Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer.
The role of lysophosphatidic acid (LPA) in cancer is poorly understood. Here we provide evidence for a role of LPA in the progression of breast cancer bone metastases. LPA receptors LPA(1), LPA(2), and LPA(3) were expressed in human primary breast tumors and a series of human breast cancer cell lines. The inducible overexpression of LPA(1) in MDA-BO2 breast cancer cells specifically sensitized these cells to the mitogenic action of LPA in vitro. In vivo, LPA(1) overexpression in MDA-BO2 cells enhanced the growth of subcutaneous tumor xenografts and promoted bone metastasis formation in mice by increasing both skeletal tumor growth and bone destruction. This suggested that endogenous LPA was produced in the tumor microenvironment. However, MDA-BO2 cells or transfectants did not produce LPA. Instead, they induced the release of LPA from activated platelets which, in turn, promoted tumor cell proliferation and the LPA(1)-dependent secretion of IL-6 and IL-8, 2 potent bone resorption stimulators. Moreover, platelet-derived LPA deprivation in mice, achieved by treatment with the platelet antagonist Integrilin, inhibited the progression of bone metastases caused by parental and LPA(1)-overexpressing MDA-BO2 cells and reduced the progression of osteolytic lesions in mice bearing CHO-beta3wt ovarian cancer cells. Overall, our data suggest that, at the bone metastatic site, tumor cells stimulate the production of LPA from activated platelets, which enhances both tumor growth and cytokine-mediated bone destruction.
Boucharaba
Ahmed
A
INSERM, U403, 69372 Lyon Cedex 08, France.
Serre
Claire-Marie
CM
Grès
Sandra
S
Saulnier-Blache
Jean Sébastien
JS
Bordet
Jean-Claude
JC
Guglielmi
Julien
J
Clézardin
Philippe
P
Peyruchaud
Olivier
O
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D001859:Bone Neoplasms / Q000473:pathology / Q000556:secondary; D001862:Bone Resorption; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006224:Cricetinae; D003470:Culture Media / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008934:Mitogens / Q000378:metabolism; D008954:Models, Biological; D009362:Neoplasm Metastasis; D010010:Osteoclasts / Q000378:metabolism; D010014:Osteolysis; D010739:Phospholipase D / Q000378:metabolism; D015539:Platelet Activation; D010974:Platelet Aggregation; D012313:RNA / Q000737:chemistry / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection
D003470:Culture Media; D016207:Cytokines; D015850:Interleukin-6; D016209:Interleukin-8; D019394:Ki-67 Antigen; D008246:Lysophospholipids; D008934:Mitogens; D012313:RNA; D010739:Phospholipase D; D004318:Doxycycline; C032881:lysophosphatidic acid