Cancer-Associated Fibroblasts: Versatile Players in the Tumor Microenvironment

Abstract

Cancer-associated fibroblasts (CAFs) are indispensable architects of the tumor microenvironment. They perform the essential functions of extracellular matrix deposition, stromal remodeling, tumor vasculature modulation, modification of tumor metabolism, and participation in crosstalk between cancer and immune cells. In this review, we discuss our current understanding of the principal differences between normal fibroblasts and CAFs, the origin of CAFs, their functions, and ultimately, highlight the intimate connection of CAFs to virtually all of the hallmarks of cancer. We address the remarkable degree of functional diversity and phenotypic plasticity displayed by CAFs and strive to stratify CAF biology among different tumor types into practical functional groups. Finally, we summarize the status of recent and ongoing trials of CAF-directed therapies and contend that the paucity of trials resulting in Food and Drug Administration (FDA) approvals thus far is a consequence of the failure to identify targets exclusive of pro-tumorigenic CAF phenotypes that are mechanistically linked to specific CAF functions. We believe that the development of a unified CAF nomenclature, the standardization of functional assays to assess the loss-of-function of CAF properties, and the establishment of rigorous definitions of CAF subpopulations and their mechanistic functions in cancer progression will be crucial to fully realize the promise of CAF-targeted therapies.

Radiation Response in the Tumour Microenvironment: Predictive Biomarkers and Future Perspectives

“…Fibroblasts recruited into the TME are transformed into cancer-associated fibroblasts (CAFs), where they play a role in regulating the extracellular matrix [ 41 ]. Furthermore, CAFs are responsible for the secretion of a number of cytokines (including interleukin 6 (IL6) and IL8), chemokines (including C-X-C motif ligand 12 (CXCL12)) and growth factors (including TGF-β and platelet-derived growth factor (PDGF)) that can influence immune cell fate and tumour progression, often contributing to the immunosuppressive TIME [ 42 ]. However, the effects of RT on the stromal compartment of the TME including CAFs are less well understood and they appear to have contradictory roles, contributing to both tumour growth and suppression [ 43 ].…”

Hold on or Cut? Integrin- and MMP-Mediated Cell–Matrix Interactions in the Tumor Microenvironment

“…However, CAFs are a heterogeneous group of cells and may originate from other cell types as well [52,65,66]. Due to their importance in tumor progression, CAFs are now considered as a promising target in cancer treatment [65,67]. Several clinical trials directed against CAF-marker proteins have also been launched to overcome drug resistance in treatment of cancer [68] Cancer cells secrete growth factors, such as TGF-β [55], that promote the differentiation CAFs from resident fibroblasts [69].…”

“…Under the influence of cancer cells, tissue-resident stromal fibroblasts differentiate into cancer-associated fibroblasts (CAFs) [ 60 , 64 , 65 ]. However, CAFs are a heterogeneous group of cells and may originate from other cell types as well [ 52 , 65 , 66 ]. Due to their importance in tumor progression, CAFs are now considered as a promising target in cancer treatment [ 65 , 67 ].…”

Noncoding RNAs in the Interplay between Tumor Cells and Cancer-Associated Fibroblasts: Signals to Catch and Targets to Hit

“…One of the most abundant cell types within tumor microenvironment is represented by cancer-associated fibroblasts (CAF), namely the fibroblasts that, corrupted by cancer cells through the secretion of cytokines and growth factors (e.g., TGF-β, IL-6), acquire a myofibroblast-like phenotype resembling that of wound healing reactive stroma [ 2 ]. In a diabolic liaison, CAFs are in turn able to induce malignant features in tumor cells by the secretion of soluble paracrine signals and the delivery extracellular vesicles [ 3 , 4 ]. CAF-induced changes cover almost all of the hallmarks of cancer, such as the increased cell proliferation, epithelial-mesenchymal transition (EMT) with enhanced invasion capabilities, angiogenesis and metabolic reprogramming ( Figure 1 a).…”

“…CAF-induced changes cover almost all of the hallmarks of cancer, such as the increased cell proliferation, epithelial-mesenchymal transition (EMT) with enhanced invasion capabilities, angiogenesis and metabolic reprogramming ( Figure 1 a). In addition, CAFs can also dramatically remodel the extracellular matrix, thus ultimately favor cancer cell dissemination and metastasis [ 3 ].…”