<i>Tgfbr1</i>Haploinsufficiency Is a Potent Modifier of Colorectal Cancer Development

Zeng, Qinghua; Phukan, Sharbani; Xu, Yanfei; Sadim, Maureen; Rosman, Diana S.; Pennison, Michael J.; Liao, Jie; Yang, Guang; Huang, Chiang Ching; Valle, Laura; Cristofano, Antonio Di; Chapelle, Albert de la; Pasche, Boris

doi:10.1158/0008-5472.can-08-3980

Cited by 51 publications

(45 citation statements)

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“…Tgfbr1 haploinsufficiency recapitulates the human condition because reduced protein level is observed in cancerized ducts of the pancreas compared with robust levels in neighboring parenchyma (7). Two recent reports suggest that constitutively decreased TGFBR1 expression is a potent modifier of colon cancer risk in mice (13) and humans (14). These findings were the impetus behind our initial hypothesis.…”

Section: Discussionmentioning

confidence: 75%

“…+/− mice were generated as previously described (13,16). EL-Kras FVB male mice were bred to Tgfbr1 +/− C57/BL6 females.…”

Section: Mice El-kras Transgenic and Tgfbr1mentioning

confidence: 99%

“…However, the effects of reduced Tgfbr1 on mutant Krasinduced precancerous lesions have not been established in vivo. Given the central role played by Tgfbr1, which initiates the TGF-β signaling cascade, and the novel evidence that constitutively decreased Tgfbr1 expression is a potent modifier of mouse (13) and human (14) colorectal cancer, and the recent findings that a TGFBR1 haplotype is associated with non-small cell cancer risk (15), we undertook this study to characterize the role of decreased TGFBR1 signaling in PC.…”

Section: Introductionmentioning

confidence: 99%

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Tgfbr1 Haploinsufficiency Inhibits the Development of Murine Mutant Kras-Induced Pancreatic Precancer

et al. 2009

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To dissect the role of constitutively altered Tgfbr1 signaling in pancreatic cancer development, we crossed ElastaseKras G12D (EL-Kras) mice with Tgfbr1 haploinsufficient mice to generate EL-Kras/Tgfbr1 +/− mice. Mice were euthanized at 6 to 9 months to compare the incidence, frequency, and size of precancerous lesions in the pancreas. Only 50% of all EL-Kras/Tgfbr1 +/− mice developed preinvasive lesions compared with 100% of EL-Kras (wild-type Tgfbr1) mice. The frequency of precancerous lesions was 4-fold lower in haploinsufficient than in control mice. Paradoxically, the precancerous lesions of EL-Kras/Tgfbr1 +/− mice were considerably larger than those in EL-Kras mice. Yet, the mitotic index of precancerous cells and the observable levels of fibrosis, lipoatrophy, and lymphocytic infiltration were reduced in EL-Kras/Tgfbr1 +/− mice. We conclude that Tgfbr1 signaling promotes the development of precancerous lesions in mice. These findings suggest that individuals with constitutively decreased TGFBR1 expression may have a decreased risk of pancreatic cancer. [Cancer Res 2009;69(24):9169-74]

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Section: Discussionmentioning

confidence: 75%

“…+/− mice were generated as previously described (13,16). EL-Kras FVB male mice were bred to Tgfbr1 +/− C57/BL6 females.…”

Section: Mice El-kras Transgenic and Tgfbr1mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tgfbr1 Haploinsufficiency Inhibits the Development of Murine Mutant Kras-Induced Pancreatic Precancer

et al. 2009

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“…Full understanding of the roles of the driver mutations in colorectal tumors has been hampered by lack of appropriate ex vivo model systems for studies of CRC progression, and thus it has been difficult to study the effects of TGF-β in intestinal adenoma cells at the early stages of tumor development. Although TGF-β receptors have been deleted in Apc-mutant mouse models of CRC (7,8), these studies do not reveal the mechanism of TGF-β action in intestinal adenomas or give further insights into how the subsequent progression mutations affect the TGF-β sensitivity.To circumvent these problems, we have here used in vivo models and the recently established intestinal ex vivo organoid cultures (9-11) for analysis of the effects of TGF-β in the early stages of intestinal carcinogenesis. In the ex vivo culture system, exogenous Wnt-ligand R-Spondin1 is essential for the survival and growth of organoids from wild-type (WT) intestinal crypts.…”

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confidence: 99%

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confidence: 99%

Oncogenic mutations in intestinal adenomas regulate Bim-mediated apoptosis induced by TGF-β

Wiener

Band

Kallio

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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In the majority of microsatellite-stable colorectal cancers (CRCs), an initiating mutation occurs in the adenomatous polyposis coli (APC) or β-catenin gene, activating the β-catenin/TCF pathway. The progression of resulting adenomas is associated with oncogenic activation of KRas and inactivation of the p53 and TGF-β/Smad functions. Most established CRC cell lines contain mutations in the TGF-β/Smad pathway, but little is known about the function of TGF-β in the early phases of intestinal tumorigenesis. We used mouse and human ex vivo 3D intestinal organoid cultures and in vivo mouse models to study the effect of TGF-β on the Lgr5 + intestinal stem cells and their progeny in intestinal adenomas. We found that the TGF-β-induced apoptosis in Apc-mutant organoids, including the Lgr5 + stem cells, was mediated by up-regulation of the BH3-only proapoptotic protein Bcl-2-like protein 11 (Bim). BH3-mimetic compounds recapitulated the effect of Bim not only in the adenomas but also in human CRC organoids that had lost responsiveness to TGF-β-induced apoptosis. However, wild-type intestinal crypts were markedly less sensitive to TGF-β than Apcmutant adenomas, whereas the KRas oncogene increased resistance to TGF-β via the activation of the Erk1/2 kinase pathway, leading to Bim down-regulation. Our studies identify Bim as a critical mediator of TGF-β-induced apoptosis in intestinal adenomas and show that the common progression mutations modify Bim levels and sensitivity to TGF-β during intestinal adenoma development.A ctivation of the β-catenin/TCF transcription factor (Wnt) pathway is the initiating event in the majority of human colorectal cancers (CRCs) and one of the key regulators of CRC pathogenesis (1, 2). The β-catenin level in cells is controlled through a multiprotein complex that contains the adenomatous polyposis coli (APC) protein. In 70-80% of individuals suffering from the sporadic version of CRC, both APC alleles are mutated and thus inactivated, resulting in elevated nuclear β-catenin levels (1). Recently, the intestinal stem cells have been identified as the cells of origin of CRC (3, 4).According to the model presented by Fearon and Vogelstein (5), the initiating APC or CTNNB1 mutation is followed by oncogenic activation of the KRAS gene and inactivation of the TGF-β signal transduction pathway and the TP53 tumor suppressor. Recent genome-wide analysis by the Cancer Genome Atlas Network has demonstrated the high frequency of mutations in the β-catenin/TCF, TGF-β, phosphoinositide 3-kinase (PI3K) and p53 pathways in CRC (6). Full understanding of the roles of the driver mutations in colorectal tumors has been hampered by lack of appropriate ex vivo model systems for studies of CRC progression, and thus it has been difficult to study the effects of TGF-β in intestinal adenoma cells at the early stages of tumor development. Although TGF-β receptors have been deleted in Apc-mutant mouse models of CRC (7,8), these studies do not reveal the mechanism of TGF-β action in intestinal adenomas or give further i...

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One Step Forward Toward Identification of the Genetic Signature of Glioblastomas

Pasche¹

2009

JAMA

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Tgfbr1Haploinsufficiency Is a Potent Modifier of Colorectal Cancer Development

Abstract: Transforming growth factor-B (TGF-B) signaling is frequently altered in colorectal cancer. Using a novel model of mice heterozygous for a targeted null mutation of

Cited by 51 publications

References 40 publications

Tgfbr1 Haploinsufficiency Inhibits the Development of Murine Mutant Kras-Induced Pancreatic Precancer

Tgfbr1 Haploinsufficiency Inhibits the Development of Murine Mutant Kras-Induced Pancreatic Precancer

Oncogenic mutations in intestinal adenomas regulate Bim-mediated apoptosis induced by TGF-β

One Step Forward Toward Identification of the Genetic Signature of Glioblastomas

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