title: HRG regulates tumor progression, epithelial to mesenchymal transition and metastasis via platelet-induced signaling in the pre-tumorigenic microenvironment.
abstract: 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 PDGFRβ. 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.
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala Biomedical Center, Uppsala University, Husargatan 3, 751 23, Uppsala, Sweden.
authors.forename: Jessica
authors.initials: J
authors.lastname: Cedervall
authors.forename: Yanyu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Maria
authors.initials: M
authors.lastname: Ringvall
authors.forename: Asa
authors.initials: A
authors.lastname: Thulin
authors.forename: Aristidis
authors.initials: A
authors.lastname: Moustakas
authors.forename: Willi
authors.initials: W
authors.lastname: Jahnen-Dechent
authors.forename: Agneta
authors.initials: A
authors.lastname: Siegbahn
authors.forename: Anna-Karin
authors.initials: AK
authors.lastname: Olsson
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D002277:Carcinoma / Q000098:blood supply* / Q000235:genetics / Q000503:physiopathology / Q000556:secondary; D002471:Cell Transformation, Neoplastic; D060833:Cellular Microenvironment; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D007340:Insulinoma / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D007515:Islets of Langerhans / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis / Q000235:genetics / Q000503:physiopathology*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000503:physiopathology*; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D000099053:Histidine-Rich Glycoprotein
chemical_list: D011506:Proteins; D025521:Tumor Suppressor Proteins; D000099053:Histidine-Rich Glycoprotein; C498588:Tbk1 protein, mouse; D020797:Receptor, Platelet-Derived Growth Factor beta; C494922:Akt2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt