The tumor microenvironment and radiotherapy response; a central role for cancer-associated fibroblasts

Tumor growth is not only dictated by events involving tumor cells, but also by the environment they reside in, the so-called tumor microenvironment (TME). In the TME, cancer-associated fibroblasts (CAFs) are often the predominant cell type. CAFs were long considered to be of limited importance in the TME, but are now recognized for their pivotal role in cancer progression. Recently, it has become evident that different subsets of CAFs exist, with certain CAF subtypes having protumorigenic properties, whereas others show more antitumorigenic characteristics. Currently, the intricate interaction between the different subsets of CAFs with tumor cells, but also with immune cells that reside in the TME, is still poorly understood. This crosstalk of CAFs with tumor and immune cells in the TME largely dictates how a tumor responds to therapy and whether the tumor will eventually be eliminated, stay dormant or will progress and metastasize. Radiotherapy (RT) is a widely used and mostly very effective local cancer treatment, but CAFs are remarkably RT resistant. Although radiation does cause persistent DNA damage, CAFs do not die upon clinically applied doses of RT, but rather become senescent. Through the secretion of cytokines and growth factors they have been implicated in the induction of tumor radioresistance and recruitment of specific immune cells to the TME, thereby affecting local immune responses. In this review we will discuss the versatile role of CAFs in the TME and their influence on RT response.