-molecules could provide a cost-efficient alternative to monoclonal antibody-based therapies for cancer and various inflammatory diseases. However, development of cancer vaccines targeting self-molecules has proven difficult. One complicating factor is that tumour cells have developed strategies to escape recognition by the immune system. Antigens specifically expressed by the tumour vasculature can therefore provide alternative targets. The present mini-review highlights potential target molecules associated with tumour angiogenesis and the approaches made to direct an immune response against them. Furthermore, the requirements on a vaccine targeting self-molecules, in contrast with those directed against virus or bacteria, are discussed.

  • 24.
    Olsson, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cedervall, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    NETosis in Cancer - Platelet-Neutrophil Crosstalk Promotes Tumor-Associated Pathology2016In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 7, article id 373Article, review/survey (Refereed)
    Abstract [en]

    It has become increasingly clear that circulating immune cells in the body have a major impact on cancer development, progression, and outcome. The role of both platelets and neutrophils as independent regulators of various processes in cancer has been known for long, but it has quite recently emerged that the platelet-neutrophil interplay is yet a critical component to take into account during malignant disease. It was reported a few years ago that neutrophils in mice with cancer have increased propensity to form neutrophil extracellular traps (NETs) - web-like structures formed by externalized chromatin and secreted proteases. The initial finding describing this as a cell death-associated process has been followed by reports of additional mechanisms for NET formation (NETosis), and it has been shown that similar structures can be formed also without lysis and neutrophil cell death as a consequence. Furthermore, presence of NETs in humans with cancer has been verified in a few recent studies, indicating that tumor-induced NETosis is clinically relevant. Several reports have also described that NETs contribute to cancer-associated pathology, by promoting processes responsible for cancer-related death such as thrombosis, systemic inflammation, and relapse of the disease. This review summarizes current knowledge about NETosis in cancer, including the role of platelets as regulators of tumor-induced NETosis. It has been shown that platelets can serve as inducers of NETosis, and the platelet-neutrophil interface can therefore be an important issue to consider when designing therapies targeting cancer-associated pathology in the future.

  • 25.
    Olsson, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cedervall, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The pro-inflammatory role of platelets in cancer2018In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 29, no 6, p. 569-573Article in journal (Refereed)
    Abstract [en]

    Thrombosis is a frequent issue in cancer patients. Tumor-induced platelet activation and coagulation does not only constitute a significant risk for thrombosis, but also contribute to tumor progression by promoting critical processes such as angiogenesis and metastasis. In addition to their role in hemostasis, platelets are increasingly recognized as regulators of inflammation. By modulating the immune system, platelets regulate several aspects of cancer-associated pathology. Platelets influence the inflammatory response in cancer by affecting the activation status of the endothelium and by recruiting leukocytes to primary and metastatic tumor sites, as well as to distant organs unaffected by tumor growth. Furthermore, platelets participate in the formation of neutrophil extracellular traps, which can promote metastasis, thrombosis, and contribute to organ failure. In this review, we discuss the role of platelets as coordinators of the immune system during malignant disease and the potential of targeting platelets to prevent cancer-associated pathology.

  • 26.
    Olsson, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kreuger, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    VEGF receptor signalling: in control of vascular function2006In: Nature reviews. Molecular cell biology, ISSN 1471-0072, E-ISSN 1471-0080, Vol. 7, no 5, p. 359-371Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth-factor receptors (VEGFRs) regulate the cardiovascular system. VEGFR1 is required for the recruitment of haematopoietic precursors and migration of monocytes and macrophages, whereas VEGFR2 and VEGFR3 are essential for the functions of vascular endothelial and lymphendothelial cells, respectively. Recent insights have shed light onto VEGFR signal transduction and the interplay between different VEGFRs and VEGF co-receptors in development, adult physiology and disease.

  • 27.
    Olsson, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Johansson, Irja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Åkerud, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Einarsson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Christofferson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sasaki, Takako
    Timpl, Rupert
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    The minimal active domain of endostatin is a heparin-binding motif that mediates inhibition of tumor vascularization2004In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 64, no 24, p. 9012-9017Article in journal (Refereed)
    Abstract [en]

    Endostatin constitutes the COOH-terminal 20,000 Da proteolytic fragment of collagen XVIII and has been shown to possess antiangiogenic and antitumorigenic properties. In the present study, we have investigated the role of the heparin-binding sites in the in vivo mechanism of action of endostatin. The majority of the heparin binding is mediated by arginines 155/158/184/270 in endostatin, but there is also a minor site constituted by arginines 193/194. Using endostatin mutants lacking either of these two sites, we show that inhibition of fibroblast growth factor-2-induced angiogenesis in the chicken chorioallantoic membrane requires both heparin-binding sites. In contrast, inhibition of vascular endothelial growth factor-A-induced chorioallantoic membrane angiogenesis by endostatin was only dependent on the minor heparin-binding site (R193/194). These arginines were also required for endostatin to inhibit fibroblast growth factor-2- and vascular endothelial growth factor-A-induced chemotaxis of primary endothelial cells. Moreover, we show that a synthetic peptide corresponding to amino acids 180-199 of human endostatin (which covers the minor heparin-binding site) inhibits endothelial cell chemotaxis and reduces tumor vascularization in vivo. Substitution of arginine residues 193/194 for alanine attenuates the antiangiogenic effects of the peptide. These data show an essential role for heparin binding in the antiangiogenic action of endostatin.

  • 28.
    Olsson, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Larsson, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dixelius, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Johansson, Irja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lee, Chunsik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Oellig, Cornelia
    Björk, Ingemar
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    A fragment of histidine-rich glycoprotein is a potent inhibitor of tumor vascularization2004In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 64, no 2, p. 599-605Article in journal (Refereed)
    Abstract [en]

    In this study, we show that recombinant human histidine-rich glycoprotein (HRGP) has potent antiangiogenic properties as judged from effects on a syngeneic tumor model in C57/bl6 mice. Growth of fibrosarcoma, a very aggressive tumor, was reduced by >60% by HRGP treatment, and tumor angiogenesis was dramatically decreased. Treatment with HRGP led to increased apoptosis and reduced proliferation in the tumors. In contrast, HRGP did not affect apoptosis or DNA synthesis in endothelial cells or tumor cells in vitro. The mechanism of action of HRGP involves rearrangement of focal adhesions and decreased attachment of endothelial cells to vitronectin and, as a consequence, reduced endothelial cell migration. By using truncated versions of HRGP, we demonstrate that the isolated 150 amino acid-residue His/Pro-rich domain, which is also released by spontaneous proteolysis from purified HRGP, mediates the inhibitory effect on chemotaxis. Moreover, the His/Pro-rich domain must be released from HRGP to exert its effect. This study shows for the first time inhibitory effects of HRGP on tumor vascularization in vivo, thus providing proof of concept that HRGP is an angiogenesis inhibitor.

  • 29. Poon, Ivan K H
    et al.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hulett, Mark D
    Parish, Christopher R
    Regulation of histidine-rich glycoprotein (HRG) function via plasmin-mediated proteolytic cleavage2009In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 424, no Part 1, p. 27-37Article in journal (Refereed)
    Abstract [en]

    The plasminogen/plasmin system is involved in a variety of normal physiological and pathological processes, including tissue remodelling, angiogenesis and tumour metastasis. Plasminogen activators and receptors for plasminogen/plasminogen activators are essential for the processing of plasminogen to form the active serine protease plasmin. Plasmin can in turn positively or negatively regulate further plasminogen activation via plasmin-mediated cleavage of receptors and activators. HRG (histidine-rich glycoprotein), a relatively abundant (approx. 100-150 microg/ml) plasma glycoprotein, has a multi-domain structure that can interact with many ligands, including Zn2+, heparin, HS (heparan sulfate) and plasminogen. HRG has been shown to function as an adaptor molecule to tether plasminogen to GAG (glycosaminoglycan)-bearing surfaces and to regulate plasminogen activation via various mechanisms. As HRG itself is sensitive to plasmin cleavage, the present study examines in detail the cleavage of human HRG by plasmin and the effect of this cleavage on various functions of HRG. HRG fragments, generated by plasmin cleavage, are held together by disulfide linkages and are not released from the molecule under non-reducing conditions. Plasmin-mediated cleavage partially inhibited HRG binding to cell surface HS, but enhanced HRG binding to necrotic cells and to plasminogen. However, both intact and plasmin-cleaved HRG enhanced the binding of plasminogen to heparin-coated surfaces to a similar extent. Furthermore, the presence of heparin, Zn2+ or acidic pH was found to protect HRG from plasmin cleavage. Thus proteolytic cleavage of HRG by plasmin may provide a feedback mechanism to regulate the effects of HRG on the plasminogen/plasmin system and other functions of HRG.

  • 30.
    Ringvall, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Huijbers, Elisabeth J. M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ahooghalandari, Parvin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Alekseeva, Ludmila
    Andronova, Tatyana
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Identification of potent biodegradable adjuvants that efficiently break self-tolerance: a key issue in the development of therapeutic vaccines2009In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 28, no 1, p. 48-52Article in journal (Refereed)
    Abstract [en]

    Monoclonal antibodies are used successfully in the treatment of many human disorders. However, these antibodies are expensive and have in many countries put a major strain on the health care economy. Therapeutic vaccines, directed against the same target molecules, may offer a solution to this problem. Vaccines usually involve lower amount of recombinant protein, approximately 10,000-20,000 times less, which is significantly more cost effective. Attempts to develop such therapeutic vaccines have also been made. However, their efficacy has been limited by the lack of potent immunostimulatory compounds, adjuvants, for human use. To address this problem we have conducted a broad screening for adjuvants that can enhance the efficacy of therapeutic vaccines, whilst at the same time being non-toxic and biodegradable. We have now identified adjuvants that show these desired characteristics. A combination of Montanide ISA720 and phosphorothioate stabilized CpG stimulatory DNA, induced similar or even higher anti-self-antibody titers compared to Freund's adjuvant, currently the most potent, but also toxic, adjuvant available. This finding removes one of the major limiting factors in the field and facilitates the development of a broad range of novel therapeutic vaccines.

  • 31.
    Ringvall, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Thulin, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Lei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Cedervall, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tsuchida-Straeten, Nobuko
    Jahnen-Dechent, Wilhelm
    Department of Biomedical Engineering, RWTH Aachen University, Biointerface Laboratory, Aachen, Germany.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Enhanced Platelet Activation Mediates the Accelerated Angiogenic Switch in Mice Lacking Histidine-Rich Glycoprotein2011In: PLoS ONE, ISSN 1932-6203, Vol. 6, no 1, p. e14526-Article in journal (Refereed)
    Abstract [en]

    Background: The heparin-binding plasma protein histidine-rich glycoprotein (HRG; alternatively, HRGP/HPRG) can suppress tumor angiogenesis and growth in vitro and in vivo. Mice lacking the HRG gene are viable and fertile, but have an enhanced coagulation resulting in decreased bleeding times. In addition, the angiogenic switch is significantly enhanced in HRG-deficient mice.

    Methodology/Principal Findings: To address whether HRG deficiency affects tumor development, we have crossed HRG knockout mice with the RIP1-Tag2 mouse, a well established orthotopic model of multistage carcinogenesis. RIP1-Tag2 HRG(-/-) mice display significantly larger tumor volume compared to their RIP1-Tag2 HRG(+/+) littermates, supporting a role for HRG as an endogenous regulator of tumor growth. In the present study we also demonstrate that platelet activation is increased in mice lacking HRG. To address whether this elevated platelet activation contributes to the increased pathological angiogenesis in HRG-deficient mice, they were rendered thrombocytopenic before the onset of the angiogenic switch by injection of the anti-platelet antibody GP1b alpha. Interestingly, this treatment suppressed the increase in angiogenic neoplasias seen in HRG knockout mice. However, if GP1b alpha treatment was initiated at a later stage, after the onset of the angiogenic switch, no suppression of tumor growth was detected in HRG-deficient mice.

    Conclusions: Our data show that increased platelet activation mediates the accelerated angiogenic switch in HRG-deficient mice. Moreover, we conclude that platelets play a crucial role in the early stages of tumor development but are of less significance for tumor growth once angiogenesis has been initiated.

  • 32.
    Roy, Ananya
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Box 7028, S-75007 Uppsala, Sweden..
    Femel, Julia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Huijbers, Elisabeth J. M.
    VUMC Canc Ctr Amsterdam, Dept Med Oncol, Angiogenesis Lab, De Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands..
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ringvall, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Åbrink, Magnus
    Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Box 7028, S-75007 Uppsala, Sweden..
    Targeting Serglycin Prevents Metastasis in Murine Mammary Carcinoma2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 5, article id e0156151Article in journal (Refereed)
    Abstract [en]

    In hematopoietic cells, serglycin proteoglycans mainly contribute to proper storage and secretion of inflammatory mediators via their negatively charged glycosaminoglycans. Serglycin proteoglycans are also expressed in cancer cells where increased expression has been linked to poor prognosis. However, the serglycin-dependent mediators promoting cancer progression remain to be determined. In the present study we report that genetic ablation of serglycin proteoglycan completely blocks lung metastasis in the MMTV-PyMT-driven mouse breast cancer model, while serglycin-deficiency did not affect primary tumour growth or number of mammary tumours. Although E-cadherin expression was higher in the serglycin-deficient primary tumour tissue, indicating reduced invasiveness, serglycin-deficient tumour cells were still detected in the circulation. These data suggest that serglycin proteoglycans play a role in extravasation as well as colonization and growth of metastatic cells. A microarray expression analysis and functional annotation of differentially expressed genes identified several biological pathways where serglycin may be important. Our results suggest that serglycin and serglycin-dependent mediators are potential drug targets to prevent metastatic disease/dissemination of cancer.

  • 33. Rydengård, Victoria
    et al.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mörgelin, Matthias
    Schmidtchen, Artur
    Histidine-rich glycoprotein exerts antibacterial activity2007In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 274, no 2, p. 377-389Article in journal (Refereed)
    Abstract [en]

    Histidine-rich glycoprotein (HRGP), an abundant heparin-binding protein found in plasma and thrombocytes, exerts antibacterial effects against Gram-positive bacteria (Enterococcus faecalis and Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa). Fluorescence studies and electron microscopy to assess membrane permeation showed that HRGP induces lysis of E. faecalisbacteria in the presence of Zn2+ or at low pH. Heparin blocked binding of the protein to E. faecalis and abolished antibacterial activity. Furthermore, truncated HRGP, devoid of the heparin-binding and histidine-rich domain, was not antibacterial. It has previously been shown that peptides containing consensus heparin-binding sequences (Cardin and Weintraub motifs) are antibacterial. Thus, the peptide (GHHPH)4, derived from the histidine-rich region of HRGP and containing such a heparin-binding motif, was antibacterial for E. faecalis in the presence of Zn2+ or at low pH. The results show a previously undisclosed antibacterial activity of HRGP and suggest that the histidine-rich and heparin-binding domain of HRGP mediates the antibacterial activity of the protein.

  • 34. Rydengård, Victoria
    et al.
    Shannon, Oonagh
    Lundqvist, Katarina
    Kacprzyk, Lukasz
    Chalupka, Anna
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mörgelin, Matthias
    Jahnen-Dechent, Willi
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Schmidtchen, Artur
    Histidine-rich glycoprotein protects from systemic Candida infection2008In: PLoS pathogens, ISSN 1553-7374, Vol. 4, no 8, p. e1000116-Article in journal (Refereed)
    Abstract [en]

    Fungi, such as Candida spp., are commonly found on the skin and at mucosal surfaces. Yet, they rarely cause invasive infections in immunocompetent individuals, an observation reflecting the ability of our innate immune system to control potentially invasive microbes found at biological boundaries. Antimicrobial proteins and peptides are becoming increasingly recognized as important effectors of innate immunity. This is illustrated further by the present investigation, demonstrating a novel antifungal role of histidine-rich glycoprotein (HRG), an abundant and multimodular plasma protein. HRG bound to Candida cells, and induced breaks in the cell walls of the organisms. Correspondingly, HRG preferentially lysed ergosterol-containing liposomes but not cholesterol-containing ones, indicating a specificity for fungal versus other types of eukaryotic membranes. Both antifungal and membrane-rupturing activities of HRG were enhanced at low pH, and mapped to the histidine-rich region of the protein. Ex vivo, HRG-containing plasma as well as fibrin clots exerted antifungal effects. In vivo, Hrg(-/-) mice were susceptible to infection by C. albicans, in contrast to wild-type mice, which were highly resistant to infection. The results demonstrate a key and previously unknown antifungal role of HRG in innate immunity.

  • 35.
    Saupe, Falk
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Huijbers, Elisabeth J. M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hein, Tobias
    Femel, Julia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Cedervall, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hellman, Lars
    Vaccines targeting self-antigens: mechanisms and efficacy-determining parameters2015In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 29, no 8, p. 3253-3262Article in journal (Refereed)
    Abstract [en]

    We recently showed that it is possible to compromise tumor vessel function and, as a consequence, suppress growth of aggressive preclinical tumors by immunizing against the tumor vascular markers extra domain-A (ED-A) or -B (ED-B) of fibronectin, using a fusion protein consisting of the ED-A or ED-B peptide fused to bacterial thioredoxin. To address the mechanism behind fusion protein-induced immunization and the specific contribution of the different vaccine constituents to elicit an anti-self-antibody response, we immunized mice with modified or unmodified self-antigens, combined with different adjuvant components, and analyzed antibody responses by ELISA in sera. Several essential requirements to circumvent tolerance were identified: (1) a potent pattern recognition receptor agonist like an oligonucleotide containing unmethylated cytosine and guanine dinucleotides (CpG); (2) a depot adjuvant to keep the CpG at the site of injection; and (3) the presence of foreign sequences in the vaccine protein. Lack of either of these factors abolished the anti-self-response (P = 0.008). In mice genetically deficient for type I IFN signaling, there was a 60% reduction in the anti-self-response compared with wildtype (P = 0.011), demonstrating a key role of this pathway in CpG-induced circumvention of self-tolerance. Identification of these mechanistic requirements to generate a potent anti-self-immune response should significantly aid the design of efficient, specific, and safe therapeutic cancer vaccines.

  • 36.
    Saupe, Falk
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Reichel, Matthias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Huijbers, Elisabeth J. M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Femel, Julia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Markgren, Per-Olof
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Andersson, C. Evalena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Deindl, Sebastian
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Hellman, Lars T.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala Univ, Dept Med Biochem & Microbiol, Husargatan 3,Box 582, SE-75123 Uppsala, Sweden..
    Development of a novel therapeutic vaccine carrier that sustains high antibody titers against several targets simultaneously2017In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 31, no 3, p. 1204-1214Article in journal (Refereed)
    Abstract [en]

    With the aim to improve the efficacy of therapeutic vaccines that target self-antigens, we have developed a novel fusion protein vaccine on the basis of the C-terminal multimerizing end of the variable lymphocyte receptor B (VLRB), the Ig equivalent in jawless fishes. Recombinant vaccines were produced in Escherichia coli by fusing the VLRB sequence to 4 different cancer-associated target molecules. The anti-self-immune response generated in mice that were vaccinated with VLRB vaccines was compared with the response in mice that received vaccines that contained bacterial thioredoxin (TRX), previously identified as an efficient carrier. The anti-self-Abswere analyzed with respect to titers, binding properties, and duration of response. VLRB-vaccinatedmice displayed a 2-to 10-fold increase in anti-self-Ab titers and a substantial decrease in Abs against the foreign part of the fusion protein compared with the response in TRX-vaccinated mice (P < 0.01). VLRB-generated Ab response had duration similar to the corresponding TRX-generatedAbs, but displayed a higher diversity in binding characteristics. Of importance, VLRB vaccines could sustain an immune response against several targets simultaneously. VLRB vaccines fulfill several key criteria for an efficient therapeutic vaccine that targets self-antigens as a result of its small size, its multimerizing capacity, and nonexposed foreign sequences in the fusion protein.- Saupe, F., Reichel, M., Huijbers, E. J. M., Femel, J., Markgren, P.- O., Andersson, C. E., Deindl, S., Danielson, U. H., Hellman, L. T., Olsson, A.- K. Development of a novel therapeutic vaccine carrier that sustains high antibody titers against several targets simultaneously.

  • 37.
    Svensson, Susanne
    et al.
    Linkoping Univ, Dept Oncol, S-58185 Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, S-58185 Linkoping, Sweden..
    Abrahamsson, Annelie
    Linkoping Univ, Dept Oncol, S-58185 Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, S-58185 Linkoping, Sweden..
    Rodriguez, Gabriela Vazquez
    Linkoping Univ, Dept Oncol, S-58185 Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, S-58185 Linkoping, Sweden..
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jensen, Lasse
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, S-58185 Linkoping, Sweden..
    Cao, Yihai
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, S-58185 Linkoping, Sweden.;Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England..
    Dabrosin, Charlotta
    Linkoping Univ, Dept Oncol, S-58185 Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, S-58185 Linkoping, Sweden..
    CCL2 and CCL5 Are Novel Therapeutic Targets for Estrogen-Dependent Breast Cancer2015In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 21, no 16, p. 3794-3805Article in journal (Refereed)
    Abstract [en]

    Purpose: Novel therapeutic targets of estrogen receptor (ER)-positive breast cancers are urgently needed because current antiestrogen therapy causes severe adverse effects, nearly 50% of patients are intrinsically resistant, and the majority of recurrences have maintained ER expression. We investigated the role of estrogen-dependent chemokine expression and subsequent cancer growth in human tissues and experimental breast cancer models. Experimental Design: For in vivo sampling of human chemokines, microdialysis was used in breast cancers of women or normal human breast tissue before and after tamoxifen therapy. Estrogen exposure and targeted therapies were assessed in immune competent PyMT murine breast cancer, orthotopic human breast cancers in nude mice, cell culture of cancer cells, and freshly isolated human macrophages. Cancer cell dissemination was investigated using zebrafish. Results: ER+ cancers in women produced high levels of extracellular CCL2 and CCL5 in vivo, which was associated with infiltration of tumor-associated macrophages. In experimental breast cancer, estradiol enhanced macrophage influx and angiogenesis through increased release of CCL2, CCL5, and vascular endothelial growth factor. These effects were inhibited by anti-CCL2 or anti-CCL5 therapy, which resulted in potent inhibition of cancer growth. In addition, estradiol induced a protumorigenic activation of the macrophages. In a zebrafish model, macrophages increased cancer cell dissemination via CCL2 and CCL5 in the presence of estradiol, which was inhibited with anti-CCL2 and anti-CCL5 treatment. Conclusions: Our findings shed new light on the mechanisms underlying the progression of ER+ breast cancer and indicate the potential of novel therapies targeting CCL2 and CCL5 pathways. (C)2015 AACR.

  • 38.
    Söderholm, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lavenius, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rönnstrand, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Nånberg, Eewa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Activation of Ras, Raf-1 and protein kinase C in differentiating human neuroblastoma cells after treatment with phorbolester and NGF2001In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 13, no 2, p. 95-104Article in journal (Refereed)
    Abstract [en]

    The human neuroblastoma cell line SH-SY5Y/TrkA differentiates in vitro and acquires a sympathetic phenotype in response to phorbolester (activator of protein kinase C, PKC) in the presence of serum or growth factors, or nerve growth factor (NGF). We have now investigated to what extent phorbolester and NGF cause activation of Ras and Raf-1 and the involvement of PKC in this response in differentiating SH-SY5Y/TrkA cells. NGF stimulated increased accumulation of Ras-GTP and a threefold activation of Raf-1. In contrast, 12-O-tetradecanoylphorbol-13-acetate (TPA) had no effect on the amount of Ras-GTP but led to a smaller activation of Raf-1. NGF caused a limited increase in phosphorylation of Raf-1 compared with TPA, and NGF-induced Raf activity was independent of PKC. Analysis of phosphorylation of the endogenous PKC substrate myristoylated alanine-rich C-kinase substrate (MARCKS), and of subcellular distribution of PKC-alpha, -delta, and -epsilon revealed that NGF only caused a very small activation of PKC in SH-SY5Y/TrkA cells. The results identify Raf-1 as a target for both TPA- and NGF-induced signals in differentiating SH-SY5Y/TrkA cells and demonstrate that signalling to Raf-1 was mediated via distinct mechanisms.

  • 39.
    Tan, E-Jean
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Reprogramming during epithelial to mesenchymal transition under the control of TGF beta2015In: CELL ADHESION & MIGRATION, ISSN 1933-6918, Vol. 9, no 3, p. 233-246Article, review/survey (Refereed)
    Abstract [en]

    Epithelial-mesenchymal transition (EMT) refers to plastic changes in epithelial tissue architecture. Breast cancer stromal cells provide secreted molecules, such as transforming growth factor (TGF), that promote EMT on tumor cells to facilitate breast cancer cell invasion, stemness and metastasis. TGF signaling is considered to be abnormal in the context of cancer development; however, TGF acting on breast cancer EMT resembles physiological signaling during embryonic development, when EMT generates or patterns new tissues. Interestingly, while EMT promotes metastatic fate, successful metastatic colonization seems to require the inverse process of mesenchymal-epithelial transition (MET). EMT and MET are interconnected in a time-dependent and tissue context-dependent manner and are coordinated by TGF, other extracellular proteins, intracellular signaling cascades, non-coding RNAs and chromatin-based molecular alterations. Research on breast cancer EMT/MET aims at delivering biomolecules that can be used diagnostically in cancer pathology and possibly provide ideas for how to improve breast cancer therapy.

  • 40.
    Thulin, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ringvall, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kårehed, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Väisänen, Timo
    Biocenter Oulu, Department of Medical Biochemistry and Molecular Biology, University of Oulu, Finland.
    Väisänen, Marja-Riitta
    Biocenter Oulu, Department of Medical Biochemistry and Molecular Biology, University of Oulu, Finland.
    Hamad, Osama
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Wang, Jian
    Department of Biomedicine, University of Bergen, Norway.
    Bjerkvig, Rolf
    Department of Biomedicine, University of Bergen, Norway.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Pihlajaniemi, Taina
    Biocenter Oulu, Department of Medical Biochemistry and Molecular Biology, University of Oulu, Finland.
    Åkerud, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Pietras, Kristian
    Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm.
    Jahnen-Dechent, Wilhelm
    Department of Biomedical Engineering, RWTH, Aachen University, Biointerface Laboratory, Germany.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Activated platelets provide a functional microenvironment for the antiangiogenic fragment of histidine-rich glycoprotein2009In: Molecular Cancer Research, ISSN 1541-7786, E-ISSN 1557-3125, Vol. 7, no 11, p. 1792-1802Article in journal (Refereed)
    Abstract [en]

    The angiogenesis inhibitor histidine-rich glycoprotein (HRG) constitutes one of several examples of molecules regulating both angiogenesis and hemostasis. The antiangiogenic properties of HRG are mediated via its proteolytically released histidine- and proline-rich (His/Pro-rich) domain.Using a combination of immunohistochemistry and massspectrometry, we here provide biochemical evidence for thepresence of a proteolytic peptide, corresponding to the antiangiogenic domain of HRG, in vivo in human tissue. This finding supports a role for HRG as an endogenous regulator of angiogenesis. Interestingly, the His/Pro-rich peptide bound to the vessel wall in tissue from cancer patients but not to the vasculature in tissue from healthy persons.Moreover, the His/Pro-rich peptide was found in close association with platelets. Relesate from in vitro–activated platelets promoted binding of the His/Pro-rich domain of HRG to endothelial cells, an effect mediated by Zn2+.Previous studies have shown that zinc-dependent bindingof the His/Pro-rich domain of HRG to heparan sulfate on endothelial cells is required for inhibition of angiogenesis.We describe a novel mechanism to increase the local concentration and activity of an angiogenesis inhibitor,which may reflect a host response to counteract angiogenesis during pathologic conditions. Our finding that tumor angiogenesis is elevated in HRG-deficient mice supports this conclusion.

  • 41.
    Vanwildemeersch, Maarten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gottfridsson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The Anti-angiogenic His/Pro-rich Fragment of Histidine-rich Glycoprotein Binds to Endothelial Cell Heparan Sulfate in a Zn2+-dependent Manner2006In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 281, no 15, p. 10298-10304Article in journal (Refereed)
    Abstract [en]

    The plasma protein histidine-rich glycoprotein (HRGP), which has been identified as an angiogenesis inhibitor, binds to heparan sulfate (HS) in a Zn2+-dependent manner. We wished to test whether this interaction is mechanistically important in mediation of the anti-angiogenic effect of HRGP. Inhibition of angiogenesis by HRGP is exerted through its central His/Pro-rich domain, which is proteolytically released. A 35-amino-acid residue synthetic peptide, HRGP330, derived from the His/Pro-rich domain retains the inhibitory effect on blood vessel formation in vitro and in vivo, an effect dependent on the presence of Zn2+. We now show that HRGP330 binds heparin/HS with the same capacity as full-length HRGP, and the binding is Zn2+-dependent. Peptides derived from the His/Pro-rich domain of HRGP downstream of HRGP330 fail to inhibit endothelial cell migration and display a significantly reduced heparin-binding capacity. An even shorter peptide, HRGP335, covering a 26-amino-acid sequence within HRGP330 retains full heparin/HS-binding capacity. Characterization of the HS interaction shows that there is a tissue-specific HS pattern recognized by HRGP335 and that the minimal length of heparin/HS required for binding to HRGP335 is an 8-mer oligosaccharide. Saturation of the HS binding sites in HRGP330 by pre-incubation with heparin abrogates the HRGP330-induced rearrangement of endothelial cell focal adhesions, suggesting that interactio

  • 42. Wentink, Madelon Q.
    et al.
    Huijbers, Elisabeth J. M.
    de Gruijl, Tanja D.
    Verheul, Henk M. W.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Griffioen, Arjan W.
    Vaccination approach to anti-angiogenic treatment of cancer2015In: Biochimica et Biophysica Acta. CR. Reviews on Cancer, ISSN 0304-419X, E-ISSN 1879-2561, Vol. 1855, no 2, p. 155-171Article, review/survey (Refereed)
    Abstract [en]

    Improvement of patient survival by anti-angiogenic therapy has proven limited. A vaccination approach inducing an immune response against the tumor vasculature combines the benefits of immunotherapy and anti-angiogenesis, and may overcome the limitations of current anti-angiogenic drugs. Strategies to use whole endo: thelial cell vaccines and DNA- or protein vaccines against key players in the VEGF signaling axis, as well as specific markers of tumor endothelial cells, have been tested in preclinical studies. Current clinical trials are now testing the promise of this specific anti-cancer vaccination approach. This review will highlight the state-of-the-art in this exciting field of cancer research.

  • 43.
    Zhang, Lei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kundu, Soumi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Feenstra, Tjerk
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jin, Chuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Laaniste, Liisi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    El Hassan, Tamador Elsir Abu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Ohlin, K Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Yu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olofsson, Tommie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Magnusson, Peetra U
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Forsberg, Karin Nilsson
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Dieterich, Lothar C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pleiotrophin promotes vascular abnormalization in gliomas and correlates with poor survival in patients with astrocytomas.2015In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 8, no 406Article in journal (Refereed)
    Abstract [en]

    Glioblastomas are aggressive astrocytomas characterized by endothelial cell proliferation and abnormal vasculature, which can cause brain edema and increase patient morbidity. We identified the heparin-binding cytokine pleiotrophin as a driver of vascular abnormalization in glioma. Pleiotrophin abundance was greater in high-grade human astrocytomas and correlated with poor survival. Anaplastic lymphoma kinase (ALK), which is a receptor that is activated by pleiotrophin, was present in mural cells associated with abnormal vessels. Orthotopically implanted gliomas formed from GL261 cells that were engineered to produce pleiotrophin showed increased microvessel density and enhanced tumor growth compared with gliomas formed from control GL261 cells. The survival of mice with pleiotrophin-producing gliomas was shorter than that of mice with gliomas that did not produce pleiotrophin. Vessels in pleiotrophin-producing gliomas were poorly perfused and abnormal, a phenotype that was associated with increased deposition of vascular endothelial growth factor (VEGF) in direct proximity to the vasculature. The growth of pleiotrophin-producing GL261 gliomas was inhibited by treatment with the ALK inhibitor crizotinib, the ALK inhibitor ceritinib, or the VEGF receptor inhibitor cediranib, whereas control GL261 tumors did not respond to either inhibitor. Our findings link pleiotrophin abundance in gliomas with survival in humans and mice, and show that pleiotrophin promotes glioma progression through increased VEGF deposition and vascular abnormalization.

  • 44.
    Zhang, Yanyu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Valsala Madhavan Unnithan, Ragaseema
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Govt Arts Coll, Thiruvananthapuram, Kerala, India.
    Hamidi, Anahita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Caja, Laia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Saupe, Falk
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cedervall, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    TANK-binding kinase 1 is a mediator of platelet-induced EMT in mammary carcinoma cells2019In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 33, no 7, p. 7822-7832Article in journal (Refereed)
    Abstract [en]

    Platelets can promote several stages of the metastatic process and thus contribute to malignant progression. As an example, platelets promote invasive properties of tumor cells by induction of epithelial to mesenchymal transition (EMT). In this study, we show that tumor necrosis factor receptor-associated factor (TRAF) family member-associated NF-kappa B activator (TANK)-binding kinase 1 (TBK1) is a previously unknown mediator of platelet-induced EMT in mammary carcinoma cells. Coculture of 2 mammary carcinoma cell lines, Ep5 from mice and MCF10A(MII) from humans, with isolated platelets induced morphologic as well as molecular changes characteristic of EMT, which was paralleled with activation of TBK1. TBK1 depletion using small interfering RNA impaired platelet-induced EMT in both Ep5 and MCF10A(MII) cells. Furthermore, platelet-induced activation of the NF-kappa B subunit p65 was suppressed after TBK1 knockdown, demonstrating that TBK1 mediates platelet-induced NF-kappa B signaling and EMT. Using an in vivo metastasis assay, we found that depletion of TBK1 from mammary carcinoma cells during in vitro preconditioning with platelets subsequently suppressed the formation of lung metastases in mice. Altogether, these results suggest that TBK1 contributes to tumor invasiveness and may be a driver of metastatic spread in breast cancer.-Zhang, Y., Unnithan, R. V. M., Hamidi, A., Caja, L., Saupe, F., Moustakas, A., Cedervall, J., Olsson, A.-K. TANK-binding kinase 1 is a mediator of platelet-induced EMT in mammary carcinoma cells.

1 - 44 of 44
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