Cancer-associated fibroblasts: from basic science to anticancer therapy

Abstract

Cancer-associated fibroblasts (CAFs), as a central component of the tumor microenvironment in primary and metastatic tumors, profoundly influence the behavior of cancer cells and are involved in cancer progression through extensive interactions with cancer cells and other stromal cells. Furthermore, the innate versatility and plasticity of CAFs allow their education by cancer cells, resulting in dynamic alterations in stromal fibroblast populations in a context-dependent manner, which highlights the importance of precise assessment of CAF phenotypical and functional heterogeneity. In this review, we summarize the proposed origins and heterogeneity of CAFs as well as the molecular mechanisms regulating the diversity of CAF subpopulations. We also discuss current strategies to selectively target tumor-promoting CAFs, providing insights and perspectives for future research and clinical studies involving stromal targeting.

Stromal-derived MAOB promotes prostate cancer growth and progression

“…S2B) ( 16 ). Given recent studies indicating gene expression and phenotypic and functional heterogeneities in CAFs ( 17 , 18 ), we also examined the expression patterns of MAOA and MAOB in different CAF subsets. To this end, we collected single-cell RNA sequencing (RNA-seq) data for 13 primary PC samples and 6 castration-resistant PC (CRPC) samples from two public datasets (GSE141445 and GSE137829).…”

“…To this end, we collected single-cell RNA sequencing (RNA-seq) data for 13 primary PC samples and 6 castration-resistant PC (CRPC) samples from two public datasets (GSE141445 and GSE137829). By distinguishing 1518 and 1144 fibroblast cells from the primary PC and CRPC cohorts, respectively, as three well-established CAF subsets, including myofibroblast-like CAF (myCAF), inflammatory CAF (iCAF), and antigen-presenting CAF (apCAF), using corresponding biomarkers (myCAF: ACTA2 , RSG5 , POSTN , and TAGLN ; iCAF: CCL2 , CXCL12 , and IL6 ; apCAF: CD74 and HLA-DRA ) ( 17 , 18 ), we found that the fibroblasts from both primary PC and CRPC were mainly composed of myCAFs with limited iCAFs and absent apCAFs (fig. S2, C and D).…”

“…1E). We then examined MAOB response to select well-established activating signals for CAF generation and activation, as exemplified by inflammatory modulators, which are released from tumor cells including PC cells during tumor-stroma coevolution ( 18 , 20 – 23 ). We demonstrated induction of MAOB and select CAF markers [fibroblast activation protein ( FAP ) and vimentin ( VIM )] at the mRNA level upon treatment with tumor necrosis factor α (TNFα) and IL-6 but not IL-1α in normal human prostate fibroblast prostate stromal cells (PrSC) cells (fig.…”

The β-arrestin1/endothelin axis bolsters ovarian fibroblast-dependent invadosome activity and cancer cell metastatic potential

“…These data support previously published findings demonstrating that the dual ET-1R receptor antagonist macitentan interrupts ET-1-driven pro-survival signals, affecting cancer cells and the feed-forward loops in the TME [ 32 ]. As different subsets of CAFs are emerging, being tumor-restraining and tumor-promoting roles, depending on the stage of the tumor and the complex context of the surrounding TME, and distinct subsets of CAFs are interconvertible via manipulation of specific signaling [ 48 ], further research is required to understand the full CAF pool in a cancer-dependent manner and precise understanding of the mechanisms governing CAF heterogeneity and plasticity is a prerequisite for therapeutic interventions that selectively target tumor-supporting CAFs. Although additional molecular studies are required to provide detailed evidence of the role of the ET A/B R/β-arr1 axis to translate these results on CAFs into clinical practice and ultimately to achieve clinical benefit, our findings establish the pivotal role of this signaling pathway in the malignant properties of ovarian fibroblasts, including their ability to degrade ECM via invadosome formation.…”

Metastatic organotropism: a brief overview

“…These PMN pro-metastatic alterations are carried out by local stromal cells activated by tumor-derived signals, such as cancer-associated fibroblasts (CAFs). These can be found both within the primary tumor microenvironment and the PMN, known for providing mechanical support for tumor cells and playing crucial roles throughout the metastatic cascade ( 14 ). CAFs and their EVs also promote the formation of the PMN, through the secretion of chemokines, cytokines and ECM components, metabolic remodeling, immunosuppression and angiogenesis, thereby creating a favorable microenvironment at the future metastatic site ( 15 ).…”