Interaction of platelet-derived autotaxin with tumor integrin aVb3 controls metastasis of breast cancer cells to bone

Raphael Leblanc, Sue Lee, Marion David, Jean Claude Bordet, Derek D. Norman, Renukadevi Patil, Duane Miller, Debashish Sahay, Johnny Ribeiro, Philippe Clézardin, Gabor Tigyi, Olivier Peyruchaud

Research output: Contribution to journalArticle

57 Citations (Scopus)

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, leadingto the productionofLPA. 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 αvβ3-Δ744 or treatment with the anti-human αvβ3 monoclonal antibody LM609, completely abolished binding of ATX to tumor cells, demonstrating the requirement of afully active integrin αvβ3inthisprocess.The present results establishanewmechanism 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.

Original languageEnglish (US)
Pages (from-to)3141-3150
Number of pages10
JournalBlood
Volume124
Issue number20
DOIs
StatePublished - Nov 13 2014

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Platelets
Integrins
Tumors
Bone
Blood Platelets
Cells
Breast Neoplasms
Neoplasm Metastasis
Bone and Bones
Neoplasms
Platelet Activation
Platelet Aggregation
Blood
Agglomeration
Chemical activation
Monoclonal Antibodies
lysophosphatidic acid
Experiments

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Interaction of platelet-derived autotaxin with tumor integrin aVb3 controls metastasis of breast cancer cells to bone. / Leblanc, Raphael; Lee, Sue; David, Marion; Bordet, Jean Claude; Norman, Derek D.; Patil, Renukadevi; Miller, Duane; Sahay, Debashish; Ribeiro, Johnny; Clézardin, Philippe; Tigyi, Gabor; Peyruchaud, Olivier.

In: Blood, Vol. 124, No. 20, 13.11.2014, p. 3141-3150.

Research output: Contribution to journalArticle

Leblanc, R, Lee, S, David, M, Bordet, JC, Norman, DD, Patil, R, Miller, D, Sahay, D, Ribeiro, J, Clézardin, P, Tigyi, G & Peyruchaud, O 2014, 'Interaction of platelet-derived autotaxin with tumor integrin aVb3 controls metastasis of breast cancer cells to bone', Blood, vol. 124, no. 20, pp. 3141-3150. https://doi.org/10.1182/blood-2014-04-568683
Leblanc, Raphael ; Lee, Sue ; David, Marion ; Bordet, Jean Claude ; Norman, Derek D. ; Patil, Renukadevi ; Miller, Duane ; Sahay, Debashish ; Ribeiro, Johnny ; Clézardin, Philippe ; Tigyi, Gabor ; Peyruchaud, Olivier. / Interaction of platelet-derived autotaxin with tumor integrin aVb3 controls metastasis of breast cancer cells to bone. In: Blood. 2014 ; Vol. 124, No. 20. pp. 3141-3150.
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