Macrophages are primed to transdifferentiate into fibroblasts in malignant ascites and pleural effusions
Macrophages are primed to transdifferentiate into fibroblasts in malignant ascites and pleural effusions
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DOI：
10.1016/j.canlet.2022.215597
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发表时间：
2022-02-15
期刊：
影响因子：
9.7
通讯作者：
Akashi, Koichi
中科院分区：
文献类型：
--
作者：
Ito, Mamoru;Nakano, Michitaka;Akashi, Koichi
癌症相关成纤维细胞（CAF）在癌症进展中起重要作用。然而，CAF的起源仍然不清楚。本研究表明，恶性腹水和胸腔积液中的巨噬细胞（腔液相关巨噬细胞：CAM）转分化为成纤维细胞样细胞。采用流式细胞术分选胃肠道肿瘤患者的CAM，并进行体外培养。CD 45（+）CD 14（+）CAMs转分化为CD 45（-）CD 90（+）成纤维细胞样细胞，呈梭形。然后，cDNA微阵列分析显示，CD 45（-）CD 90（+）成纤维细胞样细胞（巨噬细胞衍生的CAFs：MDCAFs）具有成纤维细胞特异性基因表达特征，并产生上皮细胞增殖的生长因子。将人结肠癌细胞移植到具有MDCAFs的免疫缺陷小鼠中形成的肿瘤比单独的癌细胞更大。基因本体分析表明，TGF β信号转导和细胞-基质粘附参与MDCAFs，并通过抑制TGF β和细胞粘附来取消CAM向MDCAFs的转分化。此外，造血干细胞（HSC）中的获得性遗传改变在CAM和MDCAFs中是共享的。总的来说，CAMs可能是CAF的来源，并且可能起源于HSC。我们提出CAMs转分化为MDCAFs的过程作为胃肠道癌相关纤维化的新治疗靶点。
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 TGF beta signaling and cell-matrix adhesion in MDCAFs, and trans differentiation of CAMs into MDCAFs was canceled by inhibiting TGF beta 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.