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Olsson, Anna-Karin
Publications (10 of 45) Show all publications
Tsioumpekou, M., Cunha, S. I., Ma, H., Åhgren, A., Cedervall, J., Olsson, A.-K., . . . Lennartsson, J. (2020). Specific targeting of PDGFR beta in the stroma inhibits growth and angiogenesis in tumors with high PDGF-BB expression. Theranostics, 10(3), 1122-1135
Open this publication in new window or tab >>Specific targeting of PDGFR beta in the stroma inhibits growth and angiogenesis in tumors with high PDGF-BB expression
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2020 (English)In: Theranostics, ISSN 1838-7640, E-ISSN 1838-7640, Vol. 10, no 3, p. 1122-1135Article in journal (Refereed) Published
Abstract [en]

PDGF-BB/PDGFR beta signaling plays an important role during vascularization by mediating pericyte recruitment to the vasculature, promoting the integrity and function of vessels. Until now it has not been possible to assess the specific role of PDGFR beta signaling in tumor progression and angiogenesis due to lack of appropriate animal models and molecular tools. Methods: In the present study, we used a transgenic knock-in mouse strain carrying a silent mutation in the PDGFR beta ATP binding site that allows specific targeting of PDGFR beta using the compound 1-NaPP1. To evaluate the impact of selective PDGFR beta inhibition of stromal cells on tumor growth we investigated four tumor cell lines with no or low PDGFR beta expression, i.e. Lewis lung carcinoma (LLC), EO771 breast carcinoma, B16 melanoma and a version of B16 that had been engineered to overexpress PDGF-BB (B16/PDGF-BB). Results: We found that specific impairment of PDGFR beta kinase activity by 1-NaPP1 treatment efficiently suppressed growth in tumors with high expression of PDGF-BB, i.e. LLC and B16/PDGF-BB, while the clinically used PDGFR beta kinase inhibitor imatinib did not suppress tumor growth. Notably, tumors with low levels of PDGF-BB, i.e. EO771 and B16, neither responded to 1-NaPP1 nor to imatinib treatment. Inhibition of PDGFR beta by either drug impaired tumor vascularization and also affected pericyte coverage; however, specific targeting of PDGFR beta by 1-NaPP1 resulted in a more pronounced decrease in vessel function with increased vessel apoptosis in high PDGF-BB expressing tumors, compared to treatment with imatinib. In vitro analysis of PDGFR beta ASKA mouse embryo fibroblasts and the mesenchymal progenitor cell line 10T1/2 revealed that PDGF-BB induced NG2 expression, consistent with the in vivo data. Conclusion: Specific targeting of PDGFR beta signaling significantly inhibits tumor progression and angiogenesis depending on PDGF-BB expression. Our data suggest that targeting PDGFR beta in the tumor stroma could have therapeutic value in patients with high tumor PDGF-BB expression.

Place, publisher, year, edition, pages
IVYSPRING INT PUBL, 2020
Keywords
Low molecular weight inhibitor, PDGFR beta, pericytes, tumor growth, angiogenesis
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-402371 (URN)10.7150/thno.37851 (DOI)000503870400011 ()31938055 (PubMedID)
Funder
Swedish Cancer Society, 2018/425Swedish Cancer Society, 2015/445Lars Hierta Memorial FoundationStiftelsen Längmanska kulturfonden
Available from: 2020-02-03 Created: 2020-02-03 Last updated: 2020-02-03Bibliographically approved
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
Nowak-Sliwinska, P., Alitalo, K., Allen, E., Anisimov, A., Aplin, A. C., Auerbach, R., . . . Griffioen, A. W. (2018). Consensus guidelines for the use and interpretation of angiogenesis assays. Angiogenesis, 21(3), 425-532
Open this publication in new window or tab >>Consensus guidelines for the use and interpretation of angiogenesis assays
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2018 (English)In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 21, no 3, p. 425-532Article, review/survey (Refereed) Published
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.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Angiogenesis, Aortic ring, Endothelial cell migration, Proliferation, Microfluidic, Zebrafish, Chorioallantoic membrane (CAM), Vascular network, Intussusceptive angiogenesis, Retinal vasculature, Corneal angiogenesis, Hindlimb ischemia, Myocardial angiogenesis, Recombinant proteins, Tip cells, Plug assay, Vessel co-option
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-366665 (URN)10.1007/s10456-018-9613-x (DOI)000438644400001 ()29766399 (PubMedID)
Funder
EU, European Research Council, EU-ERC680209
Available from: 2018-11-27 Created: 2018-11-27 Last updated: 2018-11-27Bibliographically 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
Macarak, E. J., Lotto, C. E., Koganti, D., Jin, X., Wermuth, P. J., Olsson, A.-K., . . . Rosenbloom, J. (2018). Trametinib prevents mesothelial-mesenchymal transition and ameliorates abdominal adhesion formation. Journal of Surgical Research, 227, 198-210
Open this publication in new window or tab >>Trametinib prevents mesothelial-mesenchymal transition and ameliorates abdominal adhesion formation
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2018 (English)In: Journal of Surgical Research, ISSN 0022-4804, E-ISSN 1095-8673, Vol. 227, p. 198-210Article in journal (Refereed) Published
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. 

Place, publisher, year, edition, pages
ACADEMIC PRESS INC ELSEVIER SCIENCE, 2018
Keywords
Abdominal adhesions, Anti-fibrotic therapeutics, Trametinib, Mesothelial-mesenchymal transition, Fibronectin EDA isoform
National Category
Surgery Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-357377 (URN)10.1016/j.jss.2018.02.012 (DOI)000433059300026 ()29804854 (PubMedID)
Available from: 2018-08-24 Created: 2018-08-24 Last updated: 2018-08-24Bibliographically approved
Saupe, F., Reichel, M., Huijbers, E. J. M., Femel, J., Markgren, P.-O., Andersson, C. E., . . . Olsson, A.-K. (2017). Development of a novel therapeutic vaccine carrier that sustains high antibody titers against several targets simultaneously. The FASEB Journal, 31(3), 1204-1214
Open this publication in new window or tab >>Development of a novel therapeutic vaccine carrier that sustains high antibody titers against several targets simultaneously
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2017 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 31, no 3, p. 1204-1214Article in journal (Refereed) Published
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.

Keywords
cancer, VLRB, tolerance, ED-A, ED-B
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-320668 (URN)10.1096/fj.201600820R (DOI)000395671200032 ()27993994 (PubMedID)
Note

De 2 sista författarna delar sistaförfattarskapet.

Available from: 2017-06-07 Created: 2017-06-07 Last updated: 2017-06-07Bibliographically 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
Roy, A., Femel, J., Huijbers, E. J. M., Spillmann, D., Larsson, E., Ringvall, M., . . . Åbrink, M. (2016). Targeting Serglycin Prevents Metastasis in Murine Mammary Carcinoma. PLoS ONE, 11(5), Article ID e0156151.
Open this publication in new window or tab >>Targeting Serglycin Prevents Metastasis in Murine Mammary Carcinoma
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 5, article id e0156151Article in journal (Refereed) Published
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.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-298897 (URN)10.1371/journal.pone.0156151 (DOI)000376881700066 ()27223472 (PubMedID)
Funder
Swedish Research Council, 2011-3533
Available from: 2016-07-12 Created: 2016-07-12 Last updated: 2017-11-28Bibliographically approved
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