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

Abstract

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‐β (TGF‐β), Hedgehog (Hh), Notch, Wnt, Hippo, nuclear factor kappa‐B (NF‐κB), 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.

Normal Uterine Fibroblast Are Reprogramed into Ovarian Cancer-Associated Fibroblasts by Ovarian Tumor-derived Conditioned Media

“…Moreover, our data clearly implicated the conditioned CAFs with TGF-beta signaling, which is associated with tumor promotion, cancer cell invasion and migration, metastasis, and poor overall survival 15,53,77 . Figure 4 shows upregulation of related TGF-beta signaling pathways SMAD and STAT in the conditioned CAFs [78][79][80] . The immunomodulatory role of the conditioned CAFs was confirmed by the upregulation of proinflammatory genes and downregulation of anti-inflammatory genes (Figure 4).…”

Cancer-associated fibroblasts in gynecological malignancies: are they really allies of the enemy?

“…Despite the considerable evidence about the pro-tumor role of CAFs in gynecological cancers, the design of personalized therapies directed at them must be careful due to the existence of evidence that proposes them as anti-tumor cells, although there are few reports that support this idea. In various cancers, clinical trials have been carried out where CAFs have been used as a therapeutic tool ( 166 – 168 ), nevertheless, few have fully reproduced the promising results obtained in the laboratory, which are necessary to include this cell type in cancer treatments. This could be a consequence of their heterogeneous origin, their different protein expression patterns and the pro-tumor and anti-tumor effects that they exert on the TME ( 169 , 170 ).…”

Cancer Stem Cells in Pancreatic Ductal Adenocarcinoma

“…The Notch pathway includes five Notch ligands: Jagged 1 and 2 (JAG1 and JAG2), as well as Delta-like 1, 3 and 4 (DLL1, DLL3 and DLL4); and four transmembrane Notch receptors: Notch 1–4 [ 52 ]. Activation of the classical Notch pathway is triggered by ligand binding to the receptor, usually as an interaction between two cells.…”

“…Binding between the Notch intracellular domain NICD and CSL removes co-repressors from CSL, attracts co-activator complex and, thus, induces transcription of target genes, e.g., Nanog and others [ 48 ]. Notch signalling is considered non-canonical if Notch activity is initiated by other ligands, or triggered in the absence of ligand binding, or involves different intranuclear events [ 52 ].…”