Interaction of platelet-derived autotaxin with tumor integrin αVß3 controls metastasis of breast cancer cells to bone.
Blood
; 124(20): 3141-50, 2014 Nov 13.
Article
en En
| MEDLINE
| ID: mdl-25277122
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 α-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 αvß3-Δ744 or treatment with the anti-human αvß3 monoclonal antibody LM609, completely abolished binding of ATX to tumor cells, demonstrating the requirement of a fully active integrin αvß3 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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Plaquetas
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Neoplasias Óseas
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Neoplasias de la Mama
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Hidrolasas Diéster Fosfóricas
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Integrina alfaVbeta3
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Blood
Año:
2014
Tipo del documento:
Article