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.
Highlights
Cancer, as a major public health problem worldwide, is the second leading cause of death with an estimated 10.0 million globally in 2020.1,2 Majority of cancer deaths from cancers are caused by local recurrence and/or distant organ/tissue metastasis.[3,4] If the cancers are identified in the early stage and occur in the original lesion site, the total 5-year relative survival rate of the ten most common cancers is ~34.2–100%, with a local recurrence rate of
What distinguishes the Wnt signaling pathway in Cancer-associated fibroblasts (CAFs) from other pathways? Notably, in contrast to the studies on mutations in APC, RNF43, ZNRF3, AXIN1/ 2, and CTNNB1 detected in human colorectal adenocarcinoma,[201] endometrial cancer,[202] hepatocellular carcinoma (HCC),[203] and gastric cancer,[204] few studies have been published related to their alterations of these genes in CAFs
To further address the role of cancer cell mutations in CAFs, using a 3D coculture model, Zhou et al found that melanoma growth was suppressed by CAF deactivation induced by β-catenin ablation, which led to the reduced production of paracrine factors and extracellular matrix (ECM) proteins.[188]
Summary
Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer. Fanglong Wu1, Jin Yang[1], Junjiang Liu[1], Ye Wang[1], Jingtian Mu1, Qingxiang Zeng[1], Shuzhi Deng[1] and Hongmei Zhou[1]. 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. 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
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