Suppressing TGFβ signaling in regenerating epithelia in an inflammatory microenvironment is sufficient to cause invasive intestinal cancer

Hiroko Oshima, Mizuho Nakayama, Tae Su Han, Kuniko Naoi, Xiaoli Ju, Yusuke Maeda, Sylvie Robine, Kiichiro Tsuchiya, Toshiro Sato, Hiroshi Sato, Makoto Mark Taketo, Masanobu Oshima

Research output: Contribution to journalArticle

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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 ApcΔ716 TGFβr2ΔIEC compound mutant mice that carry mutations in Apc and TGFβr2 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 TGFβr2ΔIEC mice with dextran sodium sulfate (DSS) that causes ulcerative colitis. Importantly, these TGFβr2ΔIEC mice developed invasive colon cancer associated with chronic inflammation.Wealso found that TGFβ signaling is suppressed in human colitis-associated colon cancer cells. In the mouse invasive tumors, macrophages infiltrated and expressed MT1-MMP, causingMMP2activation. 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 TGFβr2ΔIEC 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 TGFβr2ΔIEC 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.

Original languageEnglish
Pages (from-to)766-776
Number of pages11
JournalCancer Research
Volume75
Issue number4
DOIs
Publication statusPublished - 2015 Feb 15

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Intestinal Neoplasms
Epithelium
Epithelial Cells
Dextran Sulfate
Intestinal Mucosa
Colonic Neoplasms
Neoplasms
Organoids
Matrix Metalloproteinase 14
Colitis
Polyps
Ulcerative Colitis
Inflammatory Bowel Diseases
Intestines
Extracellular Matrix
Regeneration
Colon
Carcinogenesis
Adenocarcinoma
Macrophages

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Suppressing TGFβ signaling in regenerating epithelia in an inflammatory microenvironment is sufficient to cause invasive intestinal cancer. / Oshima, Hiroko; Nakayama, Mizuho; Han, Tae Su; Naoi, Kuniko; Ju, Xiaoli; Maeda, Yusuke; Robine, Sylvie; Tsuchiya, Kiichiro; Sato, Toshiro; Sato, Hiroshi; Taketo, Makoto Mark; Oshima, Masanobu.

In: Cancer Research, Vol. 75, No. 4, 15.02.2015, p. 766-776.

Research output: Contribution to journalArticle

Oshima, H, Nakayama, M, Han, TS, Naoi, K, Ju, X, Maeda, Y, Robine, S, Tsuchiya, K, Sato, T, Sato, H, Taketo, MM & Oshima, M 2015, 'Suppressing TGFβ signaling in regenerating epithelia in an inflammatory microenvironment is sufficient to cause invasive intestinal cancer', Cancer Research, vol. 75, no. 4, pp. 766-776. https://doi.org/10.1158/0008-5472.CAN-14-2036
Oshima, Hiroko ; Nakayama, Mizuho ; Han, Tae Su ; Naoi, Kuniko ; Ju, Xiaoli ; Maeda, Yusuke ; Robine, Sylvie ; Tsuchiya, Kiichiro ; Sato, Toshiro ; Sato, Hiroshi ; Taketo, Makoto Mark ; Oshima, Masanobu. / Suppressing TGFβ signaling in regenerating epithelia in an inflammatory microenvironment is sufficient to cause invasive intestinal cancer. In: Cancer Research. 2015 ; Vol. 75, No. 4. pp. 766-776.
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AU - Ju, Xiaoli

AU - Maeda, Yusuke

AU - Robine, Sylvie

AU - Tsuchiya, Kiichiro

AU - Sato, Toshiro

AU - Sato, Hiroshi

AU - Taketo, Makoto Mark

AU - Oshima, Masanobu

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AB - 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 ApcΔ716 TGFβr2ΔIEC compound mutant mice that carry mutations in Apc and TGFβr2 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 TGFβr2ΔIEC mice with dextran sodium sulfate (DSS) that causes ulcerative colitis. Importantly, these TGFβr2ΔIEC mice developed invasive colon cancer associated with chronic inflammation.Wealso found that TGFβ signaling is suppressed in human colitis-associated colon cancer cells. In the mouse invasive tumors, macrophages infiltrated and expressed MT1-MMP, causingMMP2activation. 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 TGFβr2ΔIEC 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 TGFβr2ΔIEC 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.

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