Transforming Growth Factor-β Signaling in Fibrotic Diseases and Cancer-Associated Fibroblasts

Abstract

Transforming growth factor-β (TGF-β) signaling is essential in embryo development and maintaining normal homeostasis. Extensive evidence shows that TGF-β activation acts on several cell types, including epithelial cells, fibroblasts, and immune cells, to form a pro-fibrotic environment, ultimately leading to fibrotic diseases. TGF-β is stored in the matrix in a latent form; once activated, it promotes a fibroblast to myofibroblast transition and regulates extracellular matrix (ECM) formation and remodeling in fibrosis. TGF-β signaling can also promote cancer progression through its effects on the tumor microenvironment. In cancer, TGF-β contributes to the generation of cancer-associated fibroblasts (CAFs) that have different molecular and cellular properties from activated or fibrotic fibroblasts. CAFs promote tumor progression and chronic tumor fibrosis via TGF-β signaling. Fibrosis and CAF-mediated cancer progression share several common traits and are closely related. In this review, we consider how TGF-β promotes fibrosis and CAF-mediated cancer progression. We also discuss recent evidence suggesting TGF-β inhibition as a defense against fibrotic disorders or CAF-mediated cancer progression to highlight the potential implications of TGF-β-targeted therapies for fibrosis and cancer.

Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer

“…The CAF-mediated TGF-β pathway contributes to cancer progression by regulating many physiological processes, including cancer cell proliferation, migration, invasion, and metastasis. 95 Previous studies showed that TGF-β-activated CAFs secreted growth factors, including TGF-β, fibroblast growth factor 2/7 (FGF2/7), VEGF, PDGF, and hepatocyte growth factor (HGF), to promote cancer cell proliferation. 96 CAFs stimulated gastric cancer cell migration and invasion, which were attenuated by Smad2 small interfering RNA (siRNA) and anti-TGF-β-neutralizing antibody.…”

TGF-β Signaling: From Tissue Fibrosis to Tumor Microenvironment

“…TGF-β is also crucial for activating cancer-associated fibroblasts (CAFs) to modulate migration and invasion of the cancer cells [ 63 , 64 ]. TGF-β is able to induce the transition process of fibroblasts towards myofibroblasts by increasing fibroblast contractility and CAF marker expression including α-smooth muscle actin (α-SMA), fibroblast activation protein (FAP), tenascin-C and platelet-derived growth factor receptor (PDGFR) [ 65 , 66 , 67 , 68 ]. Increasing evidence suggests that TGF-β1 can enhance the expression of ECM remodelling gene ACTA2 (α-SMA) [ 69 , 70 ], collagen precursor PLOD2, and membrane bound thymocyte differentiation antigen Thy1/CD90 for supporting the CAF formation [ 71 ].…”

“…ZEB1 is suggested to be upregulated and involved in the TGF-β-induced EMT, which can support metastasis and invasion of tumor cells by directly suppressing transcriptions of antifibrotic miR200c and miR141, where miR141 is an inhibitor of TGF-β as a feedback mechanism [ 142 , 143 ]. In addition, a novel Smad3-dependent long non-coding RNA Erbb4-IR showed various actions in prostate and esophageal squamous cell carcinoma, where one of the actions is to inhibit apoptosis by downregulating tumor suppressor miRNA-145, thus promoting cancer cell proliferation [ 68 , 144 ]. Upregulation of TGF-β/Smad-mediated Erbb4-IR and LRNA9884 were observed in renal fibrosis, as they up-regulate the pathogenic effectors via transcriptional regulation at genomic level [ 145 , 146 , 147 , 148 ].…”

CD34+ Stromal Cells/Telocytes as a Source of Cancer-Associated Fibroblasts (CAFs) in Invasive Lobular Carcinoma of the Breast

“…Future studies in this type of tumour could confirm or contribute to several aspects of CAFs, such as CAF heterogeneity and plasticity, factors that participate in the conversion of CD34+SCs/TCs into CAFs, and CAF functions, including extracellular matrix deposition and remodelling, CAF-related factors that participate in tumour growth, invasion, metastasis and angiogenesis, as well as those that modulate tumour immunity (for review, see [ 29 , 51 ]). Future studies should also cover the co-localization of CD34 with other fibroblastic markers due to fibroblastic heterogeneity [ 52 ], including fibronectin, which promotes the eventual acquisition of a fibrotic response, and TGF β1, which activates the fibroinflammatory genomic program [ 53 , 54 , 55 , 56 ]. Likewise, the investigation of the origin of CAFs from CD34 + SCs/TCs should extend to tumors from other tissue locations (e.g., prostate, lung or skin), for which data that indicate this possibility have been provided [ 57 , 58 , 59 ].…”