Interaction of platelet-derived autotaxin with tumor integrin alphaVbeta3 controls metastasis of breast cancer cells to bone

Leblanc, R. and Lee, S. C. and David, M. and Bordet, J. C. and Norman, D. D. and Tigyi, Gábor (2014) Interaction of platelet-derived autotaxin with tumor integrin alphaVbeta3 controls metastasis of breast cancer cells to bone. BLOOD, 124 (20). pp. 3141-3150. ISSN 0006-4971

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Abstract

Autotaxin (ATX) through its lysophospholipase D activity controls physiological levels of lysophosphatidic acid (LPA) in blood. ATX is overexpressed in multiple types of cancers and together with LPA generated during platelet activation promotes skeletal metastasis of breast cancer. However, the pathophysiological sequelae of regulated interactions between circulating LPA, ATX, and platelets remain undefined in cancer. Here we show that ATX is stored in alpha-granules of resting human platelets and released upon tumor cell-induced platelet aggregation, leading to the production of LPA. Our in vitro and in vivo experiments using human breast cancer cells that do not express ATX (MDA-MB-231, MDA-B02) demonstrate that non-tumoral ATX controls the early stage of bone colonization by tumor cells. Moreover, expression of a dominant negative integrin alphaVbeta3-Delta744 or treatment with the anti human alphaVbeta3 monoclonal antibody LM609 completely abolished binding of ATX to tumor cells, demonstrating the requirement of a fully active integrin alphaVbeta3 in this process. The present results establish a new mechanism for platelet contribution to LPA-dependent metastasis of breast cancer cells and demonstrate the therapeutic potential of disrupting the binding of non-tumor-derived ATX with the tumor cells for the prevention of metastasis.

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