Abstract 893: The spleen as a key player in chemotherapy resistance.
Authors: Houthuijzen Julia M. , Daenen Laura G.M. , Roodhart Jeanine M.L. , Govaert Klaas M. , van Rooijen Nico , van de Lest Chris , Voest Emile E. 
Published: August 2014

Abstract
The development of resistance to chemotherapy is one of the most important obstacles to continued effective treatment of cancer in patients. Chemotherapy resistance is generally believed to be mediated by tumor cell-intrinsic factors or by the tumor microenvironment. We recently identified an important network that is responsible for reversible systemic resistance to chemotherapy. Mesenchymal stem cells (MSCs), activated by chemotherapy, secrete two specific polyunsaturated fatty acids that confer resistance to a broad spectrum of anti-cancer agents. These 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)), can independently induce chemotherapy resistance at picomolar concentrations. Our findings clearly showed that these PIFAs do not directly cause chemotherapy resistance in the tumor cells. Here, we show that the intermediate compartment between PIFAs and chemoresistance are F4/80 positive cells residing in the spleen. Several lines of evidence identified these splenocytes as key mediators of systemic chemoresistance. First, PIFAs were unable to induce resistance in splenectomized tumor-bearing mice. Second, administration of conditioned medium from splenocytes (sCM) activated by the PIFAs to splenectomized mice was able to re-introduce systemic chemotherapy resistance in various mouse models (mean tumor volume in mm3 8 days after treatment ± SEM control: 290.7 ± 33.4, cisplatin: 118.2 ± 8.9 and cisplatin + sCM: 261.1 ± 29.7). Third, analysis of the different cell types present in the spleen indicated that PIFA-activated F4/80+ /CD11blow expressing cells were able to induce systemic resistance in splenectomized mice. Finally, administration of liposomal clodronate to tumor-bearing mice treated with chemotherapy and PIFAs was able to inhibit induction of resistance. Thus, we propose a model where PIFAs activate F4/80+/CD11blow plenocytes leading to the production and secretion of secondary factors that induce resistance to chemotherapy. In addition, mass spectrometry analysis of the sCM from F4/80+/CD11blow splenocytes revealed that several lipid-like molecules were differentially present in the sCM of splenocytes cultured with 12-S-HHT versus splenocytes cultured with a vehicle control. Total lipids fractions extracted from spleen CM containing these lipid-like molecules were able to induce resistance in splenectomized mice. Taken together, our findings provide a novel role for the spleen in inducing a systemic protection against chemotherapy.
Citation Format: Julia M. Houthuijzen, Laura G.M. Daenen, Jeanine M.L. Roodhart, Klaas M. Govaert, Nico van Rooijen, Chris van de Lest, Emile E. Voest. The spleen as a key player in chemotherapy resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 893. doi:10.1158/1538-7445.AM2013-893