Cancer-Associated Fibroblast Subpopulations With Diverse and Dynamic Roles in the Tumor Microenvironment

<jats:title>Abstract</jats:title> <jats:p>Close interactions between cancer cells and cancer-associated fibroblasts (CAF) have repeatedly been reported to support tumor progression. Yet, targeting CAFs has so far failed to show a real benefit in cancer treatment, as preclinical studies have shown that such a strategy can enhance tumor growth. Accordingly, recent paradigm-shifting data suggest that certain CAF subpopulations could also show tumor-inhibitory capabilities. The present review aims to provide an in-depth description of the cellular heterogeneity of the CAF compartment in tumors. Through combining information from different cancer types, here we define 4 main CAF subpopulations that might cohabitate in any tumor microenvironment (TME). In addition, a model for the evolution of CAFs during tumor development is introduced. Moreover, the presence of tumor-inhibitory CAFs in the TME as well as their molecular characteristics are extensively discussed. Finally, the potential cellular origins of these distinct CAF subpopulations are reviewed. To our knowledge, this is the first attempt at establishing a broad but comprehensive classification of CAF subpopulations. Altogether, the present manuscript aims to provide the latest developments and innovative insights that could help refine future therapeutic targeting of CAFs for cancer treatment.</jats:p>