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Platelet-specific ablation of PDGFB impairs vascular function and pericyte recruitment in tumors and promotes metastasis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Science for Life Laboratory, SciLifeLab. 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, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Platelet-derived growth factor B (PDGFB) plays a crucial role in recuitment of PDGF-receptor b positive pericytes to blood vessels and the endothelium is an essential source of PDGFB in this process. PDGFB was originally isolated from platelets, which consitute a major reservoir of this growth factor. Under physiological conditions, platelets are not activated unless there is a wound, which then leads to rapid activation and degranulation of the platelet content. However, in the tumor microenvironment platelets are continuously activated, exposing tumors to the plethora of growth factors contained in platelet granules. In the current study we address the role of platelet-derived PDGFB in vascular function and pericyte recruitment in tumors by creating a platelet-specific knock-out of PDGFB. We find that mice with PDGFB-deficient platelets are viable and fertile. Furthermore, vascular function and pericyte recruitment to healthy vessels were unaffected by the lack of PDGFB in platelets. In contrast, tumor vascular function, as well as pericyte coverage, is significantly impaired in mice with PDGFB-deficient platelets. Moreover, lack of PDGFB in platelets leads to enhanced spontaneous liver metastasis in a model for pancreatic neuroendocrine carcinoma, further indicating that platelet-derived PDGFB contributes to maintain vascular integrity in the tumor microenvironment where extensive vascular remodeling is ongoing. With this finding we identify a previously unknown role for platelet-derived PDGFB.

Keyword [en]
Platelet, pericyte, PDGFB, vascular function, metastasis
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-306176OAI: oai:DiVA.org:uu-306176DiVA: diva2:1039989
Available from: 2016-10-25 Created: 2016-10-25 Last updated: 2016-10-26
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)
Opponent
Supervisors
Available from: 2016-11-23 Created: 2016-10-25 Last updated: 2016-11-28

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Cedervall, Jessica
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Department of Medical Biochemistry and MicrobiologyScience for Life Laboratory, SciLifeLabDepartment of Medical SciencesDepartment of Immunology, Genetics and Pathology
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