Cancer-Associated Fibroblasts Enhance Oxaliplatin Resistance in Colorectal Cancer Cells via Paracrine IL-6: An In Vitro Study

Abstract

Background: Colorectal cancer (CRC) often develops resistance to oxaliplatin (L-OHP), a key chemotherapeutic agent. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are implicated in chemoresistance, but their role in L-OHP resistance via interleukin-6 (IL-6) secretion remains unclear. Objectives: The presnt study investigated how CAFs contribute to L-OHP resistance in CRC, focusing on IL-6 secretion and its impact on cancer cell survival. Methods: NIH3T3 fibroblasts were co-cultured with murine (CT26) or human (DLD1) colon cancer cells and treated with L-OHP. The supernatant IL-6 levels were measured by enzyme-linked immunosorbent assay (ELISA). Indirect co-culture using Transwell chambers was employed to separate CAF and tumor cell effects. Conditioned media (CM) from both cell types were collected and analyzed for IL-6. Cytotoxicity assays were conducted to assess the survival of L-OHP-treated CT26 cells in the presence of CAF-derived CM, with or without an IL-6-neutralizing antibody. Results: Co-culture significantly increased IL-6 secretion, which was further amplified by L-OHP. The IL-6 levels in CAF-derived CM were approximately 3.5-fold higher than in tumor cell-derived CM. The CAF-derived CM improved the survival of L-OHP-treated CT26 cells, an effect reversed by IL-6-neutralizing antibodies. Furthermore, adding exogenous IL-6 to tumor cell-derived CM also enhanced survival. Similar IL-6 upregulation in cisplatin-treated CAFs suggests a broader role in platinum-based resistance. Conclusions: The CAFs promote L-OHP resistance in CRC through IL-6 secretion, enhancing cancer cell survival. Therefore, targeting CAFs and IL-6 signaling may help overcome chemoresistance in CRC.