Macrophages are primed to transdifferentiate into fibroblasts in malignant ascites and pleural effusions

Mamoru Ito, Michitaka Nakano, Hiroshi Ariyama, Kyoko Yamaguchi, Risa Tanaka, Yuichiro Semba, Takeshi Sugio, Kohta Miyawaki, Yoshikane Kikushige, Shinichi Mizuno, Taichi Isobe, Kenro Tanoue, Ryosuke Taguchi, Shohei Ueno, Takahito Kawano, Masaharu Murata, Eishi Baba, Koichi Akashi

研究成果: ジャーナルへの寄稿学術誌査読

抄録

Cancer-associated fibroblasts (CAFs) play an important role in cancer progression. However, the origin of CAFs remains unclear. This study shows that macrophages in malignant ascites and pleural effusions (cavity fluid-associated macrophages: CAMs) transdifferentiate into fibroblast-like cells. CAMs obtained from gastrointestinal cancer patients were sorted by flow cytometry and cultured in vitro. CD45 +CD14 + CAMs transdifferentiated into CD45 -CD90 + fibroblast-like cells that exhibited spindle shapes. Then, cDNA microarray analysis showed that the CD45 -CD90 + fibroblast-like cells (macrophage-derived CAFs: MDCAFs) had a fibroblast-specific gene expression signature and produced growth factors for epithelial cell proliferation. Human colon cancer cells transplanted into immunodeficient mice with MDCAFs formed larger tumors than cancer cells alone. Gene ontology analyses showed the involvement of TGFβ signaling and cell-matrix adhesion in MDCAFs, and transdifferentiation of CAMs into MDCAFs was canceled by inhibiting TGFβ and cell adhesion. Furthermore, the acquired genetic alterations in hematopoietic stem cells (HSCs) were shared in CAMs and MDCAFs. Taken together, CAMs could be a source of CAFs and might originate from HSCs. We propose the transdifferentiation process of CAMs into MDCAFs as a new therapeutic target for fibrosis associated with gastrointestinal cancer.

本文言語英語
ページ(範囲)215597
ジャーナルCancer Letters
532
DOI
出版ステータス印刷前の電子出版 - 2月 10 2022

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