Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer
Ahmed Boucharaba, … , Philippe Clézardin, Olivier Peyruchaud
Ahmed Boucharaba, … , Philippe Clézardin, Olivier Peyruchaud
Published December 15, 2004
Citation Information: J Clin Invest. 2004;114(12):1714-1725. https://doi.org/10.1172/JCI22123.
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Article Oncology

Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer

Abstract

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 LPA1, LPA2, and LPA3 were expressed in human primary breast tumors and a series of human breast cancer cell lines. The inducible overexpression of LPA1 in MDA-BO2 breast cancer cells specifically sensitized these cells to the mitogenic action of LPA in vitro. In vivo, LPA1 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 LPA1-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 LPA1-overexpressing MDA-BO2 cells and reduced the progression of osteolytic lesions in mice bearing CHO-β3wt 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.

Authors

Ahmed Boucharaba, Claire-Marie Serre, Sandra Grès, Jean Sébastien Saulnier-Blache, Jean-Claude Bordet, Julien Guglielmi, Philippe Clézardin, Olivier Peyruchaud

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Effect of LPA1 overexpression in MDA-BO2 cells on osteolytic lesions and...
Effect of LPA1 overexpression in MDA-BO2 cells on osteolytic lesions and on skeletal and subcutaneous tumor growth. (A) Animals fed without or with doxycycline were inoculated intravenously with MDA-BO2 or clone no. 3 cells. (Upper panels) Representative radiographs of hind limbs from mice bearing MDA-BO2 or clone no. 3 cells 30 days after tumor cell inoculation. In the absence of doxycycline, there was a marked increase in the extent of osteolytic lesions (arrows) in mice bearing clone no. 3 cells. (Lower panels) Representative bone histology of Goldner’s trichrome–stained tibial metaphysis from metastatic animals. Bone is stained in green; bone marrow and tumor cells are stained red. Trabecular bone was completely destroyed and replaced by tumor cells (T) in tibial metaphysis from untreated animals bearing clone no. 3 cells. Scale bar: 1 mm. (B) Animals fed without (open symbols) or with (filled symbols) doxycycline were inoculated subcutaneously into the flank with MDA-BO2 (triangles), clone no. 3 (circles), or clone no. 79 (squares) cells. Tumors were measured at the indicated time points. V (in mm3) is expressed as the mean ± SD of 9 animals per group. P < 0.05; **P < 0.005 doxycycline-free versus doxycycline-fed tumor-bearing animals. (C) Subcutaneous (upper panels) and skeletal (lower panels) tumor tissue sections immunostained with an antibody against the nuclear Ki-67 antigen. The mitotic index (numbers on each panel) was calculated as the percentage of nuclei positive for Ki-67. Results are the mean ± SD of 6 independent tumor sections. #P < 0.0001 doxycycline-free versus doxycycline-fed tumor-bearing animals. Scale bars: 100 μm.