Platelets – Multifaceted players in tumor progression and vascular function

Zhang, Y. 2016. Platelets – Multifaceted players in tumor progression and vascular function. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1271. 59 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-9739-2. 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 tumorinduced 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 NFkB 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.