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Cedervall, Jessica
Publications (10 of 15) Show all publications
Zhang, Y., Valsala Madhavan Unnithan, R., Hamidi, A., Caja, L., Saupe, F., Moustakas, A., . . . Olsson, A.-K. (2019). TANK-binding kinase 1 is a mediator of platelet-induced EMT in mammary carcinoma cells. The FASEB Journal, 33(7), 7822-7832
Open this publication in new window or tab >>TANK-binding kinase 1 is a mediator of platelet-induced EMT in mammary carcinoma cells
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2019 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 33, no 7, p. 7822-7832Article in journal (Refereed) Published
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.

Keywords
platelets, cancer, TBK1, NF-kappa B, metastasis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-392047 (URN)10.1096/fj.201801936RRR (DOI)000476234700004 ()30912981 (PubMedID)
Funder
Swedish Research Council, 2016-03036Swedish Cancer Society, CAN 2017/522Swedish Society of Medicine, SLS-683851
Note

Ragaseema Valsala Madhavan Unnithan and Anahita Hamidi contributed equally to this work.

Jessica Cedervall and Anna-Karin Olsson contributed equally to this work.

Available from: 2019-09-10 Created: 2019-09-10 Last updated: 2019-09-10Bibliographically approved
Cedervall, J., Hamidi, A. & Olsson, A.-K. (2018). Platelets, NETs and cancer. Paper presented at 9th International Conference on Thrombosis and Hemostasis Issues in Cancer (ICTHIC), APR 13-15, 2018, Bergamo, ITALY. Thrombosis Research, 164, S148-S152
Open this publication in new window or tab >>Platelets, NETs and cancer
2018 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 164, p. S148-S152Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
PERGAMON-ELSEVIER SCIENCE LTD, 2018
Keywords
Cancer, Thrombosis, Platelets, Neutrophil extracellular traps, NETs
National Category
Hematology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-358569 (URN)10.1016/j.thromres.2018.01.049 (DOI)000432889200027 ()29703474 (PubMedID)
Conference
9th International Conference on Thrombosis and Hemostasis Issues in Cancer (ICTHIC), APR 13-15, 2018, Bergamo, ITALY
Funder
Swedish Research Council, 2016-03036Swedish Cancer Society, 2017/522
Available from: 2018-09-17 Created: 2018-09-17 Last updated: 2018-09-17Bibliographically approved
Olsson, A.-K. & Cedervall, J. (2018). The pro-inflammatory role of platelets in cancer. Platelets, 29(6), 569-573
Open this publication in new window or tab >>The pro-inflammatory role of platelets in cancer
2018 (English)In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 29, no 6, p. 569-573Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS INC, 2018
Keywords
Cancer, inflammation, NETs, neutrophil extracellular traps, neutrophils, platelets
National Category
Cancer and Oncology Cell Biology
Identifiers
urn:nbn:se:uu:diva-362860 (URN)10.1080/09537104.2018.1453059 (DOI)000441736900006 ()29584534 (PubMedID)
Available from: 2018-10-11 Created: 2018-10-11 Last updated: 2018-10-11Bibliographically approved
Cedervall, J., Dragomir, A., Saupe, F., Zhang, Y., Ärnlöv, J., Larsson, E., . . . Olsson, A.-K. (2017). Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice.. Oncoimmunology, 6(8), Article ID e1320009.
Open this publication in new window or tab >>Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice.
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2017 (English)In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 6, no 8, article id e1320009Article in journal (Refereed) Published
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.

Keywords
Cancer, DNase I, GSK484, kidney injury, neutrophil extracellular traps
National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-329754 (URN)10.1080/2162402X.2017.1320009 (DOI)000408961700006 ()28919990 (PubMedID)
Available from: 2017-09-20 Created: 2017-09-20 Last updated: 2019-04-02Bibliographically approved
Olsson, A.-K. & Cedervall, J. (2016). NETosis in Cancer - Platelet-Neutrophil Crosstalk Promotes Tumor-Associated Pathology. Frontiers in Immunology, 7, Article ID 373.
Open this publication in new window or tab >>NETosis in Cancer - Platelet-Neutrophil Crosstalk Promotes Tumor-Associated Pathology
2016 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 7, article id 373Article, review/survey (Refereed) Published
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.

Keywords
cancer, neutrophil extracellular traps, neutrophils, platelets
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-311406 (URN)10.3389/fimmu.2016.00373 (DOI)000383682500004 ()27708646 (PubMedID)
Funder
Swedish Cancer Society, 11 0653Magnus Bergvall Foundation, 2015-01164
Available from: 2016-12-27 Created: 2016-12-27 Last updated: 2018-01-13Bibliographically approved
Cedervall, J., Dimberg, A. & Olsson, A.-K. (2016). Tumor-induced neutrophil extracellular traps-drivers of systemic inflammation and vascular dysfunction. Oncoimmunology, 5(3), Article ID e1098803.
Open this publication in new window or tab >>Tumor-induced neutrophil extracellular traps-drivers of systemic inflammation and vascular dysfunction
2016 (English)In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 5, no 3, article id e1098803Article in journal, Editorial material (Other academic) Published
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.

Keywords
Cancer, inflammation, NETs, neutrophil extracellular traps, systemic, vascular function
National Category
Cancer and Oncology Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-299093 (URN)10.1080/2162402X.2015.1098803 (DOI)000373385700035 ()
Available from: 2016-07-14 Created: 2016-07-14 Last updated: 2018-01-10Bibliographically approved
Cedervall, J., Zhang, Y., Huang, H., Zhang, L., Femel, J., Dimberg, A. & Olsson, A.-K. (2015). Neutrophil Extracellular Traps Accumulate in Peripheral Blood Vessels and Compromise Organ Function in Tumor-Bearing Animals. Cancer Research, 75(13), 2653-2662
Open this publication in new window or tab >>Neutrophil Extracellular Traps Accumulate in Peripheral Blood Vessels and Compromise Organ Function in Tumor-Bearing Animals
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2015 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 13, p. 2653-2662Article in journal (Refereed) Published
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.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-259098 (URN)10.1158/0008-5472.CAN-14-3299 (DOI)000357334700008 ()26071254 (PubMedID)
Funder
Swedish Cancer Society, 11 0653Swedish Research Council, 2010-6903-75363-44, 2012-77PK-22157-01-2
Available from: 2015-07-28 Created: 2015-07-27 Last updated: 2017-12-04Bibliographically approved
Svensson, B., Nagubothu, S. R., Nord, C., Cedervall, J., Hultman, I., Ahrlund-Richter, L., . . . Hertegard, S. (2015). Stem Cell Therapy in Injured Vocal Folds: A Three-Month Xenograft Analysis of Human Embryonic Stem Cells. BioMed Research International, Article ID 754876.
Open this publication in new window or tab >>Stem Cell Therapy in Injured Vocal Folds: A Three-Month Xenograft Analysis of Human Embryonic Stem Cells
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2015 (English)In: BioMed Research International, ISSN 2314-6133, E-ISSN 2314-6141, article id 754876Article in journal (Refereed) Published
Abstract [en]

We have previously shown that human embryonic stem cell (hESC) therapy to injured rabbit vocal folds (VFs) induces human tissue generation with regained VF vibratory capacity. The aims of this study were to test the sustainability of such effect and to what extent derivatives of the transplanted hESCs are propagated in the VFs. The VFs of 14 New Zealand rabbits were injured by a localized resection. HESCs were transplanted to 22 VFs which were analyzed for persistence of hESCs after six weeks and after three months. At three months, the VFs were also analyzed for viscoelasticity, measured as dynamic viscosity and elastic modulus, for the lamina propria (Lp) thickness and relative content of collagen type I. Three months after hESC cell therapy, the dynamic viscosity and elastic modulus of the hESC treated VFs were similar to normal controls and lower than untreated VFs (P <= 0.011). A normalized VF architecture, reduction in collagen type I, and Lp thickness were found compared with untreated VFs (P <= 0.031). At three months, no derivatives of hESCs were detected. HESCs transplanted to injured rabbit VFs restored the vibratory characteristics of the VFs, with maintained restored function for three months without remaining hESCs or derivatives.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-268724 (URN)10.1155/2015/754876 (DOI)000364082500001 ()
Funder
The Karolinska Institutet's Research Foundation
Available from: 2015-12-09 Created: 2015-12-09 Last updated: 2017-12-01Bibliographically approved
Cedervall, J., Dimberg, A. & Olsson, A.-K. (2015). Tumor-Induced Local and Systemic Impact on Blood Vessel Function. Mediators of Inflammation, Article ID 418290.
Open this publication in new window or tab >>Tumor-Induced Local and Systemic Impact on Blood Vessel Function
2015 (English)In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, article id 418290Article, review/survey (Refereed) Published
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.

National Category
Cancer and Oncology Medical Genetics
Identifiers
urn:nbn:se:uu:diva-279222 (URN)10.1155/2015/418290 (DOI)000366855100001 ()
Available from: 2016-03-01 Created: 2016-02-29 Last updated: 2018-01-10Bibliographically approved
Saupe, F., Huijbers, E. J. M., Hein, T., Femel, J., Cedervall, J., Olsson, A.-K. & Hellman, L. (2015). Vaccines targeting self-antigens: mechanisms and efficacy-determining parameters. The FASEB Journal, 29(8), 3253-3262
Open this publication in new window or tab >>Vaccines targeting self-antigens: mechanisms and efficacy-determining parameters
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2015 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 29, no 8, p. 3253-3262Article in journal (Refereed) Published
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.

Keywords
cancer, ED-B of fibronectin, adjuvant, CpG, type I IFN
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-261251 (URN)10.1096/fj.15-271502 (DOI)000358796900014 ()25868727 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2015-09-01 Created: 2015-08-31 Last updated: 2017-12-04Bibliographically approved
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