Production of IL1-beta by ovarian cancer cells induces mesothelial cell beta1-integrin expression facilitating peritoneal dissemination

Molecular profiling of the isogeneic lines identified differentially expressed genes, and investigation for a role in dissemination for specific factors was achieved by development of a co-culture adhesion assay utilizing monolayers of human mesothelial cells.After murine intraperitoneal inoculation, the FOC3 cell line formed no metastases, but the MFOC3 subline formed metastases in > 80% of SCID mice. MFOC3 cells also adhered 2-3 times more avidly to mesothelial monolayers. This adhesion was inhibited by neutralizing antibodies to IL-1β and enhanced by recombinant IL-1β (p < 0.01). IL-1β induced mesothelial cell β1-integrin, and an antibody to this subunit also inhibited the adhesion of MFOC3 to mesothelial cells in vitro and significantly reduced metastases in vivo. Immunohistochemical analysis of a cohort of 96 ovarian cancer cases showed that negative IL-1β expression was significantly associated with an improved overall survival rate.These results suggest that a IL-1β/β1-integrin axis plays a role in ovarian tumor cell adhesion to mesothelia, a crucial step in ovarian cancer dissemination.Ovarian cancer (OC) is the most lethal gynecologic malignancy in industrialized countries. The overall 5-year survival rate of ovarian cancer patients is 30% to 50%, largely due to the fact that the majority of these patients are diagnosed at an advanced stage (III or IV) of disease at initial diagnosis [1]. Substantial advances in the treatment of primary OC have occurred, but patient morbidity and mortality remain high due to metastatic dissemination [2]. Ovarian tumor cells primarily disseminate by shedding into the peritoneal cavity where they can implant on to the mesothelium that covers the omentum and bowel surface [3]. In order for the tumor cells to establish secondary foci and invade the underlying stroma, they need to adhere to and interact with the peritoneal mesothelial cells. This is a crucial step in OC progression and is a possible target for chemotherapeutic i