Microvesicles Derived from Activated Platelets Enhance the Invasive Potential of Breast Cancer Cells.

Abstract

There is increasing evidence that platelets contribute to cancer metastasis, and yet platelet concentrates are frequently transfused to cancer patients to treat thrombocytopenia after chemotherapy. Recently we reported that microvesicles derived from activated platelets (PMV) transfer various surface receptors/adhesion molecules to normal and malignant target cells and modulate their biological responses (Blood 2001; 98:3143; Exp Hematol 2002; 30:450). In this work, we hypothesized that the interaction of PMV with cancer cells increases their invasive and metastatic potential. PMV were isolated from outdated platelet concentrates and pre-incubated with human breast cancer cell lines (MDA-MB-231, BT-549 and T47D), and the effect of PMV on the invasive/metastatic potential of these cancer cells was evaluated. We determined (i) the transfer of the platelet-derived antigen CD41 to cancer cells and the adhesion of these cells to human umbilical vein endothelial cells (HUVEC), (ii) the expression of matrix metalloproteinases (MMPs) by breast cancer cells and their ability to cross the reconstituted basement membrane Matrigel, (iii) the expression of CXCR4, the cognate receptor of the a-chemokine SDF-1, produced in bone marrow, in these cell lines after incubation with PMV, and (iv) the effects of PMV on the interactions of the tumor cells with stroma. We found that PMV transfer platelet-derived CD41 integrin to the surface of breast cancer cells and promote their adhesion to HUVEC. Preincubation with PMV upregulates the mRNA for MMP-9 and protein secretion in invasive breast cancer cells (MDA-MB-231 and BT-549) and enhances their trans-Matrigel chemoinvasion. PMV also transfer CXCR4 to the surface of the breast cancer cells and stimulate the trans-Matrigel migration of MDA-MB-231 cells towards SDF-1, which was abrogated by AMD3100, a CXCR4 antagonist. Finally we found that PMV increase activation of the latent form of MMP-2 constitutively secreted by fibroblastic cells in co-cultures of tumor cells with bone marrow stroma. Thus, we conclude that PMV may enhance the invasive and metastatic potential of breast cancer cells. Because concentrations of PMV are known to be higher in old platelet concentrates than in fresh ones, we recommend that cancer patients should preferably be transfused with fresh platelet concentrates only.