Interaction of tumor cells and cancer-associated fibroblasts in radiation-induced senescence

Abstract

Background Despite significant progress in tumor therapy, recurrences continue to pose a major challenge in clinical oral oncology. Recent studies suggest that senescence and intercellular signaling within the tumor microenvironment play a crucial role in post-radiation recurrence. As these mechanisms remain incompletely understood, this study examined the interactions between co-cultured tumor cells and cancer-associated fibroblasts (CAFs) under the influence of radiation. Methods A549 tumor cells and primary CAFs were cultured individually and in co-culture and then exposed to 16 Gray irradiation. Changes in cell morphology and secretome were measured, and medium transfer experiments assessed tumor cell migration. Six days post-irradiation, the proportions of apoptotic, necrotic, dead, and viable cells were assessed. Long-term cultures were used to document tumor cell reproliferation. Results Post-irradiation fewer tumor cells underwent senescence in co-culture with CAFs compared to mono-culture, without an increase in long-term tumor cell reproliferation in the co-cultures. MCP-1 (CCL2) secretion was lower in co-culture, potentially contributing to the reduced senescence. IL-6 secretion was higher, consistent with its role in promoting tumor invasion. IL-8 expression was elevated in non-irradiated co-cultures; its reduction post-irradiation may explain the lower senescence in co-culture. CAFs produced OPG, potentially driving migration. TIMP-1 was consistently secreted across all conditions. CAF-conditioned medium promoted migration of A549 and FaDu cells. Conclusion This study demonstrates that CAFs modulate tumor cell senescence and enhance migration following irradiation. These findings highlight the role of CAFs in progression and radiation response. Targeting CAF-related mechanisms during radiotherapy may improve therapeutic outcomes across epithelial cancer types.