Okubo Shoki, Mezawa Yoshihiro, Wang Zixu, Acar Ahmet, Ito Yasuhiko, Takano Atsushi, Miyagi Yohei, Yokose Tomoyuki, Yamashita Toshinari, Daigo Yataro, Shirakihara Takuya, Orimo Akira
Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
Department of Molecular Pathogenesis, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
Mol Oncol. 2025 Sep;19(9):2557-2573. doi: 10.1002/1878-0261.70074. Epub 2025 Jul 11.
Carcinoma-associated fibroblasts (CAFs), which are abundant in the tumor microenvironment, influence cancer hallmarks. We previously described transforming growth factor-β (TGF-β)-Smad2/3 signaling as being activated in myofibroblastic CAFs (myCAFs) in an autocrine fashion by increasing TGF-β production. However, factors regulating such autocrine TGF-β signaling remain poorly understood. Herein, we show that the abundance of endoglin (ENG), a TGF-β superfamily coreceptor expressed on human breast myCAFs, is significantly associated with poorer outcomes of breast cancer patients. Inhibition of ENG expression on myCAFs not only suppressed the TGF-β-Smad2/3 pathway and TGF-β1 expression but also attenuated the ability of myCAF to promote primary tumor growth and metastasis. Mechanistically, ENG facilitates TGF-β-Smad2/3 signaling in myCAFs, presumably through association with a TGF-β ligand-receptor complex, leading to self-stimulating TGF-β1 production. Stromal TGF-β1, in turn, induces partial epithelial-mesenchymal transition in cancer cells in a paracrine manner, resulting in suppression of primary tumor growth and promotion of invasion and metastasis. ENG-primed TGF-β autocrine signaling also produces other factors that could mediate primary tumor growth promotion by myCAFs. Collectively, these findings suggest that ENG-primed TGF-β autocrine and paracrine signaling mediates tumor- and metastasis-promoting abilities of myCAFs.
癌相关成纤维细胞（CAFs）在肿瘤微环境中大量存在，影响癌症的特征。我们之前描述过，转化生长因子-β（TGF-β）-Smad2/3信号通路在肌成纤维细胞性CAFs（myCAFs）中通过增加TGF-β的产生以自分泌方式被激活。然而，调节这种自分泌TGF-β信号的因素仍知之甚少。在此，我们表明，内皮糖蛋白（ENG）在人乳腺myCAFs上表达，其丰度与乳腺癌患者较差的预后显著相关。抑制myCAFs上ENG的表达不仅抑制了TGF-β-Smad2/3通路和TGF-β1的表达，还减弱了myCAF促进原发性肿瘤生长和转移的能力。从机制上讲，ENG可能通过与TGF-β配体-受体复合物结合，促进myCAFs中的TGF-β-Smad2/3信号传导，导致自我刺激TGF-β1的产生。反过来，基质TGF-β1以旁分泌方式诱导癌细胞发生部分上皮-间质转化，从而抑制原发性肿瘤生长并促进侵袭和转移。ENG引发的TGF-β自分泌信号还产生其他因子，这些因子可能介导myCAFs促进原发性肿瘤生长。总的来说，这些发现表明ENG引发的TGF-β自分泌和旁分泌信号介导了myCAFs的肿瘤促进和转移能力。
