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- W4362524703 abstract "Abstract Diffuse-type gastric carcinoma is characterized by highly invasive growth, massive fibrosis, and peritoneal metastasis. Peritoneal metastasis is the leading cause of death in diffuse-type gastric carcinoma; however, the underlying molecular mechanisms remain largely unknown. Recent studies have established a concept of polyclonal metastasis, in which metastases arise from circulating tumor cell clusters with high metastatic potential. Polyclonal metastasis is a cause of tumor heterogeneity that contributes to tumor progression and therapeutic resistance. However, the clonality of peritoneally metastasized tumors and the evidence for polyclonal metastasis in diffuse-type gastric carcinoma have been poorly elucidated. In this study, we utilized multicolor fluorescent lineage tracking to examine the clonality of peritoneal metastasis in mouse xenograft models. When peritoneal metastasis was induced by intraperitoneal or orthotopic injection of multicolored cancer cells, each peritoneally metastasized tumor exhibited multicolor fluorescence, showing that it contains multiclonal cancer cell populations. Peritoneal cytology and in situ fluorescent imaging of micrometastases revealed that multicolored cancer cell clusters formed within the peritoneal cavity and collectively attached to the peritoneum. In vitro, peritoneal lavage fluid or cleared ascitic fluid derived from cancer patients elicited cancer cell clustering, which was inhibited by anticoagulants. Immunofluorescence and immunoblotting revealed that cancer cell clusters formed in vitro and in vivo were associated with fibrin formation. Moreover, tissue factor knockout in cancer cells significantly reduced fibrin formation, cell clustering, peritoneal attachment, and peritoneal metastasis. In an in vitro adhesion assay, fibrin formation facilitated the cancer cell-mesothelial cell adhesion. Thus, these results demonstrate that cancer cells activate the coagulation cascade through tissue factor to form fibrin-mediated cell clusters and accelerate peritoneal attachment, leading to the development of polyclonal peritoneal metastasis. Our findings identify a novel mechanism of peritoneal metastasis that may be a potential therapeutic target. Citation Format: Makoto Miyazaki, Yuko Nagamura, Hideki Yamaguchi. Tissue factor-induced fibrinogenesis and cancer cell clustering contribute to polyclonal peritoneal metastasis in diffuse-type gastric carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2473." @default.
- W4362524703 created "2023-04-06" @default.
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- W4362524703 date "2023-04-04" @default.
- W4362524703 modified "2023-09-25" @default.
- W4362524703 title "Abstract 2473: Tissue factor-induced fibrinogenesis and cancer cell clustering contribute to polyclonal peritoneal metastasis in diffuse-type gastric carcinoma" @default.
- W4362524703 doi "https://doi.org/10.1158/1538-7445.am2023-2473" @default.
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