Reverse of microtubule-directed chemotherapeutic drugs resistance induced by cancer-associated fibroblasts in breast cancer

摘要

Purpose: This study was designed to expound the underlying mechanism of microtubule-directed chemotherapeutic drugs resistance induced by cancer-associated fibroblasts (CAFs) in breast cancer. Materials and methods: We collected 10 microtubule-directed chemotherapeutic drugs resistant breast tumor samples and 10 normal breast tumor samples to analyze the CAFs distribution by immunohistochemistry and flow cytometry. We also detected the collagen expression in CAFs by real-time PCR. We detected the activation of PI3K/AKT signaling pathway in tumor cells by Western blotting and immunofluorescence. The subcutaneous 4T1/MCF-7 bearing mice were used to investigate the anticancer effects of integrin β1 inhibitor combined with microtubule-directed chemotherapeutic drugs. Results: In our studies, accumulation of CAFs was observed in tumor samples from microtubule-directed chemotherapeutic drugs resistant patients. Those isolated CAFs could efficiently induce the acquisition of microtubule-directed chemotherapeutic drugs resistance in breast cancer cells. More importantly, we found that CAFs could regulate the microtubule-directed chemotherapeutic drugs resistance through the secretion of collagen to activate the integrin β1/PI3K/AKT signaling pathway. Combination of integrin α2β1 inhibitor and paclitaxel/vincristine sulfate could efficiently overcome the microtubule-directed chemotherapeutic drugs resistance induced by CAFs and enhanced the anticancer effects of chemotherapy in subcutaneous 4T1/MCF-7 bearing mice. Conclusion: Our results demonstrated that CAFs constitute a supporting niche for cancer drug resistance acquisition. Thus, traditional microtubule-directed chemotherapeutic drugs combined with integrin β1 inhibitor may present an innovative therapeutic strategy for breast cancer therapy.