Cancer-associated fibroblasts in radiotherapy: Bystanders or protagonists?

BACKGROUND

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.

MAIN CONTENT

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.

CONCLUSION

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.

Radiotherapy (RT) is currently used to treat more than 50% of all diagnosed cancer cases and counts for around 40% of all cure rates. The primary goal of RT has always been to induce damage on tumor cells; thus, it has been traditionally believed that the therapeutic efficacy of RT is mediated exclusively by its capacity to directly kill malignant cells. However, tumors are complex tissues composed of multiple cellular and acellular elements often referred as the tumor microenvironment (TME) or tumor stroma. Both, the malignant and the non-malignant cells in tumors receive the same prescribed radiation dose during treatment. In recent years, it has become more and more evident the fundamental role played by elements of the TME on therapy outcomes. One of the most abundant and influential elements of the reactive stroma in tumors are cancer-associated fibroblasts (CAFs). CAFs are also exposed to the full prescribed radiation dose during the course of radiotherapy. Accumulated evidence suggests that, upon radiation, fibroblasts/CAFs avoid cell death but instead enter a permanent senescent (growth arrest) 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. Further research using appropriate experimental models to study CAFs, and more information from clinical research is needed to unveil the ultimate role played by CAFs on radiotherapy.

Informations de copyright

© 2023. The Author(s).