title: TAM receptors Tyro3 and Mer as novel targets in colorectal cancer.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Tyro3 and Mer represent novel therapeutic targets in CRC and warrant further preclinical and clinical investigation in the future.
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University Heidelberg, Heidelberg, Germany.
authors.forename: Robin
authors.initials: R
authors.lastname: Schmitz
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University Heidelberg, Heidelberg, Germany.|Biochemistry Center, University of Heidelberg, Heidelberg, Germany.
authors.forename: Aida Freire
authors.initials: AF
authors.lastname: Valls
authors.affiliation: Biochemistry Center, University of Heidelberg, Heidelberg, Germany.
authors.forename: Rosario
authors.initials: R
authors.lastname: Yerbes
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University Heidelberg, Heidelberg, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: von Richter
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, University of Dresden, Dresden, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kahlert
authors.affiliation: Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Loges
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, University of Dresden, Dresden, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Weitz
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University Heidelberg, Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Biochemistry Center, University of Heidelberg, Heidelberg, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ruiz de Almodovar
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University Heidelberg, Heidelberg, Germany.
authors.forename: Alexis
authors.initials: A
authors.lastname: Ulrich
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University Heidelberg, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmidt
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D001798:Blood Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D017293:Protein S; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D000076202:c-Mer Tyrosine Kinase / Q000235:genetics / Q000378:metabolism*; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D000964:Antimetabolites, Antineoplastic; D001798:Blood Proteins; D005472:Fluorouracil; D036341:Intercellular Signaling Peptides and Proteins; D017293:Protein S; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases; D011994:Recombinant Proteins; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C523390:PROS1 protein, human; C097072:MERTK protein, human; C084944:TYRO3 protein, human
keywords: Gas6; Mer; colorectal cancer; macrophages; tyro3