Mouse models for colorectal cancer

Heyer, Joerg; Yang, Kan; Lipkin, Martin; Edelmann, Winfried; Kucherlapati, Raju

doi:10.1038/sj.onc.1203036

Cited by 100 publications

(79 citation statements)

References 63 publications

(56 reference statements)

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“…Although several mouse models with colorectal cancer were reported, metastases were rather infrequently noticed (Heyer et al, 1999;Boivin et al, 2003). Metastases in our model may have occurred because of the long latency of sporadic tumors, supported by the fact that Vil-Cre Â LoxP-Tag mice with shorter tumor latency did not develop metastases.…”

Section: Sporadic Colorectal Cancer Modelsupporting

confidence: 53%

“…Mouse models based on certain genetic alterations are conventional transgene or knockout mice mimicking the hereditary but not the sporadic form of colorectal cancer, the most frequent form in humans Vogelstein, 1996, 1998;Heyer et al, 1999;Boivin et al, 2003). In some tumor transplantation models with colon carcinoma cells immune responses against a defined antigen were analyzed.…”

Section: Introductionmentioning

confidence: 99%

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The immune response to sporadic colorectal cancer in a novel mouse model

et al. 2010

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Current mouse models do not reflect the sporadic nature of colon cancer and do not allow the analysis of antitumor immune response because of the lack of known tumorspecific antigens. Two transgenic mouse models with spontaneous tumor development were generated, directing the expression of SV40T antigen (Tag) either constitutively (Vil-Cre Â LoxP-Tag-transgenic mice) or stochastically (Vil-Cre-ER T2 Â LoxP-Tag-transgenic mice) into the putative stem cell region of the crypt of Lieberku¨hn. Tumor development and antitumor immune response were monitored. Vil-Cre Â LoxP-Tag mice developed multiple adenocarcinomas of the small intestine and colon at an average age of 6 months. During the tumor development, Tag-specific immunoglobulin G (IgG) antibodies were induced in half of the mice, although they had developed neonatal cytotoxic T lymphocyte (CTL) tolerance. This model shows similarity to hereditary colon cancer but not to the sporadic tumor development. Therefore, the conditional Vil-Cre-ER T2 Â LoxP-Tag mice were established, in which expression of the dormant Tag was induced by stochastic, tissue-specific activation of Cre recombinase. These mice spontaneously developed highly invasive, metastasizing colon carcinomas at an average age of 20 months. Colon carcinomas expressed epithelial and/or neuroendocrine markers depending on the grade of differentiation. Young Vil-Cre-ER T2 Â LoxP-Tag mice had retained CTL responses against epitope IV of Tag. The tumors induced strong anti-Tag IgG responses. We report, for the first time, a mouse model based on stochastic, tissue-specific activation of a dormant oncogene in the colon allowing the analysis of antitumor immune response against primary colorectal cancer.

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Section: Sporadic Colorectal Cancer Modelsupporting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

The immune response to sporadic colorectal cancer in a novel mouse model

et al. 2010

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“…Although an presumed inactivating MCC mutation in the mouse alone failed to induce any evident CRC, the homozygous mice displayed a slightly higher proliferation rate of the epithelial crypt cells (Heyer et al, 1999). In earlier studies, loss of heterozygosity (LOH), deletions and mutations of the MCC gene were found in human CRC (Ashton-Rickardt et al, 1991;Kinzler et al, 1991a, b;Nishisho et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Mutated in colorectal cancer, a putative tumor suppressor for serrated colorectal cancer, selectively represses β-catenin-dependent transcription

et al. 2008

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Mutated in colorectal cancer (MCC ) was originally identified as a candidate gene for familial adenomatous polyposis (FAP) but further study identified adenomatous polyposis coli (APC) as responsible for FAP and the physiologic/pathologic roles of MCC remained poorly understood. Recently, MCC promoter methylation was discovered as a frequent early event in a distinct subset of precursor lesions and colorectal cancer (CRC) associated with the serrated CRC pathway. Here we provide the first evidence of the biological significance of MCC loss in CRC and the molecular pathways involved. We show MCC expression is dramatically decreased in many CRC cell lines and the distinct subset of sporadic CRC characterized by the CpG island methylator phenotype and BRAF V600E mutation due to promoter methylation as reported previously. Importantly, we find MCC interacts with b-catenin and that reexpression of MCC in CRC cells specifically inhibits Wnt signaling, b-catenin/T-cell factor/lymphoid-enhancer factor-dependent transcription and cellular proliferation even in the presence of oncogenic mutant APC. We also show that MCC is localized in the nucleus and identify two functional nuclear localization signals. Taken together, MCC is a nuclear, b-catenininteracting protein that can act as a potential tumor suppressor in the serrated CRC pathway by inhibiting Wnt/b-catenin signal transduction.

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“…[2][3][4][5] These mouse models, which allow monitoring of the phenotypic effects of known genetic alterations, have proved invaluable in understanding disease course and evaluating novel therapies. 6 The typically slower growth rates in the resulting spontaneous tumors compared to implanted cell lines more closely emulate the rates of human tumor growth.…”

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confidence: 99%

A novel mouse model for segmental orthotopic colon cancer

Alencar¹,

King²,

Funovics³

et al. 2005

Intl Journal of Cancer

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Spontaneous colon tumor mouse strains offer numerous advantages in modeling disease. However, the wide temporal window in which lesions form and the stochastic nature of lesion location require larger cohorts for assessment of disease modulation. Reliable, reproducible and inexpensive mouse models of early-stage and invasive cancer would add to existing transgenic models. We show a new method for the creation of orthotopic murine tumors centered in the mucosal and submucosal layers anywhere in the colon, allowing creation of lesions of known age, location and extent. The system overcomes the disadvantages of heterotopic implantation and allows evaluation of lesions distally in the colon as well as proximally, thereby providing an additional method to study the effects of regionality. Invasion, host vascularization and application to disparate cell lines are demonstrated. Noninvasive imaging with magnetic resonance and colonoscopy, allowed in part by the tumor location, show potential applications of this approach. ' 2005 Wiley-Liss, Inc.Key words: colon cancer; mouse model; colonoscopy; magnetic resonance imaging A number of spontaneous colorectal tumor mouse strains have been developed that model human cancer syndromes, such as HNPCC, 1 and familial adenomatous polyposis. 2-5 These mouse models, which allow monitoring of the phenotypic effects of known genetic alterations, have proved invaluable in understanding disease course and evaluating novel therapies. 6 The typically slower growth rates in the resulting spontaneous tumors compared to implanted cell lines more closely emulate the rates of human tumor growth. However, many of the most-used mouse models form adenomas primarily in the small bowel, with relatively few lesions in the descending and sigmoid colon. Noninvasive serial imaging of small bowel lesions to evaluate anatomic size changes is quite challenging in humans and markedly more difficult in mice. Additionally, few transgenic models of invasive colorectal cancer exist; 7 the commonly used Apc Min1/2 mice typically develop adenomas but not invasive adenocarcinomas.A disadvantage for the use of these models to evaluate therapeutics is that the broad temporal variability in lesion formation and the difficulty in nondestructive serial evaluation require very large cohorts of animals to be examined over extended periods of time to realize efficacy of treatment, with mortality often used as an end point. Alternatively, heterotopic s.c. implantation of tumor cell lines suffers from incongruent host stroma, which has been shown to change tumorigenicity 8 and cell cycle regulation 9 for implanted tumors compared to implantation in the native tissue bed. Additionally, direct injection of tumor cells into murine colonic mucosa or submucosa is technically difficult and has not been reported. We hypothesized that orthotopic implantation could be achieved with focal enzymatic disruption of the colonic mucosal layer only and placement of tumor cells intraluminally. The resulting tumors ''arise'' from the muco...

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Mouse models for colorectal cancer

Cited by 100 publications

References 63 publications

The immune response to sporadic colorectal cancer in a novel mouse model

The immune response to sporadic colorectal cancer in a novel mouse model

Mutated in colorectal cancer, a putative tumor suppressor for serrated colorectal cancer, selectively represses β-catenin-dependent transcription

A novel mouse model for segmental orthotopic colon cancer

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