Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer

Proc Natl Acad Sci U S A. 2013 Aug 6;110(32):13091-6. doi: 10.1073/pnas.1302507110. Epub 2013 Jul 22.


The receptor tyrosine kinases Axl and Mer, belonging to the Tyro3, Axl and Mer (TAM) receptor family, are expressed in a number of tumor cells and have well-characterized oncogenic roles. The therapeutic targeting of these kinases is considered an anticancer strategy, and various inhibitors are currently under development. At the same time, Axl and Mer are expressed in dendritic cells and macrophages and have an essential function in limiting inflammation. Inflammation is an enabling characteristic of multiple cancer hallmarks. These contrasting oncogenic and anti-inflammatory functions of Axl and Mer posit a potential paradox in terms of anticancer therapy. Here we demonstrate that azoxymethane (AOM) and dextran sulfate sodium (DSS)-induced inflammation-associated cancer is exacerbated in mice lacking Axl and Mer. Ablation of Axl and Mer signaling is associated with increased production of proinflammatory cytokines and failure to clear apoptotic neutrophils in the intestinal lamina propria, thereby favoring a tumor-promoting environment. Interestingly, loss of these genes in the hematopoietic compartment is not associated with increased colitis. Axl and Mer are expressed in radioresistant intestinal macrophages, and the loss of these genes is associated with an increased inflammatory signature in this compartment. Our results raise the possibility of potential adverse effects of systemic anticancer therapies with Axl and Mer inhibitors, and underscore the importance of understanding their tissue and cell type-specific functions in cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / immunology
  • Axl Receptor Tyrosine Kinase
  • Azoxymethane
  • Colitis / chemically induced
  • Colitis / genetics
  • Colitis / immunology*
  • Colon / immunology
  • Colon / metabolism
  • Colon / pathology
  • Colonic Neoplasms / chemically induced
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / immunology*
  • Cytokines / genetics
  • Cytokines / immunology
  • Dextran Sulfate
  • Female
  • Flow Cytometry
  • Gene Expression / immunology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Mucous Membrane / immunology
  • Mucous Membrane / metabolism
  • Mucous Membrane / pathology
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Phagocytosis / genetics
  • Phagocytosis / immunology
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / immunology*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / immunology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • c-Mer Tyrosine Kinase


  • Cytokines
  • Proto-Oncogene Proteins
  • Dextran Sulfate
  • Mertk protein, mouse
  • Receptor Protein-Tyrosine Kinases
  • c-Mer Tyrosine Kinase
  • Azoxymethane
  • Axl Receptor Tyrosine Kinase
  • AXL receptor tyrosine kinase, mouse