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

Abstract

BackgroundA crucial step in the metastatic spread of ovarian cancer (OC) is the adhesion and implantation of tumor cells to the peritoneal mesothelium. In order to study this step in the cascade, we derived a pro-metastatic human ovarian carcinoma cell line (MFOC3) from the non-metastatic FOC3 line.MethodsMolecular 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.ResultsAfter 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.ConclusionsThese 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.

ASSOCIATION BETWEEN GROWTH FACTOR HEREGULIN -1^|^alpha; AND RECEPTORS IN GROWTH OF OVARIAN CANCER CELL LINE WITH HIGH POTENTIALITY OF PERITONEAL DISSEMINATION

“…Clarification of the molecular -level mechanism of the formation of peritoneal dissemination, including the intracellular or intermolecular signal transduction mechanism is crucially important in the diagnosis, treatment, and management of ovarian cancer 4,5) . In this study, we compared FOC -3 cell line (low potentiality of peritoneal dissemination) and MFOC -3 cell line (high potentiality of peritoneal dissemination) for HRG mRNA expression and protein expression of HRG -1α and related receptors HER -2, HER -3, and HER -4.…”

“…In order to improve the prognosis for ovarian cancer, we believe that it is necessary to elucidate the mechanism of the formation of peritoneal dissemination. Our research group has already succeeded in the establishment of cell lines with the high potentiality of peritoneal dissemination (MFOC -3) using cell line without the potential of peritoneal dissemination derived from human ovarian serous adenocarcinoma (FOC -3) in the peritoneal cavity of mice 4) . Heregulin (HRG) may play an essential role in neurogenesis and cardiogenesis during the fetal stage.…”

Changes in the coelomic microclimate during carbon dioxide laparoscopy: morphological and functional implications

“…Initial adhesion of tumour cells when introduced to the mesothelial surface is rapid, with binding to ECM proteins collagens type I and IV, laminin, fibronectin via integrins, and hyaluronan expressed on the surface of human peritoneal mesothelial cells via CD44 [73,74]. Adhesion of tumour cells is increased by peritoneal injury during open surgery [71] or by cold/dry CO 2 -pneumoperitoneum during laparoscopy [5,18,73]. Peritoneal acidosis and CO 2 insufflation results in local production of IL-1β, IL-6 and TNFα [11,14].…”

“…Watanabe (2012) demonstrated that the behaviour of pro-metastatic (MFOC3) vs. non metastatic ovarian cancer cells (FOC3) were related to upregulated genomic expression of cell adhesion molecules (ADAM9, ITGA8, CTNNβ1 (Catenin, β1), fibrinolytic mediators (PAI2, uPA), cytokines (IL-1β,TNF), apoptosis inhibitors (API -1 and -2), growth factors (TGFβ1, NRG, FGF-1), ITGA (integrin α), LAMβ1 (Laminin, β1) and SDC1 (Syndecan 1) [73]. IL-1β expression was increased by 11.1 fold and PAI2 by 25.6 fold in the pro-metastatic ovarian cells compared to the non-metastasizing variant.…”

“…This may favour the adhesion and proliferation of epithelial malignancies such as colonic, ovarian, pancreatic and gastric carcinoma [18,73]. Initial adhesion of tumour cells when introduced to the mesothelial surface is rapid, with binding to ECM proteins collagens type I and IV, laminin, fibronectin via integrins, and hyaluronan expressed on the surface of human peritoneal mesothelial cells via CD44 [73,74]. Adhesion of tumour cells is increased by peritoneal injury during open surgery [71] or by cold/dry CO 2 -pneumoperitoneum during laparoscopy [5,18,73].…”