Tpl2 regulates intestinal myofibroblast HGF release to suppress colitis-associated tumorigenesis

J Clin Invest. 2012 Nov;122(11):4231-42. doi: 10.1172/JCI63917. Epub 2012 Oct 15.


The tumor microenvironment plays a significant role in colitis-associated cancer (CAC). Intestinal myofibroblasts (IMFs) are cells in the intestinal lamina propria secreting factors that are known to modulate carcinogenesis; however, the physiological role of IMFs and signaling pathways influencing CAC have remained unknown. Tumor progression locus 2 (Tpl2) is a MAPK that regulates inflammatory and oncogenic pathways. In this study we addressed the role of Tpl2 in CAC using complete and tissue-specific ablation of Tpl2 in mutant mice. Tpl2-deficient mice did not exhibit significant differences in inflammatory burdens following azoxymethane (AOM)/dextran sodium sulfate (DSS) administration compared with wild-type mice; however, the mutant mice developed significantly increased numbers and sizes of tumors, associated with enhanced epithelial proliferation and decreased apoptosis. Cell-specific ablation of Tpl2 in IMFs, but not in intestinal epithelial or myeloid cells, conferred a similar susceptibility to adenocarcinoma formation. Tpl2-deficient IMFs upregulated HGF production and became less sensitive to the negative regulation of HGF by TGF-β3. In vivo inhibition of HGF-mediated c-Met activation blocked early, enhanced colon dysplasia in Tpl2-deficient mice, indicating that Tpl2 normally suppresses the HGF/c-Met pathway. These findings establish a mesenchyme-specific role for Tpl2 in the regulation of HGF production and suppression of epithelial tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / etiology
  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology
  • Animals
  • Azoxymethane / adverse effects
  • Azoxymethane / pharmacology
  • Carcinogens / pharmacology
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Colitis / chemically induced
  • Colitis / complications
  • Colitis / genetics
  • Colitis / metabolism*
  • Colitis / pathology
  • Dextran Sulfate / adverse effects
  • Dextran Sulfate / pharmacology
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / metabolism*
  • Intestinal Mucosa / metabolism*
  • Intestinal Neoplasms / etiology
  • Intestinal Neoplasms / genetics
  • Intestinal Neoplasms / metabolism*
  • Intestinal Neoplasms / pathology
  • Intestines / pathology
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • Mice
  • Mice, Knockout
  • Mucous Membrane / metabolism
  • Mucous Membrane / pathology
  • Myofibroblasts / metabolism*
  • Myofibroblasts / pathology
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism
  • Signal Transduction*


  • Carcinogens
  • HGF protein, mouse
  • Proto-Oncogene Proteins
  • Hepatocyte Growth Factor
  • Dextran Sulfate
  • Proto-Oncogene Proteins c-met
  • MAP Kinase Kinase Kinases
  • Map3k8 protein, mouse
  • Azoxymethane