Abstract 705: Interfering with mesenchymal stem cell-induced chemoresistance via COX-1 and thromboxane synthase inhibition
Authors: Roodhart Jeanine M.L. , Daenen Laura G.M , Stigter Edwin C.A. , Schipper Henk S. , Kalkhoven Erik , Medema Rene H. , Brenkman Arjan B. , Voest Emile E. 
Published: June 2012

Abstract
Background: Environment-mediated resistance to chemotherapy is emerging as a cause of treatment failure. We showed that mesenchymal stem cells (MSCs) induce resistance to a broad spectrum of chemotherapies. Upon platinum stimulation, two unique 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)) are produced by MSCs, which, via a paracrine mechanism, induce chemoresistance in tumors.
Aim: Here, we aim to prevent MSC-induced chemoresistance by blocking PIFA production.
Method: Various mouse models were established in which recruitment of MSCs to tumors was mimicked by iv administration of MSCs. Furthermore, cultured MSCs were treated with various drugs in order to block their chemo-protective capacity. Conditioned media were subsequently analyzed in vivo.
Results: Conditioned medium of platinum-stimulated, cultured MSCs induced chemoresistance in tumor-bearing mice. However, the capacity to secrete the chemo-protective PIFAs was only retained by mesenchymal cells with multi-lineage differentiation potential: MSCs and mouse embryonic fibroblasts (MEFs). More differentiated progeny from the mesenchymal lineage including 3T3 Fibroblasts, pre-adipocytes (3T3-L1), differentiated adipocytes, pre-osteoblasts (MC3T3) and differentiated osteoblasts were not capable of PIFA production upon platinum stimulation. Furthermore, this cytoprotective response was specific for multipotent cells from the mesenchymal lineage, since administration of hematopoietic stem cells did not influence the tumor response to chemotherapy.
One of the identified PIFAs, KHT(n-6), is known to be a by-product of thromboxane A2 synthesis, which is a downstream product of the cyclooxygenase (COX)-1 and thromboxane synthase (TxS) pathway. Interestingly, conditioned media from MSCs pre-treated with SC-560, a highly selective COX-1 inhibitor, indomethacin, a relatively selective COX-1 inhibitor or one of two specific TxS inhibitors (ozagrel and furegrelate) did not induce chemoresistance in vivo. Of note, selective COX-2 inhibition in MSC by celecoxib did not affect their capacity to induce chemoresistance, suggestive of a specific COX-1/TxS-dependent PIFA production. When mice were treated with either indomethacin or ozagrel as single agents no anti-tumor effect was observed. However, combining these drugs with cisplatin in vivo had an additive anti-tumor effect compared to cisplatin alone.
Conclusion: We show a novel mechanism of chemoresistance mediated by PIFA released from early, multipotent cells of the mesenchymal lineage. The production of these PIFAs is dependent on COX-1 and TxS, and blocking these enzymes enhanced the antitumor effects of cisplatin in vivo, making these enzymes drugable targets to prevent PIFA-induced chemoresistance.
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 705. doi:10.1158/1538-7445.AM2011-705