title: A novel and essential role for FcγRIIa in cancer cell-induced platelet activation.
abstract: Platelets play a role in cancer by acting as a dynamic reservoir of effectors that facilitate tumor vascularization, growth, and metastasis. However, little information is available about the mechanism of tumor cell-induced platelet secretion (TCIPS) or the molecular machinery by which effector molecules are released from platelets. Here we demonstrate that tumor cells directly induce platelet secretion. Preincubation of platelets with human colon cancer (Caco-2), prostate cancer (PC3M-luc), or breast cancer cells (MDA-MB-231;MCF-7) resulted in a marked dose-dependent secretion of dense granules. Importantly, TCIPS preceded aggregation which always displayed a characteristic lag time. We investigated the role of platelet receptors and downstream molecules in TCIPS. The most potent modulators of TCIPS were the pharmacologic antagonists of Syk kinase, phospholipase C and protein kinase C, all downstream mediators of the immunoreceptor tyrosine-based activation motif (ITAM) cascade in platelets. Supporting this, we demonstrated a central role for the immune Fcγ receptor IIa (FcγRIIa) in mediating platelet-tumor cell cross-talk. In conclusion, we demonstrate that cancer cells can promote platelet dense-granule secretion, which is required to augment platelet aggregation. In addition, we show a novel essential role for FcγRIIa in prostate cancer cell-induced platelet activation opening the opportunity to develop novel antimetastatic therapies.
authors.affiliation: Molecular and Cellular Therapeutics Department and.
authors.forename: Annachiara
authors.initials: A
authors.lastname: Mitrugno
authors.forename: David
authors.initials: D
authors.lastname: Williams
authors.forename: Steven W
authors.initials: SW
authors.lastname: Kerrigan
authors.forename: Niamh
authors.initials: N
authors.lastname: Moran
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D045744:Cell Line, Tumor; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015539:Platelet Activation; D010974:Platelet Aggregation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D019038:Platelet Glycoprotein GPIb-IX Complex; D044463:Receptor, PAR-1 / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism*; D058470:Receptors, Purinergic P2Y / Q000378:metabolism; D017482:Receptors, Thromboxane / Q000378:metabolism; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C080568:Fc gamma receptor IIA; D008562:Membrane Glycoproteins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; D044463:Receptor, PAR-1; D017452:Receptors, IgG; D058470:Receptors, Purinergic P2Y; D017482:Receptors, Thromboxane; C094990:adhesion receptor; D019869:Phosphatidylinositol 3-Kinases; D051417:Focal Adhesion Kinase 1; D019061:src-Family Kinases