Abstract
Abstract Background: Hyperthermia therapy is a medical procedure where local body tissues are exposed to high temperatures ranging from 40oC to 43oC with the aim of killing microscopic tumor residue, being more susceptible to heat than normal cells. When combined with hyperthermia during cytoreductive surgeries, intraperitoneal chemotherapy was clinically proved to be more effective. While hyperthermia's cytotoxicity was tested on cancer cells, its effect on interactions between cancer cells and tumor stroma cells was minimally scrutinized. In this study, we investigate the effect of tumor associated mesenchymal stem cells, on inducing resistance of ovarian cancer cells (OCC) to hyperthermia. Methods: OCC viability was challenges by heat shock at 42 degrees, in simple or co-culture systems. Cell viability was determined using Calcein Violet AM by Fluorescence Activated Cell Sorting, FACS. The same experiment was replicated using a transwell system. Using the trogocytosis assay we measured the interaction between the different cell types. Multiparameter flow cytometry was used to study the relation between intercellular interaction and thermoresistance. Finally using inhibitors and blocking antibodies we were able to analyse the role of SDF1 pathway in thermoresistance. Results: At 42oC, an increase in viability of OCC, co-cultured with ‘MSC, was detected in comparison to cells cultured alone. The same result was attained using the transwell experiment. Antibody and siRNA for CXCR4 reversed the heat resistant effect of MSC cells on OCC. More interestingly we were able to demonstrate an increased expression of CXCR4 in cancer cells co-cultured with the MSC, and increased thermoresistance in the subset of cancer cells with more interaction (as measured by oncologic trogocytosis). Conclusions: This study proved that contact and non contact-based cell to cell interactions between MSC cells and OCC help ovarian cancer cells resist hyperthermia. Within these interactions, MSC-secreted SDF-1 could be the major inducer of heat resistance. Combining monoclonal antibody against CXCR4 with hyperthermic intraperitoneal chemotherapy could eliminate the protective effect of tumor associated mesenchymal stem cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1006.
Published Version
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