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

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A 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. Methods 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. Results 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. Conclusions 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.

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Publié le 01 janvier 2012
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Watanabe et al . Journal of Ovarian Research 2012, 5 :7 http://www.ovarianresearch.com/content/5/1/7
R E S E A R C H Open Access Production of IL1-beta by ovarian cancer cells induces mesothelial cell beta1-integrin expression facilitating peritoneal dissemination Takafumi Watanabe 1* , Toshihiro Hashimoto 2 , Takashi Sugino 3 , Shu Soeda 1 , Hiroshi Nishiyama 1 , Yutaka Morimura 2 , Hidekazu Yamada 1 , Steve Goodison 4* and Keiya Fujimori 1
Abstract Background: A 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. Methods: 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. Results: 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-1 b and enhanced by recombinant IL-1 b ( p < 0.01). IL-1 b induced mesothelial cell b 1-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-1 b expression was significantly associated with an improved overall survival rate. Conclusions: These results suggest that a IL-1 b / b 1-integrin axis plays a role in ovarian tumor cell adhesion to mesothelia, a crucial step in ovarian cancer dissemination. Keywords: ovarian cancer, peritoneal dissemination, IL-1 β , β 1 integrin, mesothelial cell
Background they can implant on to the mesothelium that covers the Ovarian cancer (OC) is the most lethal gynecologic omentum and bowel surface [3]. In order for the tumor malignancy in industrialized countries. The overall 5- cells to establish secondary foci and invade the underly-year survival rate of ovarian cancer patients is 30% to ing stroma, they need to adhere to and interact with the 50%, largely due to the fact that the majority of these peritoneal mesothelial cells. This is a crucial step in OC patients are diagnosed at an advanced stage (III or IV) progression and is a possible target for chemotherapeu-of disease at initial diagnosis [1]. Substantial advances in tic intervention, yet few studies have focused on this the treatment of primary OC have occurred, but patient interaction. Identifying crucial factors involved in the morbidity and mortality remain high due to metastatic crosstalk between the tumor cells and the mesothelial dissemination [2]. Ovarian tumor cells primarily disse- microenvironment will not only improve our under-minate by shedding into the peritoneal cavity where standing of the disease but will ultimately enable us to provide better patient care. * 1 Correspondence: t-wata@fmu.ac.jp; steven.goodison@orlandohealth.com Details of the mechanisms involved in OC cell adher-SDchepoaorltomfeMntedoifciOneb,stFeutkriucsshianmda,GJaypnaencology,FukushimaMedicalUniversity ence to mesothelium are unclear, but the dynamics of 4 Cancer Research Institute, M. D. Anderson Cancer Center Orlando, Orlando, this interaction appear to be relatively rapid, in the FFLu,llUliSstAofahrinformationisavailableattheendofthearticle order of minutes [4,5]. Potent ial molecular interactions ut o © 2012 Watanabe et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.