Cancer-Associated Fibroblasts Suppress Cancer Development: The Other Side of the Coin.

Zhanhuai Wang,Wei Yu,Yang Tang,Jun Ye,Bin Yuan,Yinuo Tan,Qi Yang

doi:10.3389/fcell.2021.613534

Abstract

Cancer-associated fibroblasts (CAFs) are the main stromal components of cancer, representing a group of heterogeneous cells. Many studies indicate that CAFs promote tumor development. Besides, evidence of the tumor suppression effects of CAFs keeps on merging. In the tumor microenvironment, multiple stimuli can activate fibroblasts. Notably, this does not necessarily mean the activated CAFs become strong tumor promoters immediately. The varying degree of CAFs activation makes quiescent CAFs, tumor-restraining CAFs, and tumor-promoting CAFs. Quiescent CAFs and tumor-restraining CAFs are more present in early-stage cancer, while comparatively, more tumor-promoting CAFs present in advanced-stage cancer. The underlying mechanism that balances tumor promotion or tumor inhibition effects of CAFs is mostly unknown. This review focus on the inhibitory effects of CAFs on cancer development. We describe the heterogeneous origin, markers, and metabolism in the CAFs population. Transgenetic mouse models that deplete CAFs or deplete CAFs activation signaling in the tumor stroma present direct evidence of CAFs protective effects against cancer. Moreover, we outline CAFs subpopulation and CAFs derived soluble factors that act as a tumor suppressor. Single-cell RNA-sequencing on CAFs population provides us new insight to classify CAFs subsets. Understanding the full picture of CAFs will help translate CAFs biology from bench to bedside and develop new strategies to improve precision cancer therapy.

Highlights

Fibroblasts are one of the significant stromal components in many organs, e.g., the gastrointestinal tract
Despite numerous results indicating cancer-associated fibroblasts (CAFs)’ pro-tumorigenic effects, here, we provide shreds of evidence that CAFs subsets restrain tumor progression
CD271 + CAFs predominantly existed in the areas with strong a-SMA expression in the tumor, which suggested CD271 + CAFs was a subpopulation of SMA + CAFs

Summary

Introduction

Fibroblasts are one of the significant stromal components in many organs, e.g., the gastrointestinal tract. They participate in adjacent tissue components’ function through paracrine signaling and juxtacrine signaling (Biswas et al, 2015; Kalluri, 2016). One of their most crucial tasks is regulating ECM synthesis. CAFs are a group of heterogeneous cells and are the most prevalent stromal components of the tumor microenvironment. Previous studies have focused on tumor cells, yet it is increasingly recognized that the stromal components of the tumor microenvironment play critical roles in cancer progression (Hanahan and Weinberg, 2011). In cancer biology, understanding the functional evolution of CAFs during cancer development becomes a fundamental question to answer

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