Fibroblasts in Orchestrating Colorectal Tumorigenesis and Progression

Abstract

Cancer-associated fibroblasts (CAFs) are an abundant component of the tumor microenvironment and have been shown to possess critical functions in tumor progression. Although their roles predominantly have been described as tumor-promoting, more recent findings have identified subsets of CAFs with tumor-restraining functions. Accumulating evidence underscores large heterogeneity in fibroblast subsets in which distinct subsets differentially impact the initiation, progression, and metastasis of colorectal cancer. In this review, we summarize and discuss the evolving role of CAFs in colorectal cancer, highlighting the ongoing controversies regarding their distinct origins and multifaceted functions. In addition, we explore how CAFs can confer resistance to current therapies and the challenges of developing effective CAF-directed therapies. Taken together, we believe that, in this rapidly evolving field, it is crucial first to understand CAF dynamics comprehensively, and to bridge existing knowledge gaps regarding CAF heterogeneity and plasticity before further exploring the clinical targeting of CAFs.

Keywords: Adenoma-to-Carcinoma Transition; Cancer-Associated Fibroblast; Colorectal Cancer; Heterogeneity.

Figure 1

The origins and heterogeneity of CAFs. CAFs form a heterogeneous cell population with diverse origins. Activation of tissue-resident fibroblasts is the largest source of CAFs. Circulating bone marrow–derived mesenchymal stem cells (MSCs) can be recruited to the tumor to become a part of the CAF population. Nonfibroblastic cells, such as epithelial and endothelial cells, can differentiate into CAFs via epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndoMT), respectively. Pericytes also are recognized as a potential source of CAFs through transdifferentiation. Single-cell sequencing has identified 2 major subsets of CAFs in human primary CRC, designated as CAF-A and CAF-B. CAF-A is characterized by marker genes such as FAP, matrix metalloproteinase (MMP)-2, and COL1A2, and is reported to be involved in ECM remodeling. On the other hand, CAF-B expresses marker genes such as α-SMA, transgelin, and platelet-derived growth factor subunit A (PDGFA), but its specific function remains unknown. Additionally, a CAF subset expressing MHC-II, known as antigen-presenting CAFs, may exist in CRC, but their role in T-cell activation and immunosuppression has yet to be elucidated.