Platinum sensitivity of ovarian cancer cells does not influence their ability to induce M2-type macrophage polarization.

Abstract

Development of platinum resistance in ovarian cancer is mediated by both cancer cells and tumor microenvironment. Activation of epithelial-mesenchymal transition program in cancer cells may lead to enrichment for resistant clones. These processes can be affected by tumor-associated macrophages, a highly plastic population of cells that participate in tumor progression and response to treatment by shaping the microenvironment. We aimed to study how platinum resistance influences the crosstalk between macrophages and ovarian cancer cells. Using cisplatin-sensitive ovarian cancer cell line A2780, we developed and characterized cisplatin-resistant A2780Cis and cisplatin and doxorubicin co-resistant A2780Dox cell lines. Next, we set up an indirect coculture system with THP-1 cell line-derived M0-type-, M1-type- and M2-type-like polarized macrophages. We monitored the expression of genes associated with cellular stemness, multidrug resistance, and epithelial-mesenchymal transition in cancer cells, and expression profile of M1/M2 markers in macrophages. Development of drug resistance in ovarian cancer cell lines was accompanied by increased migration, clonogenicity, and upregulated expression of transcription factors, associated with cellular stemness and epithelial-mesenchymal transition. Upon coculture, we noted that the most relevant changes in gene expression profile occurred in A2780 cells. Moreover, M0- and M1-type macrophages, but not M2-type macrophages, showed significant transcriptional alterations. Our results provide the evidence for bidirectional interplay between cancer cells and macrophages. Independent of platinum resistance status, ovarian cancer cells polarize macrophages toward M2-like type, whereas macrophages induce epithelial-mesenchymal transition and stemness-related gene expression profile in cisplatin-sensitive, but not cisplatin-resistant cancer cells.