Endoglin mediates the tumor- and metastasis-promoting traits of stromal myofibroblasts in human breast carcinomas.

Abstract

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.