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.