Signaling pathways in cancer-associated fibroblasts: recent advances and future perspectives

As a critical component of the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) play important roles in cancer initiation and progression. Well-known signaling pathways, including the transforming growth factor-beta (TGF-beta), Hedgehog (Hh), Notch, Wnt, Hippo, nuclear factor kappa-B (NF-kappa B), Janus kinase (JAK)/signal transducer and activator of transcription (STAT), mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)/AKT pathways, as well as transcription factors, including hypoxia-inducible factor (HIF), heat shock transcription factor 1 (HSF1), P53, Snail, and Twist, constitute complex regulatory networks in the TME to modulate the formation, activation, heterogeneity, metabolic characteristics and malignant phenotype of CAFs. Activated CAFs remodel the TME and influence the malignant biological processes of cancer cells by altering the transcriptional and secretory characteristics, and this modulation partially depends on the regulation of signaling cascades. The results of preclinical and clinical trials indicated that therapies targeting signaling pathways in CAFs demonstrated promising efficacy but were also accompanied by some failures (e.g., NCT01130142 and NCT01064622). Hence, a comprehensive understanding of the signaling cascades in CAFs might help us better understand the roles of CAFs and the TME in cancer progression and may facilitate the development of more efficient and safer stroma-targeted cancer therapies. Here, we review recent advances in studies of signaling pathways in CAFs and briefly discuss some future perspectives on CAF research.

Automated summary

Cancer-associated fibroblasts (CAFs) play important roles in tumor initiation and progression, and their characteristics and malignant phenotype are regulated by signaling pathways and transcription factors in the tumor microenvironment. Targeting signaling pathways in CAFs shows promise in cancer therapy, but there are also challenges and failures. Understanding the signaling cascades in CAFs helps us better understand their roles in cancer progression and may lead to the development of more effective and safer therapies.