Cancer-Associated Fibroblasts: Understanding Their Heterogeneity

SIMPLE SUMMARY: Cancer-associated fibroblasts (CAFs) play an important contributory role in the microenvironment of tumors. They originate from different cells, have multiple pro-and anti-tumorigenic functions in tumors and their presence is variable among cancer types. Recently, there has been evidence that CAFs represent a highly heterogeneous group of cells that can now be characterized and identified at the single cell level. This review article summarizes our recent understanding of the highly heterogeneous nature of the origin, phenotype and function of CAFs and how such understanding will lead to a more precise approach to target or use CAFs and their precursor cells in the treatment of cancer. ABSTRACT: The tumor microenvironment (TME) plays a critical role in tumor progression. Among its multiple components are cancer-associated fibroblasts (CAFs) that are the main suppliers of extracellular matrix molecules and important contributors to inflammation. As a source of growth factors, cytokines, chemokines and other regulatory molecules, they participate in cancer progression, metastasis, angiogenesis, immune cell reprogramming and therapeutic resistance. Nevertheless, their role is not fully understood, and is sometimes controversial due to their heterogeneity. CAFs are heterogeneous in their origin, phenotype, function and presence within tumors. As a result, strategies to target CAFs in cancer therapy have been hampered by the difficulties in better defining the various populations of CAFs and by the lack of clear recognition of their specific function in cancer progression. This review discusses how a greater understanding of the heterogeneous nature of CAFs could lead to better approaches aimed at their use or at their targeting in the treatment of cancer.