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  • 1.
    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.

  • 2.
    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.

  • 3.
    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.

  • 4.
    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.

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