title: Release of angiogenesis regulatory proteins from platelet alpha granules: modulation of physiologic and pathologic angiogenesis.
abstract: An association between platelets, angiogenesis, and cancer has long been recognized, but the mechanisms linking them remains unclear. Platelets regulate new blood vessel growth through numerous stimulators and inhibitors of angiogenesis by several pathways, including differential exocytosis of angiogenesis regulators. Herein, we investigated the differential release of angiogenesis stimulators and inhibitors from platelets. Activation of human platelets with adenosine diphosphate (ADP) stimulated the release of VEGF, but not endostatin whereas, thromboxane A(2) (TXA(2)) released endostatin but not VEGF. Platelet releasates generated by activation with ADP promoted migration and formation of capillary structures by human umbilical vein endothelial cells (HUV-EC-Cs) in in vitro angiogenesis models. Conversely, TXA(2)-stimulated platelet releasate inhibited migration and formation of capillary structures. Because tumor growth beyond 1-2 mm(3) is angiogenesis-dependent, we hypothesized that cancer cells preferentially stimulate platelets to secrete their pro-angiogenic payload. In support of this, the breast cancer cell line MCF-7 stimulated secretion of VEGF and a pro-angiogenic releasate from platelets. Furthermore, the antiplatelet agent aspirin inhibited platelet-mediated angiogenesis after exposure to ADP or MCF-7 cells providing a potential mechanism for how aspirin may impact malignancy. Manipulation of differentially mediated release of angiogenic factors from platelets may provide a new modality for cancer treatment.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. ebattinelli@partners.org
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Battinelli
authors.forename: Beth A
authors.initials: BA
authors.lastname: Markens
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Italiano
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D043924:Angiogenesis Modulating Agents / Q000378:metabolism* / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism*; D001943:Breast Neoplasms / Q000473:pathology; D002277:Carcinoma / Q000473:pathology; D002478:Cells, Cultured; D043169:Endostatins / Q000378:metabolism / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D005260:Female; D006801:Humans; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000517:prevention & control; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D022142:Secretory Vesicles / Q000187:drug effects / Q000378:metabolism*; D013928:Thromboxane A2 / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000494:pharmacology
chemical_list: D043924:Angiogenesis Modulating Agents; D043169:Endostatins; D042461:Vascular Endothelial Growth Factor A; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; D001241:Aspirin