TAM receptors Tyro3 and Mer as novel targets in colorectal cancer.

// Robin Schmitz 1 , Aida Freire Valls 1, 2 , Rosario Yerbes 2 , Sophie von Richter 1 , Christoph Kahlert 3 , Sonja Loges 4 , Jurgen Weitz 3 , Martin Schneider 1 , Carmen Ruiz de Almodovar 2 , Alexis Ulrich 1 , Thomas Schmidt 1 1 Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University Heidelberg, Heidelberg, Germany 2 Biochemistry Center, University of Heidelberg, Heidelberg, Germany 3 Department of Visceral, Thoracic and Vascular Surgery, University of Dresden, Dresden, Germany 4 Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Correspondence to: Thomas Schmidt, email: thomas.schmidt1@med.uni-heidelberg.de Keywords: colorectal cancer, tyro3, Mer, Gas6, macrophages Received: January 25, 2016      Accepted: June 26, 2016      Published: July 28, 2016 ABSTRACT Purpose: CRC remains the third most common cancer worldwide with a high 5-year mortality rate in advanced cases. Combined with chemotherapy, targeted therapy is an additional treatment option. However as CRC still escapes targeted therapy the vigorous search for new targets is warranted to increase patients´ overall survival. Results: In this study we describe a new role for Gas6/protein S-TAM receptor interaction in CRC. Gas6, expressed by tumor-infiltrating M2-like macrophages, enhances malignant properties of tumor cells including proliferation, invasion and colony formation. Upon chemotherapy macrophages increase Gas6 synthesis, which significantly attenuates the cytotoxic effect of 5-FU chemotherapy on tumor cells. The anti-coagulant protein S has similar effects as Gas6. In CRC patient samples Tyro3 was overexpressed within the tumor. In-vitro inhibition of Tyro3 and Mer reduces tumor cell proliferation and sensitizes tumor cells to chemotherapy. Moreover high expression of Tyro3 and Mer in tumor tissue significantly shortens CRC patients´ survival. Experimental design: Various in vitro models were used to investigate the role of Gas6 and its TAM receptors in human CRC cells, by stimulation (rhGas6) and knockdown (siRNA) of Axl, Tyro3 and Mer. In terms of a translational research, we additionally performed an expression analysis in human CRC tissue and analyzed the medical record of these patients. Conclusions: Tyro3 and Mer represent novel therapeutic targets in CRC and warrant further preclinical and clinical investigation in the future.