Abstract 159: CD90(+) intraperitoneal mesothelial-like cells (MLC) promote peritoneal metastasis by forming a tumor permissive microenvironment

Abstract

Abstract Background: Peritoneal cavity is a common metastatic site of gastrointestinal as well as ovarian cancer, but the mechanisms to develop peritoneal metastasis has not been fully elucidated. Method: Peritoneal fluids were obtained in patients with liver cirrhosis or gastrointestinal cancer, and cells were cultured on collagen-coated plate and their characteristics were functionally analyzed both in vitro and in vivo. Results: We found that CD90(+)CD45(-) cells exist as a minor population (0.01∼6.81%) in human peritoneal fluids. However, those cells vigorously grew in culture on type I collagen-coated plate, showing the morphology of mesothelial cells, and names as mesothelial-like cells (MLC). The cultured MLC, when injected into the abdominal cavity of nude mice whose peritoneum was scratched by mechanical scraping, were incorporated into the damaged peritoneum. Interestingly, the MLC possessed the potential to differentiate into adipocytes, osteocytes, and chondrocytes in appropriate culture conditions. Moreover, the MLC markedly suppressed T cell proliferation stimulated with coated anti-CD3 mAb. Those findings are identical to the characteristics reported for mesenchymal stem cells (MSC). Moreover, by the stimulation of TGF-β, the MLC highly expressed type I collagen, vimentin, α-smooth muscle actin (SMA) and Fibroblast activated protein (FAP)-α, which are characteristics of activated myofibroblasts. From these facts, MLC with CD45(-)CD90(+) phenotype are supposed to be a intraperitoneal MSC. Then, we examined the possible role of the MLC on the development of peritoneal metastasis. Intraperitoneal co-injection of PKH26 stained MLC with human gastric cancer cell line, MKN45, significantly enhanced the rate of metastatic formation on peritoneum in nude mice. Histological examination revealed that many MLC are engrafted in metastatic nodules and they were mainly located at fibrous area in peritoneal nodules. Immunostaining showed that the MLC in peritoneal nodules are positive for type I collagen. Finally, Dasatinib, a potent tyrosine kinase inhibitor, strongly inhibited the in vitro proliferation of MLC, but had no effects on MKN45. However, oral administration of Dasatinib significantly inhibited the development of peritoneal metastasis of MKN45, and the tumor nodules developed in Dasatinib-treated mice showed significantly less fibrous components. Conclusion: These facts strongly suggests that intraperitoneal free floating MLC play a positive role on the development of peritoneal metastasis, possibly though the production of tumor permissive microenvironment and thus the functional blockade of MLC can be a reasonable strategy to treat peritoneal recurrences in abdominal malignancy. Citation Format: Joji Kitayama, Shiegenobu Emoto, Hironori Yamaguchi, Hironori Ishigami, Toshiaki Watanabe. CD90(+) intraperitoneal mesothelial-like cells (MLC) promote peritoneal metastasis by forming a tumor permissive microenvironment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 159. doi:10.1158/1538-7445.AM2014-159