Abstract 697: Mesenchymal stem cell-induced resistance: Implications for reversible resistance
Authors: Daenen Laura , Roodhart Jeanine M.L. , Stigter Edwin C.A. , Beijnen Jos H. , Medema Rene H. , Brenkman Arjan B. , Voest Emile E. 
Published: June 2012

Abstract
Background. We showed that mesenchymal stem cells (MSCs) induce chemoresistance via a paracrine mechanism. Upon platinum exposure, MSCs produce cytoprotective factors that induce resistance to a broad spectrum of chemotherapies. Via a metabolomics approach, two unique platinum-induced polyunsaturated fatty acids (PIFAs), 12-oxo-5,8,10-heptadecatrienoic acid (KHT(n-6)) and hexadeca-4,7,10,13-tetraenoic acid (16:4(n-3)) were identified as responsible factors.
Aim. We aimed to characterize the tumor cell response to the PIFAs that mediate a novel form of chemoresistance.
Methods. Various tumor-bearing mouse models were established in which recruitment of MSCs to tumors was mimicked by iv administration of MSCs. In addition, conditioned medium from MSCs, containing the cytoprotective PIFAs, was administered together with chemotherapy to mice.
Results. We determined that the PIFAs had to be present within three hours of start of cisplatin treatment to exert their protective effect. When the interval between chemotherapy and PIFA administration was longer, tumors remained sensitive to the therapy, indicating that the protective factors intervene with the early effects of chemotherapy. Furthermore, the tumor-protective effect exerted by the PIFAs was reversible, as omitting the PIFAs during a subsequent cycle of cisplatin restored sensitivity to chemotherapy. Interestingly, a single MSC administration to tumor-bearing mice induced permanent resistance to chemotherapy during at least three following treatment cycles, suggestive of a continuous PIFA production by activated MSCs in vivo. The early, reversible effects of the PIFAs could point to alterered pharmacokinetics (PK) as mechanism behind the observed chemoresistance. To address this PK of both cisplatin, irinotecan (CPT-11) and its active metabolite SN-38 were measured in plasma and tumor tissue. However, no differences were observed in the PK in the presence or absence of PIFAs 16:4(n-3) and KHT(n-6), confirming similar chemotherapeutic exposure of the tumors. When adding the PIFAs to tumor cells in vitro, no resistance to chemotherapy was observed, suggestive of an indirect effect of these fatty acids in vivo. This was confirmed when the PIFAs were injected into mice and subsequently mouse blood was harvested in order to incubate this with tumor cells. Plasma of the mice that had been pretreated with PIFAs conferred resistance to chemotherapy, suggestive of a secondary, circulating factor that is produced in response to the PIFAs in mice.
Conclusion. We conclude that minute quantities of 16:4(n-3) and KHT(n-6), fatty acids excreted by MSCs, induced an indirect, acute and reversible protection of tumor cells. A decreased tumor exposure to cytotoxic agents was excluded as a potential explanation. These findings point to an intricate production of cytoprotective factors regulated by the interplay between MSC and a yet unknown cellular compartment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 697. doi:10.1158/1538-7445.AM2011-697