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Multiple Actions of the Chemokine CXCL12 on Epithelial Tumor Cells in Human Ovarian Cancer

Cancer Research U.K., Translational Oncology Laboratory, Bart’s and the London, Queen Mary’s School of Medicine and Dentistry, London EC1M 6BQ, United Kingdom [C. J. S., J. L. W., K. S., G. D. W., F. R. B.]; Department of Histopathology, Division of Investigative Sciences, Imperial College Faculty of Medicine, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, United Kingdom [G. S.]; Departments of Obstetrics and Gynaecology and Pathology, University of South Florida, Tampa, Florida 33606 [G. D. W.]; and AnorMED, Inc., Langley, British Columbia, V2Y 1N5, Canada [S. F., G. B.]

Of 14 chemokine receptors investigated, only CXCR4 was expressed on ovarian cancer cells [C. J. Scotton et al., Cancer Res., 61: 4961–4965, 2001]. To further understand the role of this chemokine receptor in ovarian tumor biology, we studied the action of its ligand, CXCL12 (stromal cell-derived factor 1), on the CXCR4-expressing ovarian cancer cell lines IGROV. Ligand stimulation of the CXCR4 receptor resulted in sustained activation of Akt/protein kinase B and biphasic phosphorylation of p44/42 mitogen-activated protein kinase in IGROV. When IGROV cells were cultured under suboptimal conditions, CXCL12 stimulated their in vitro growth, an effect that was abrogated by neutralizing antibodies to CXCR4. This increase in cell number was attributable to stimulation of DNA synthesis, not protection from apoptosis. CXCL12 treatment of IGROV cells also induced mRNA and protein for tumor necrosis factor , a cytokine that is expressed by tumor cells in ovarian cancer biopsies. IGROV cells invaded through Matrigel toward a CXCL12 gradient. Invasion was abrogated by the broad spectrum matrix metalloproteinase and TNF converting enzyme inhibitor Marimastat and was partially inhibited by neutralizing antitumor necrosis factor antibodies. These effects were not limited to the IGROV cell line. They could also be demonstrated in the CAOV-3 ovarian cancer cell line and primary ovarian tumor cells isolated from ovarian ascites. These biological effects of CXCL12 on IGROV cells were also inhibited by the small molecular weight CXCR4 antagonist AMD3100. Finally, we found abundant intracellular CXCL12 protein in tumor cells in 15 of 18 ovarian cancer biopsies but not in epithelial cells from normal ovary or borderline disease. The chemokine CXCL12 may have multiple biological effects in ovarian cancer, stimulating cell migration and invasion through extracellular matrix, as well as DNA synthesis and establishment of a cytokine network in situations that are suboptimal for tumor cell growth.

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