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Download Mesenchymal stem cells as key players in chemotherapy resistance
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Mesenchymal stem cells as key players in chemotherapy resistance Julia Houthuijzen Molecular Oncology Netherlands Cancer Institute Emile Voest Introduction • Chemotherapy is one of the most used anti-cancer treatments • Of the top 10 most common cancer types combined 50% of patients receive chemotherapy • Problem is development of resistance to chemotherapy • Tumor intrinsic • Mutations that affect drug metabolism • Tumor extrinsic • Tumor microenvironment • Host-mediated resistance http://chemoth.com/economics, Meads et al. 2009 Mesenchymal stem cells, friend or foe? • MSCs home to damaged tissues • Differentiation • Induction of repair • MSCs have immune suppressive function • Succesfully used for treatment in myocardial infarction and graft-vs-host disease • These functions can influence tumor progression Loebinger et al. 2009 Cancer Res. Patel et al. 2010 J Immunol. Mesenchymal stem cells, friend or foe? Houthuijzen et al. Brit J Cancer 2012, Daenen et al. Oncogene 2014 MSCs induce chemotherapy resistance Roodhart et al. Cancer Cell 2011 Secreted factors from MSCs induce chemoresistance • Very little homing of GFP+ MSCs to the tumor (0.05-0.1%) • Effect due to secreted factors from MSCs Roodhart et al. Cancer Cell 2011 Platinum-induced fatty acids mediate chemotherapy resistance 12-S-HHT 16:4(n-3) Roodhart et al. Cancer Cell 2011 Only platinum-containing chemotherapeutics can activate MSCs to produce PIFAs Roodhart et al. Cancer Cell 2011 PIFAs only protect against DNAdamaging chemotherapeutics Houthuijzen et al. Nature Comms 2014 16:4(n-3) and 12-S-HHT induce resistance independently and is reversible Roodhart et al. Cancer Cell 2011 PIFA production is dependent on COX-1, cPLA2 and TXAS Roodhart et al. Cancer Cell 2011 Inhibition of COX-1 or TXAS increases chemotherapy efficacy Phase I clinical trail to determine safety of combination treatment of platinumbased chemotherapy and indomethacine Roodhart et al. Cancer Cell 2011 Resistance inducing potential is restricted to MSCs and MEFs cPLA2 COX-1 TXAS iCa2+ ? Roodhart et al. Cancer Cell 2011 cPLA2 expression is restricted to MSCs + + CD45 – – bone marrow n+ Li n/C D4 Li 5+ n/C D4 5- Lineage markers Li BM p-cPLA 2 cPLA 2 Actin Unpublished data ? PIFAs protect against chemotherapy by altering the DNA-damage response Houthuijzen et al. Nature Comms 2014 PIFAs protect against chemotherapy by altering the DNA-damage response PIFAs protect against chemotherapy by altering the DNA-damage response No HR restored HR Unpublished data Conclusions • MSCs induce chemotherapy resistance via the release of PIFAs • PIFA production is initiated by platinum-based chemotherapeutics • PIFAs induce resistance against a broad range of DNA damaging drugs • PIFA production is restricted to MSCs and MEFs • Differentiation leads to loss of PIFA production • COX-1, cPLA2 and TXAS are required for PIFA production • cPLA2 expression is limited to MSCs • PIFAs function by altering the DNA damage response Acknowledgements University Medical Center Utrecht & Netherlands Cancer Institute • Prof. Emile Voest University of Kyoto, Japan • Jeanine Roodhart • Akira Hirasawa • Laura Daenen • Miranda van Amersfoort University of Glasgow, Scotland • Johan Gerrits • Brain Hudson • Edwin Stigter • Graeme Milligan • Chris van de Lest • Sven Rottenberg National Research Institute of Fisheries, Japan • Kenji Ishihara University of Louisville, KY, USA • Bodduluri Haribabu University of South Denmark • Trond Ulven
