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

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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.

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