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HRG regulates tumor progression, epithelial to mesenchymal transition and metastasis via platelet-induced signaling in the pre-tumorigenic microenvironment
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 Medical Biochemistry and Microbiology.
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 Medical Sciences, Coagulation and inflammation science.
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2013 (English)In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 16, no 4, 889-902 p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
2013. Vol. 16, no 4, 889-902 p.
Keyword [en]
Platelets, Angiogenesis, HRG, Metastasis, EMT
National Category
Basic Medicine
Identifiers
URN: urn:nbn:se:uu:diva-209153DOI: 10.1007/s10456-013-9363-8ISI: 000324326900013OAI: oai:DiVA.org:uu-209153DiVA: diva2:656280
Available from: 2013-10-15 Created: 2013-10-15 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Platelets – Multifaceted players in tumor progression and vascular function
Open this publication in new window or tab >>Platelets – Multifaceted players in tumor progression and vascular function
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Platelets play a crucial role for blood hemostasis, the process that prevents bleeding. In addition, platelets have been demonstrated to promote cancer progression and cancer related complications like metastasis and thrombosis. Platelets can affect cancer related diseases either directly or by interacting with other blood cells or molecules in the circulation of individuals with cancer. The current thesis addresses the role of platelets in tumor progression and tumor-induced systemic effects of cancer, with a special focus on the effects on the vasculature.

In the first paper, the role of platelets in tumor progression in histidine-rich glycoprotein (HRG)-deficient mice was addressed. We report that HRG-deficient mice show enhanced tumor growth, epithelial to mesenchymal transition (EMT) and metastasis. The enhanced platelet activity in the absence of HRG is responsible for the accelerated tumor progression.

In the second paper, we demonstrate that platelet-derived PDGFB is a central player to keep the tumor vessels functional. Moreover, in a pancreatic neuroendocrine carcinoma model with PDGFB-deficient platelets, spontaneous liver metastasis was enhanced. With this finding we identify a previously unknown role of platelet derived PDGFB.

In the third paper, we found that TBK1 mediates platelet-induced EMT by activation of NF-kB signaling, which suggest that TBK1 contributes to tumor invasiveness in mammary epithelial tumors.

In the last paper, we report that the vascular function in organs that are neither affected by the primary tumor, nor represent metastatic sites, is impaired in mice with cancer. We show that tumor-induced formation of intravascular neutrophil extracellular traps (NETs), a fibril matrix consisting of neutrophils with externalized DNA and histones, granule proteases and platelets, are responsible for the impaired peripheral vessel function.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1271
Keyword
Cancer, Tumor, Platelet, HRG, PDGFB, TBK1, NETs, Angiogenesis, EMT, Metastasis
National Category
Cancer and Oncology
Research subject
Medical Science; Oncology; Biology with specialization in Molecular Cell Biology
Identifiers
urn:nbn:se:uu:diva-306129 (URN)978-91-554-9739-2 (ISBN)
Public defence
2016-12-16, B41, Uppsala Biomedical Center (BMC), Husargatan 3, Uppsala, 09:15 (English)
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Available from: 2016-11-23 Created: 2016-10-25 Last updated: 2016-11-28

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Cedervall, JessicaZhang, YanyuRingvall, MariaThulin, ÅsaMoustakas, AristidisSiegbahn, AgnetaOlsson, Anna-Karin

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Cedervall, JessicaZhang, YanyuRingvall, MariaThulin, ÅsaMoustakas, AristidisSiegbahn, AgnetaOlsson, Anna-Karin
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Department of Medical Biochemistry and MicrobiologyCoagulation and inflammation scienceLudwig Institute for Cancer Research
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