Change search
ReferencesLink to record
Permanent link

Direct link
Platelets – Multifaceted players in tumor progression and vascular function
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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 [en]
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: urn:nbn:se:uu:diva-306129ISBN: 978-91-554-9739-2OAI: oai:DiVA.org:uu-306129DiVA: diva2:1039996
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
List of papers
1. HRG regulates tumor progression, epithelial to mesenchymal transition and metastasis via platelet-induced signaling in the pre-tumorigenic microenvironment
Open this publication in new window or tab >>HRG regulates tumor progression, epithelial to mesenchymal transition and metastasis via platelet-induced signaling in the pre-tumorigenic microenvironment
Show others...
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.

Keyword
Platelets, Angiogenesis, HRG, Metastasis, EMT
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-209153 (URN)10.1007/s10456-013-9363-8 (DOI)000324326900013 ()
Available from: 2013-10-15 Created: 2013-10-15 Last updated: 2016-10-26Bibliographically approved
2. Platelet-specific ablation of PDGFB impairs vascular function and pericyte recruitment in tumors and promotes metastasis
Open this publication in new window or tab >>Platelet-specific ablation of PDGFB impairs vascular function and pericyte recruitment in tumors and promotes metastasis
Show others...
(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
Platelet, pericyte, PDGFB, vascular function, metastasis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-306176 (URN)
Available from: 2016-10-25 Created: 2016-10-25 Last updated: 2016-10-26
3. TBK1, an NF-κB activating kinase, is required for platelet-induced EMT
Open this publication in new window or tab >>TBK1, an NF-κB activating kinase, is required for platelet-induced EMT
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Platelets can promote several steps during the metastatic process, and hence

contribute to malignant progression. During early stages of metastasis, platelets

promote invasive properties of tumor cells by induction of epithelial to mesenchymal transition (EMT). In this study we show that TANK binding kinase-1 (TBK1) is a previously unknown mediator of platelet-induced EMT - a finding that suggests a possible role of TBK1 as a potential driver of metastatic disease. Using the two mammary epithelial cell lines Ep5 and MCF10A (M2), we show that co-culture with isolated platelets induced morphological as well as molecular features indicative of EMT, and that this is paralleled with activation of TBK1. Inhibiting TBK1 using siRNA suppressed platelet induced EMT in both Ep5 and MCF10A (M2) cells. Furthermore, platelet induced NF-κB signaling was suppressed after TBK1 knock down, suggesting that TBK1 is a crucial mediator of platelet-induced NF-κB signaling and subsequent EMT. Altogether, these results suggest that TBK1 contribute to tumor invasiveness and may hence be a driver of metastatic spread in mammary epithelial tumors.

Keyword
platelets, cancer, TBK1, EMT
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-306182 (URN)
Available from: 2016-10-25 Created: 2016-10-25 Last updated: 2016-10-26
4.
The record could not be found. The reason may be that the record is no longer available or you may have typed in a wrong id in the address field.

Open Access in DiVA

fulltext(1300 kB)50 downloads
File information
File name FULLTEXT01.pdfFile size 1300 kBChecksum SHA-512
415e6ff0ae0a77f3bb2e1f96cb89c233db397233b1abc626fd09cdd179fa1c92acf5163e2e16795c07d7f8f4e0b8864cd523a52036a69b24a242b22c2f55aa11
Type fulltextMimetype application/pdf
errata(11 kB)25 downloads
File information
File name ERRATA01.pdfFile size 11 kBChecksum SHA-512
d2bd5d3aae6712ca28c0c5de7455acbbf9a0faf86cc4cd425836991a198287c7ee8159500bd2e3d07a931769f0db49fe54e94644fb71b657cf54b43f223afca9
Type errataMimetype application/pdf
Buy this publication >>

Search in DiVA

By author/editor
Zhang, Yanyu
By organisation
Department of Medical Biochemistry and MicrobiologyScience for Life Laboratory, SciLifeLab
Cancer and Oncology

Search outside of DiVA

GoogleGoogle Scholar
Total: 50 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Total: 237 hits
ReferencesLink to record
Permanent link

Direct link