Targeting cancer associated fibroblast overcomes cisplatin resistance: a cellular and molecular study

Nowadays, one of the main challenge for clinicians is drug resistance and response to chemotherapy agents. The optimal effect of chemotherapy agents on tumor cells can be achieved by targeting of cancer associated fibroblasts (CAF). One of the main genotoxic drug used for chemotherapy in bladder cancer patients is cisplatin. While it is applied in bladder cancer, resistance to cisplatin is wildly common. The purpose of this study is evaluating cisplatin resistance in CAFs isolated from tumor tissues.Method: CAFs were confirmed with FSP1 anti body. Cisplatin cytotoxicity on CAFs isolated from bladder tumor tissues, was determined using MTT assay. Also the drug inhibitory effects on these cells were evaluated for apoptosis and cell cycle analyses. Furthermore, ERCC1, MLH1, MSH2, and CTR1 mRNA expression levels within tumor cells were carried out by real-time q-PCRResults: cisplatin showed more cytotoxicity effect in no recurrence (NR) group than recurrence (R) group and it has statistically significant. Flowcytometery analysis show that apoptosis is main mechanism of program cell death while cell cycle arrest occurred in different phases. Furthermore, the levels of MLH1 and MSH2 expression in R group were less than NR group. By contrast, the levels of ERCC1 and CTR1 expression in R group were higher versus NR group. These results indicated that a significant relationship was observed between level of MLH1, MSH2, and CTR1 mRNA expression in two groups (P- value≥ 0.05). and no statistical significance was observed between the level of ERCC1 mRNA expression in both groups.Conclusion: CAFs can be induced chemotherapy resistance in patients using different mechanisms, therefore, targeting these cells in tumor microenvironment help to response to chemotherapy in patients.