Abstract
Ovarian cancer is characterized by metastases to the peritoneal surface lining the abdominal cavity. It remains unclear which factors promote the implantation of ovarian cancer cells onto the peritoneal lining. We have recently investigated interactions between ovarian cancer cells (OVCAR-5, OVCAR-3, and SKOV-3) and mesothelial cells isolated from omental tissues (LP-9). We conducted a proteomic screen of the conditioned medium of co-cultures of ovarian cancer and mesothelial cells. One of the molecules identified to be modulated is the extracellular matrix adhesion protein, transforming growth factor-beta-induced protein (TGFβI, also known as b ig-H3 or keratoepithelin) which is induced by transforming growth factor-beta in many cell types which has been shown to promote adhesion and migration of hepatoma and astrocytoma cells and enhance colon cancer cell extravasation. In this study we investigated the expression of TGFβI in ovarian cancer tissues and the effects of recombinant TGFβI on ovarian cancer motility and adhesion to peritoneal mesothelial cells. In functional assays, treatment with recombinant TGFβI significantly increased adhesion of all three ovarian cancer cell lines to LP-9 mesothelial cells by up to 25% (P<0.01) and increased motility in OVCAR-5 cells by 62% (P<0.001). Furthermore, addition of a neutralising TGFβI antibody reduced OVCAR-5 adhesion to LP-9 to 79% of control level (P<0.001). TGFβI produced by LP-9 cells was processed to smaller forms when co-cultured with ovarian cancer cell lines by western blotting. MALDI-TOF/TOF mass spectrometry identified TGFβI processing at both the N and C terminal domains. The addition of broad spectrum protease inhibitors blocked the TGFβI processing and reduced OVCAR-5 adhesion to LP-9 cells to 60% of control level (P<0.001). We conclude that although some ovarian cancer cells produce low levels of TGFβI, TGFβI abundantly expressed by peritoneal mesothelial cells can promote ovarian cancer cell adhesion and motility.
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