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

Abstract

To flourish, cancers greatly depend on their surrounding tumor microenvironment (TME), and cancer-associated fibroblasts (CAFs) in TME are critical for cancer occurrence and progression because of their versatile roles in extracellular matrix remodeling, maintenance of stemness, blood vessel formation, modulation of tumor metabolism, immune response, and promotion of cancer cell proliferation, migration, invasion, and therapeutic resistance. CAFs are highly heterogeneous stromal cells and their crosstalk with cancer cells is mediated by a complex and intricate signaling network consisting of transforming growth factor-beta, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin, mitogen-activated protein kinase, Wnt, Janus kinase/signal transducers and activators of transcription, epidermal growth factor receptor, Hippo, and nuclear factor kappa-light-chain-enhancer of activated B cells, etc., signaling pathways. These signals in CAFs exhibit their own special characteristics during the cancer progression and have the potential to be targeted for anticancer therapy. Therefore, a comprehensive understanding of these signaling cascades in interactions between cancer cells and CAFs is necessary to fully realize the pivotal roles of CAFs in cancers. Herein, in this review, we will summarize the enormous amounts of findings on the signals mediating crosstalk of CAFs with cancer cells and its related targets or trials. Further, we hypothesize three potential targeting strategies, including, namely, epithelial–mesenchymal common targets, sequential target perturbation, and crosstalk-directed signaling targets, paving the way for CAF-directed or host cell-directed antitumor therapy.

Canonical TGFβ Signaling and Its Contribution to Endometrial Cancer Development and Progression—Underestimated Target of Anticancer Strategies

“…During endometrial cancer progression, in particular initiation of the metastatic process, a vital role is played by the tumor microenvironment serving as a reservoir of cytokines, growth factors, and other factors. Among these molecules, TGFβ1 is released directly or as cargo in exosomes released from cancer cells, and/or immunological cells trigger the transformation of normal fibroblast (NF) to cancer-associated fibroblasts (CAFs) [261]. TGFβ1-induced CAFs transition is additionally enhanced by the action of miR¬21 through the translation inhibition of Smad7 mRNA.…”

Crosstalk Between the Tumor Microenvironment and Cancer Cells: A Promising Predictive Biomarker for Immune Checkpoint Inhibitors

“…Moreover, subgroup TH1 cells that secrete interferon-γ play more critical roles in vessel normalization (Tian et al, 2017). CAFs can induce angiogenesis by secreting cytokines such as VEGF, CXCL12 and CTGF (Wu et al, 2021). VEGF/VEGFR-2 signaling induces the proliferation, migration, and angiogenesis of vascular endothelial cells, but also elevates the permeability of blood vessels.…”

Metronomic Anti-Cancer Therapy: A Multimodal Therapy Governed by the Tumor Microenvironment

“…CAFs, which are a major cell population in the tumoral stroma, are phenotypically and functionally heterogeneous and are not completely characterized [183,184]. Their heterogeneity may depend on the multiplicity of origins or their different spatial distribution inside the tumor [185][186][187].…”