Cancer-associated fibroblasts in radiotherapy: Bystanders or protagonists?

The primary goal of radiotherapy (RT) is to induce cellular damage on malignant cells; however, it is becoming increasingly recognized the important role played by the tumor microenvironment (TME) in therapy outcomes. Therapeutic irradiation of tumor lesions provokes profound cellular and biological reconfigurations within the TME that ultimately may influence the fate of the therapy.

Cancer-associated fibroblasts (CAFs) are known to participate in all stages of cancer progression and are increasingly acknowledged to contribute to therapy resistance. Accumulated evidence suggests that, upon radiation, fibroblasts/CAFs avoid cell death but instead enter a permanent senescent state, which in turn may influence the behavior of tumor cells and other components of the TME. Despite the proposed participation of senescent fibroblasts on tumor radioprotection, it is still incompletely understood the impact that RT has on CAFs and the ultimate role that irradiated CAFs have on therapy outcomes. Some of the current controversies may emerge from generalizing observations obtained using normal fibroblasts and CAFs, which are different cell entities that may respond differently to radiation exposure.

In this review we present current knowledge on the field of CAFs role in radiotherapy; we discuss the potential tumorigenic functions of radiation-induced senescent fibroblasts and CAFs and we make an effort to integrate the knowledge emerging from preclinical experimentation with observations from the clinics. Video Abstract.