title: Activation of tumour cell ECM degradation by thrombin-activated platelet membranes: potentially a P-selectin and GPIIb/IIIa-dependent process.
abstract: The promotion of tumour metastasis by platelets may occur through several mechanisms including the induction of a more metastatic phenotype in tumour cells and assisted extravasation of circulating tumour cells. Whilst the mechanisms underlying platelet-assisted extravasation have been extensively studied, much less attention has been paid to the mechanisms underlying platelet promotion of an aggressive phenotype within a tumour cell population. Herein, we demonstrate in vitro that MDA-MB-231 breast carcinoma cells incubated with washed thrombin-activated platelet membranes adopt a Matrigel-degrading phenotype in a dose- and contact time-dependent manner. The same phenotypic change was observed with three other human tumour cell lines of diverse anatomical origin. Moreover, tumour cell lines that had been cultured with washed thrombin-activated platelet membranes had a greater metastatic capacity when injected into mice. This in vivo effect was reliant upon a co-incubation period of >2 h implying a mechanism involving more than platelet membrane binding that occurred within 5 min. Upon further investigation it was found that simultaneous blocking of the platelet-membrane proteins P-selectin and GPIIb/IIIa prevented interactions between platelet membranes and MDA-MB-231 cells but also significantly reduced the ability of tumour cells to degrade Matrigel. These results confirm that platelets induce a more aggressive phenotype in tumour cells but also identify the platelet proteins involved in this effect. P-selectin and GPIIb/IIIa also play a role in assisting tumour cell extravasation and, thus, are ideal targets for the therapeutic intervention of both stages of platelet-assisted metastasis.
authors.affiliation: Cancer & Vascular Biology Group, The John Curtin School of Medical Research, The Australian National University, Building 131, Garran Rd, Acton, Canberra, ACT, 2601, Australia.
authors.forename: J H
authors.initials: JH
authors.lastname: Pang
authors.forename: L A
authors.initials: LA
authors.lastname: Coupland
authors.forename: C
authors.initials: C
authors.lastname: Freeman
authors.forename: B H
authors.initials: BH
authors.lastname: Chong
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Parish
mesh_terms: D000818:Animals; D017209:Apoptosis; D001792:Blood Platelets / Q000187:drug effects / Q000473:pathology*; D002448:Cell Adhesion; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005434:Flow Cytometry; D006490:Hemostatics / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D019007:P-Selectin / Q000378:metabolism*; D015539:Platelet Activation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D013917:Thrombin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D006490:Hemostatics; D019007:P-Selectin; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013917:Thrombin