CD90+ mesothelial-like cells in peritoneal fluid promote peritoneal metastasis by forming a tumor permissive microenvironment.
The peritoneal cavity is a common target of metastatic gastrointestinal and ovarian cancer cells, but the mechanisms leading to peritoneal metastasis have not been fully elucidated. In this study, we examined the roles of cells in peritoneal fluids on the development of peritoneal metastasis. We found that a minor subset of human intraperitoneal cells with CD90(+)/CD45(-) phenotype vigorously grew in culture with mesothelial-like appearance. The mesothelial-like cells (MLC) displayed the characteristics of mesenchymal stem cell, such as differentiating into adipocytes, osteocytes, and chondrocytes, and suppressing T cell proliferation. These cells highly expressed type I collagen, vimentin, α-smooth muscle actin and fibroblast activated protein-α by the stimulation with TGF-β, which is characteristic of activated myofibroblasts. Intraperitoneal co-injection of MLCs with the human gastric cancer cell line, MKN45, significantly enhanced the rate of metastatic formation in the peritoneum of nude mice. Histological examination revealed that many MLCs were engrafted in metastatic nodules and were mainly located at the fibrous area. Dasatinib, a potent tyrosine kinase inhibitor, strongly inhibited the proliferation of MLCs but not MKN45 in vitro. Nevertheless, oral administration of Dasatinib significantly inhibited the development of peritoneal metastasis of MKN45, and resulted in reduced fibrillar formation of metastatic nodules. These results suggest floating MLCs in the peritoneal fluids support the development of peritoneal metastasis possibly through the production of the permissive microenvironment, and thus the functional blockade of MLCs is a reasonable strategy to treat recurrent abdominal malignancies.
Department of Surgical Oncology, University of Tokyo, Tokyo, Japan.
Joji
J
Kitayama
Department of Surgical Oncology, University of Tokyo, Tokyo, Japan.
Shigenobu
S
Emoto
Department of Surgical Oncology, University of Tokyo, Tokyo, Japan.
Hironori
H
Yamaguchi
Department of Surgical Oncology, University of Tokyo, Tokyo, Japan.
Hironori
H
Ishigami
Department of Surgical Oncology, University of Tokyo, Tokyo, Japan.
Toshiaki
T
Watanabe
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D024042:Collagen Type I / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000378:metabolism / Q000473:pathology*; D010537:Peritoneum / Q000378:metabolism / Q000473:pathology*; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology; D018800:Thy-1 Antigens / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000502:physiology*
D024042:Collagen Type I; D018800:Thy-1 Antigens; D016212:Transforming Growth Factor beta