Tpl2 regulates intestinal myofibroblast HGF release to suppress colitis-associated tumorigenesis.
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.
Institute of Immunology, Biomedical Sciences Research Centre Alexander Fleming, Vari, Attica, Greece.
Vasiliki
V
Koliaraki
Manolis
M
Roulis
George
G
Kollias
D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001397:Azoxymethane / Q000009:adverse effects / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003092:Colitis / Q000139:chemically induced / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate / Q000009:adverse effects / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007414:Intestinal Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007422:Intestines / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000378:metabolism / Q000473:pathology; D058628:Myofibroblasts / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D002273:Carcinogens; C553307:HGF protein, mouse; D011518:Proto-Oncogene Proteins; D017228:Hepatocyte Growth Factor; D016264:Dextran Sulfate; D019859:Proto-Oncogene Proteins c-met; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse; D001397:Azoxymethane