title: Suppressing TGFβ signaling in regenerating epithelia in an inflammatory microenvironment is sufficient to cause invasive intestinal cancer.
abstract: Genetic alterations in the TGFβ signaling pathway in combination with oncogenic alterations lead to cancer development in the intestines. However, the mechanisms of TGFβ signaling suppression in malignant progression of intestinal tumors have not yet been fully understood. We have examined Apc(Δ716) Tgfbr2(ΔIEC) compound mutant mice that carry mutations in Apc and Tgfbr2 genes in the intestinal epithelial cells. We found inflammatory microenvironment only in the invasive intestinal adenocarcinomas but not in noninvasive benign polyps of the same mice. We thus treated simple Tgfbr2(ΔIEC) mice with dextran sodium sulfate (DSS) that causes ulcerative colitis. Importantly, these Tgfbr2(ΔIEC) mice developed invasive colon cancer associated with chronic inflammation. We also found that TGFβ signaling is suppressed in human colitis-associated colon cancer cells. In the mouse invasive tumors, macrophages infiltrated and expressed MT1-MMP, causing MMP2 activation. These results suggest that inflammatory microenvironment contributes to submucosal invasion of TGFβ signaling-repressed epithelial cells through activation of MMP2. We further found that regeneration was impaired in Tgfbr2(ΔIEC) mice for intestinal mucosa damaged by DSS treatment or X-ray irradiation, resulting in the expansion of undifferentiated epithelial cell population. Moreover, organoids of intestinal epithelial cells cultured from irradiated Tgfbr2(ΔIEC) mice formed "long crypts" in Matrigel, suggesting acquisition of an invasive phenotype into the extracellular matrix. These results, taken together, indicate that a simple genetic alteration in the TGFβ signaling pathway in the inflamed and regenerating intestinal mucosa can cause invasive intestinal tumors. Such a mechanism may play a role in the colon carcinogenesis associated with inflammatory bowel disease in humans.
authors: Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors: Hiroko
authors: H
authors: Oshima
authors: Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. Core Research for Evolutional Science and Technology (CREST), the Japan Science and Technology Agency, Tokyo, Japan.
authors: Mizuho
authors: M
authors: Nakayama
authors: Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. Core Research for Evolutional Science and Technology (CREST), the Japan Science and Technology Agency, Tokyo, Japan.
authors: Tae-Su
authors: TS
authors: Han
authors: Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors: Kuniko
authors: K
authors: Naoi
authors: Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors: Xiaoli
authors: X
authors: Ju
authors: Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors: Yusuke
authors: Y
authors: Maeda
authors: Equipe de Morphogenese et Signalisation cellulaires, Institut Curie, Paris, France.
authors: Sylvie
authors: S
authors: Robine
authors: Department of Advanced Therapeutics for Gastrointestinal Disease, Graduate School Tokyo Medical and Dental University, Tokyo, Japan.
authors: Kiichiro
authors: K
authors: Tsuchiya
authors: Department of Gastroenterology, Keio University School of Medicine, Tokyo, Japan.
authors: Toshiro
authors: T
authors: Sato
authors: Division of Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors: Hiroshi
authors: H
authors: Sato
authors: Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors: Makoto Mark
authors: MM
authors: Taketo
authors: Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. oshimam@staff.kanazawa-u.ac.jp.
authors: Masanobu
authors: M
authors: Oshima
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D007414:Intestinal Neoplasms / Q000235:genetics*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics*; D059016:Tumor Microenvironment
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse