Abstract 800: Formation of chemotherapy resistance-inducing fatty acids by mesenchymal stem cells depends on COX-1, thromboxane synthase and intracellular calcium

The development of resistance to chemotherapy is considered to be one of the most important obstacles to continued effective treatment of cancer in patients. We recently have identified an important mechanism that is responsible for systemic resistance to chemotherapy. Circulating mesenchymal stem cells (MSCs) activated by chemotherapy secrete specific polyunsaturated fatty acids that confer resistance to a broad spectrum of anti-cancer agents. These factors were identified to be two distinct platinum-induced polyunsaturated fatty acids (PIFAs) 12-S-keto-5,8,10-heptadecatrienoic acid (KHT) and 4,7,10,13-hexadecatetraenoic acid (16:4(n-3)) that were able to induce chemotherapy resistance in picomolar concentrations. Interestingly, the production of these PIFAs is restricted to MSCs and mouse embryonic fibroblasts (MEFs), other stem cells like hematopoietic stem cells and cancer stem cells are not able to form the PIFAs after cisplatin stimulation. Research from our lab showed that the production of these PIFAs can be blocked by cyclooxygenase-1 (COX-1), thromboxane A synthase (TXAS) and intracellular calcium inhibitors, suggesting that these are important in the production of the PIFAs, and indicating that the PIFAs are formed in the pathways of arachidonic acid (AA) and eicosapentaenoic acid (EPA). Lipid peroxidation with subsequent release of oxygen radicals could be a trigger for the formation of PIFA. We therefore tested whether reactive oxygen species (ROS) were involved in the production of the PIFAs. Neither increasing ROS by hydrogen peroxide, nor scavenging of ROS by glutathione in the MSCs influenced the level of resistance to chemotherapy in mice. In addition, intracellular ROS levels in the MSCs treated with cisplatin for various intervals did not change as was determined by DCFDA fluorescence. Our findings provide a new paradigm on how MSCs can induce a systemic protection against chemotherapy through the secretion of two distinct fatty acids that are formed in response to platinum-containing chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 800. doi:1538-7445.AM2012-800