Cancer‐associated fibroblasts that restrain cancer progression: Hypotheses and perspectives

Abstract

The roles of cancer-associated fibroblasts (CAF) in the progression of various types of cancers are well established. CAF promote cancer progression through pleiotropic mechanisms, including the secretion of soluble factors and extracellular matrix, physical interactions with cancer cells, and the regulation of angiogenesis, immunity and metabolism. Their contribution to therapeutic resistance is also well appreciated. Therefore, CAF have been considered as a therapeutic target in cancer. However, recent studies in autochthonous pancreatic cancer models suggest that specific subset(s) of CAF exhibit cancer-restraining roles, indicating that CAF are functionally and molecularly heterogeneous, which is supported by recent single-cell transcriptome analyses. While cancer-promoting CAF (pCAF) have been extensively studied, the nature and specific marker(s) of cancer-restraining CAF (rCAF) have remained uncharacterized. Interestingly, a recent study provided insight into the nature of rCAF and suggested that they may share molecular properties with pancreatic stellate cells (PSC) and mesenchymal stem/stromal cells (MSC). Complicating this finding is that PSC and MSC have been shown to promote the formation of a tumor-permissive and tumor-promoting environment in xenograft tumor models. However, these cells undergo significant transcriptional and epigenetic changes during ex vivo culture, which confounds the interpretation of experimental results based on the use of cultured cells. In this short review, we describe recent studies and hypotheses on the identity of rCAF and discuss their analogy to fibroblasts that suppress fibrosis in fibrotic diseases. Finally, we discuss how these findings can be exploited to develop novel anticancer therapies in the future. K E Y W O R D Scancer-restraining cancer-associated fibroblasts, fibrosis, Meflin, mesenchymal stem/stromal cells, tumor microenvironment

Index of Cancer-Associated Fibroblasts Is Superior to the Epithelial–Mesenchymal Transition Score in Prognosis Prediction

“…Recently, in five head and neck patient-derived xenograft mouse models, Yegodayev et al [ 18 ] demonstrated that TGFβ-activated stromal CAFs limited cetuximab efficacy in vivo, which can be improved by an SMAD3 inhibitor, SIS3. Given these promising results, comprehensive consensuses about the roles of CAFs in tumorigenesis are emerging [ 15 , 46 ].…”

Identifying cancer-associated fibroblasts as emerging targets for hepatocellular carcinoma

“…However, for the current status, it is formidable to target CAFs precisely without damaging normal tissue due to the elusive sources and less specific markers. Additionally, considering the existence of cancer-restraining CAFs in other cancer types, the exact roles of CAFs in HCC should be further determined [ 135 , 136 ]. In conclusion, it is attached great significance to further investigating the roles and mechanisms involved in the CAFs in HCC progression, which will provide candidate targets for HCC treatment.…”

Cancer-Associated Fibroblasts: Understanding Their Heterogeneity

“…In human pancreatic ductal adenocarcinoma (PDAC) tumors and in transgenic mice engineered to carry KRas and p53 mutations under the control of the pancreatic specific Cre promoter (KPC), different subpopulations of CAFs were identified based on their expression of meflin, a glycosylphosphatidylinositol-anchored protein expressed by MSCs that maintains their undifferentiated state. Meflin-poor CAFs (pCAFs) have a pro-tumorigenic function, whereas meflin-rich CAFs (rCAFs) suppress PDAC progression by acting on ECM remodeling, hypoxia and cancer initiation [ 61 , 62 ]. The concept that some subpopulations of CAFs exert their function through the production of ECM proteins whereas other subpopulations of CAFs act as inflammatory cells is suggested by some recent reports.…”