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Interaction of platelet-derived autotaxin with tumor integrin ?V?3 controls metastasis of breast cancer cells to bone.


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. In this study, we show that ATX is stored in ?-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 and MDA-B02) demonstrate that nontumoral ATX controls the early stage of bone colonization by tumor cells. Moreover, expression of a dominant negative integrin ?v?3-?744 or treatment with the anti-human ?v?3 monoclonal antibody LM609, completely abolished binding of ATX to tumor cells, demonstrating the requirement of a fully active integrin ?v?3 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 nontumor-derived ATX with the tumor cells for the prevention of metastasis.

SUBMITTER: Leblanc R 

PROVIDER: S-EPMC4231421 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Interaction of platelet-derived autotaxin with tumor integrin αVβ3 controls metastasis of breast cancer cells to bone.

Leblanc Raphael R   Lee Sue-Chin SC   David Marion M   Bordet Jean-Claude JC   Norman Derek D DD   Patil Renukadevi R   Miller Duane D   Sahay Debashish D   Ribeiro Johnny J   Clézardin Philippe P   Tigyi Gabor J GJ   Peyruchaud Olivier O  

Blood 20141002 20


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. In this study, we show that ATX is stored in α-granules of resting human pl  ...[more]

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