TGF-β Receptor Inactivation and Mutant Kras Induce Intestinal Neoplasms in Mice via a β-Catenin-Independent Pathway

Patty Trobridge, Sue Knoblaugh, M. Kay Washington, Nina M. Munoz, Karen D. Tsuchiya, Andres Rojas, Xiaoling Song, Cornelia M. Ulrich, Takehiko Sasazuki, Senji Shirasawa, William M. Grady

研究成果: ジャーナルへの寄稿記事

72 引用 (Scopus)

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Background & Aims: During colorectal cancer pathogenesis, mutations and epigenetic events cause neoplastic behavior in epithelial cells by deregulating the Wnt, Ras-Raf-extracellular signal-regulated kinase (ERK), and transforming growth factor (TGF)-β-signaling pathways, among others. The TGF-β-signaling pathway is often inactivated in colon cancer cells by mutations in the gene encoding the TGF-β receptor TGFBR2. The RAS-RAF-ERK pathway is frequently up-regulated in colon cancer via mutational activation of KRAS or BRAF. We assessed how these pathways interact in vivo and affect formation of colorectal tumors. Methods: We analyzed intestinal tumors that arose in mice that express an oncogenic (active) form of Kras and that have Tgfbr2 inactivations-2 common molecular events observed in human colorectal tumors. LSL-KrasG12D mice were crossed with Villin-Cre;Tgfbr2E2flx/E2flx mice, which do not express Tgfbr2 in the intestinal epithelium. Results: Neither inactivation of Tgfbr2 nor expression of oncogenic Kras alone was sufficient to induce formation of intestinal neoplasms. Histologic abnormalities arose in mice that expressed Kras, but only the combination of Tgfbr2 inactivation and Kras activation led to intestinal neoplasms and metastases. The cancers arose via a β-catenin-independent mechanism; the epidermal growth factor-signaling pathway was also activated. Cells in the resulting tumors proliferated at higher rates, expressed decreased levels of p15, and expressed increased levels of cyclin D1 and cdk4, compared with control cells. Conclusions: A combination of inactivation of the TGF-β-signaling pathway and expression of oncogenic Kras leads to formation of invasive intestinal neoplasms through a β-catenin-independent pathway; these adenocarcinomas have the capacity to metastasize.

元の言語英語
ジャーナルGastroenterology
136
発行部数5
DOI
出版物ステータス出版済み - 1 1 2009
外部発表Yes

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Intestinal Neoplasms
Catenins
Growth Factor Receptors
Transforming Growth Factors
Colorectal Neoplasms
Extracellular Signal-Regulated MAP Kinases
Colonic Neoplasms
Neoplasms
Mutation
Cyclin D1
Intestinal Mucosa
Epidermal Growth Factor
Epigenomics
Adenocarcinoma
Epithelial Cells
Neoplasm Metastasis
Genes

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

これを引用

Trobridge, P., Knoblaugh, S., Washington, M. K., Munoz, N. M., Tsuchiya, K. D., Rojas, A., ... Grady, W. M. (2009). TGF-β Receptor Inactivation and Mutant Kras Induce Intestinal Neoplasms in Mice via a β-Catenin-Independent Pathway. Gastroenterology, 136(5). https://doi.org/10.1053/j.gastro.2009.01.066

TGF-β Receptor Inactivation and Mutant Kras Induce Intestinal Neoplasms in Mice via a β-Catenin-Independent Pathway. / Trobridge, Patty; Knoblaugh, Sue; Washington, M. Kay; Munoz, Nina M.; Tsuchiya, Karen D.; Rojas, Andres; Song, Xiaoling; Ulrich, Cornelia M.; Sasazuki, Takehiko; Shirasawa, Senji; Grady, William M.

:: Gastroenterology, 巻 136, 番号 5, 01.01.2009.

研究成果: ジャーナルへの寄稿記事

Trobridge, P, Knoblaugh, S, Washington, MK, Munoz, NM, Tsuchiya, KD, Rojas, A, Song, X, Ulrich, CM, Sasazuki, T, Shirasawa, S & Grady, WM 2009, 'TGF-β Receptor Inactivation and Mutant Kras Induce Intestinal Neoplasms in Mice via a β-Catenin-Independent Pathway', Gastroenterology, 巻. 136, 番号 5. https://doi.org/10.1053/j.gastro.2009.01.066
Trobridge, Patty ; Knoblaugh, Sue ; Washington, M. Kay ; Munoz, Nina M. ; Tsuchiya, Karen D. ; Rojas, Andres ; Song, Xiaoling ; Ulrich, Cornelia M. ; Sasazuki, Takehiko ; Shirasawa, Senji ; Grady, William M. / TGF-β Receptor Inactivation and Mutant Kras Induce Intestinal Neoplasms in Mice via a β-Catenin-Independent Pathway. :: Gastroenterology. 2009 ; 巻 136, 番号 5.
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abstract = "Background & Aims: During colorectal cancer pathogenesis, mutations and epigenetic events cause neoplastic behavior in epithelial cells by deregulating the Wnt, Ras-Raf-extracellular signal-regulated kinase (ERK), and transforming growth factor (TGF)-β-signaling pathways, among others. The TGF-β-signaling pathway is often inactivated in colon cancer cells by mutations in the gene encoding the TGF-β receptor TGFBR2. The RAS-RAF-ERK pathway is frequently up-regulated in colon cancer via mutational activation of KRAS or BRAF. We assessed how these pathways interact in vivo and affect formation of colorectal tumors. Methods: We analyzed intestinal tumors that arose in mice that express an oncogenic (active) form of Kras and that have Tgfbr2 inactivations-2 common molecular events observed in human colorectal tumors. LSL-KrasG12D mice were crossed with Villin-Cre;Tgfbr2E2flx/E2flx mice, which do not express Tgfbr2 in the intestinal epithelium. Results: Neither inactivation of Tgfbr2 nor expression of oncogenic Kras alone was sufficient to induce formation of intestinal neoplasms. Histologic abnormalities arose in mice that expressed Kras, but only the combination of Tgfbr2 inactivation and Kras activation led to intestinal neoplasms and metastases. The cancers arose via a β-catenin-independent mechanism; the epidermal growth factor-signaling pathway was also activated. Cells in the resulting tumors proliferated at higher rates, expressed decreased levels of p15, and expressed increased levels of cyclin D1 and cdk4, compared with control cells. Conclusions: A combination of inactivation of the TGF-β-signaling pathway and expression of oncogenic Kras leads to formation of invasive intestinal neoplasms through a β-catenin-independent pathway; these adenocarcinomas have the capacity to metastasize.",
author = "Patty Trobridge and Sue Knoblaugh and Washington, {M. Kay} and Munoz, {Nina M.} and Tsuchiya, {Karen D.} and Andres Rojas and Xiaoling Song and Ulrich, {Cornelia M.} and Takehiko Sasazuki and Senji Shirasawa and Grady, {William M.}",
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T1 - TGF-β Receptor Inactivation and Mutant Kras Induce Intestinal Neoplasms in Mice via a β-Catenin-Independent Pathway

AU - Trobridge, Patty

AU - Knoblaugh, Sue

AU - Washington, M. Kay

AU - Munoz, Nina M.

AU - Tsuchiya, Karen D.

AU - Rojas, Andres

AU - Song, Xiaoling

AU - Ulrich, Cornelia M.

AU - Sasazuki, Takehiko

AU - Shirasawa, Senji

AU - Grady, William M.

PY - 2009/1/1

Y1 - 2009/1/1

N2 - Background & Aims: During colorectal cancer pathogenesis, mutations and epigenetic events cause neoplastic behavior in epithelial cells by deregulating the Wnt, Ras-Raf-extracellular signal-regulated kinase (ERK), and transforming growth factor (TGF)-β-signaling pathways, among others. The TGF-β-signaling pathway is often inactivated in colon cancer cells by mutations in the gene encoding the TGF-β receptor TGFBR2. The RAS-RAF-ERK pathway is frequently up-regulated in colon cancer via mutational activation of KRAS or BRAF. We assessed how these pathways interact in vivo and affect formation of colorectal tumors. Methods: We analyzed intestinal tumors that arose in mice that express an oncogenic (active) form of Kras and that have Tgfbr2 inactivations-2 common molecular events observed in human colorectal tumors. LSL-KrasG12D mice were crossed with Villin-Cre;Tgfbr2E2flx/E2flx mice, which do not express Tgfbr2 in the intestinal epithelium. Results: Neither inactivation of Tgfbr2 nor expression of oncogenic Kras alone was sufficient to induce formation of intestinal neoplasms. Histologic abnormalities arose in mice that expressed Kras, but only the combination of Tgfbr2 inactivation and Kras activation led to intestinal neoplasms and metastases. The cancers arose via a β-catenin-independent mechanism; the epidermal growth factor-signaling pathway was also activated. Cells in the resulting tumors proliferated at higher rates, expressed decreased levels of p15, and expressed increased levels of cyclin D1 and cdk4, compared with control cells. Conclusions: A combination of inactivation of the TGF-β-signaling pathway and expression of oncogenic Kras leads to formation of invasive intestinal neoplasms through a β-catenin-independent pathway; these adenocarcinomas have the capacity to metastasize.

AB - Background & Aims: During colorectal cancer pathogenesis, mutations and epigenetic events cause neoplastic behavior in epithelial cells by deregulating the Wnt, Ras-Raf-extracellular signal-regulated kinase (ERK), and transforming growth factor (TGF)-β-signaling pathways, among others. The TGF-β-signaling pathway is often inactivated in colon cancer cells by mutations in the gene encoding the TGF-β receptor TGFBR2. The RAS-RAF-ERK pathway is frequently up-regulated in colon cancer via mutational activation of KRAS or BRAF. We assessed how these pathways interact in vivo and affect formation of colorectal tumors. Methods: We analyzed intestinal tumors that arose in mice that express an oncogenic (active) form of Kras and that have Tgfbr2 inactivations-2 common molecular events observed in human colorectal tumors. LSL-KrasG12D mice were crossed with Villin-Cre;Tgfbr2E2flx/E2flx mice, which do not express Tgfbr2 in the intestinal epithelium. Results: Neither inactivation of Tgfbr2 nor expression of oncogenic Kras alone was sufficient to induce formation of intestinal neoplasms. Histologic abnormalities arose in mice that expressed Kras, but only the combination of Tgfbr2 inactivation and Kras activation led to intestinal neoplasms and metastases. The cancers arose via a β-catenin-independent mechanism; the epidermal growth factor-signaling pathway was also activated. Cells in the resulting tumors proliferated at higher rates, expressed decreased levels of p15, and expressed increased levels of cyclin D1 and cdk4, compared with control cells. Conclusions: A combination of inactivation of the TGF-β-signaling pathway and expression of oncogenic Kras leads to formation of invasive intestinal neoplasms through a β-catenin-independent pathway; these adenocarcinomas have the capacity to metastasize.

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U2 - 10.1053/j.gastro.2009.01.066

DO - 10.1053/j.gastro.2009.01.066

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