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Cancer-associated fibroblasts (CAFs) represent a heterogeneous population of connective tissue cells that are both numerically and functionally prominent constituents of solid neoplasms. The role that CAFs play on tumor responses to radiotherapy is largely unknown. This study was undertaken to explore potential changes in the protumorigenic and immunosuppressive functions of CAFs in the context of radiotherapy.

In vitro experiments were performed using human CAFs isolated from fresh non-small cell lung carcinoma tumor tissues. Radiation-induced phenotypic and epigenetic changes in CAFs were studied Tumor regulatory functions of irradiated (iCAFs) and control CAFs was compared in co-culture systems with different lung tumor cell lines. Pro-tumorigenic and radioprotective effects of iCAFs were studied using proliferation, migration and clonogenic assays. Induction of EMT in tumor cells by iCAFs was also explored. Radiation-induced CAFs changes and tumor growth regulation was also studied in in vivo models.

Our data show a dose-dependent induction of cell senescence in CAFs, with a concomitant reduction of the proliferative and migratory capacity. Expression of CAF specific markers FAP-1, FSP-1, PDGFRa/b and α-SMA remained unchanged following exposure to ionizing radiation (IR), whereas expression of podoplanin was reduced. The proliferative and migratory rate of tumor cells remained unchanged upon co-culturing with irradiated or control CAFs, and clonogenic survival of tumor cells was also unaffected. However, CAF-mediated EMT effects on tumor cells was reduced upon radiation. Preliminary in vivo observations indicate that ionizing radiation does not alter the amount or the expression of CAF activation markers in tumors. We are presently exploring the contribution of CAFs on radiotherapy responses by means of CAF-depletion and CAF-overexpression in in vivo models.

IR delivered at clinically relevant doses induces important phenotypic changes in CAFs but does not appear to alter substantially CAF-mediated pro-tumorigenic or radioprotective functions in tumor cells. CAF abundance and cell signature markers remain unchanged upon external beam radiotherapy of subcutaneously grown tumors. The ultimate role of CAFs on tumor responses to radiotherapy warrant further investigations.