The roles of cancer-associated fibroblasts (CAFs) in the progression of various types of cancers are well established. CAFs 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, CAFs have been considered as a therapeutic target in cancer. However, recent studies in autochthonous pancreatic cancer models suggest that specific subset(s) of CAFs exhibit cancer-restraining roles, indicating that CAFs are functionally and molecularly heterogeneous, which is supported by recent single-cell transcriptome analyses. While cancer-promoting CAFs (pCAFs) have been extensively studied, the nature and specific marker(s) of cancer-restraining CAFs (rCAFs) have remained uncharacterized. Interestingly, a recent study provided insights into the nature of rCAFs and suggested that they may share molecular properties with pancreatic stellate cells (PSCs) and mesenchymal stem/stromal cells (MSCs). Complicating this finding is that PSCs and MSCs 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 rCAFs 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.
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