Mouse models for the study of colon carcinogenesis

Rosenberg, Daniel W.; Giardina, Charles; Tanaka, Takuji

doi:10.1093/carcin/bgn267

Cited by 367 publications

(381 citation statements)

References 192 publications

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“…In the hCYP1A mice, PhIP/DSS treatments caused rapid destruction of colon mucosa with severe inflammation, followed by the appearance of reactive hyperplastic and low-grade dysplastic crypts, and then manifestation of high-grade dysplastic lesions, adenomas, and finally adenocarcinomas ( Figure 2A). These histopathologic features are very similar to those found in the murine AOM/DSS-induced models (Rosenberg et al, 2009;) and resemble human colon carcinogenesis, which is believed to progress from indefinite dysplasia to low-grade dysplasia to high-grade dysplasia to carcinoma (Boivin et al, 2003;De Lerma Barbaro et al, 2014;Itzkowitz et al, 2004). However, only one out of thirteen (7.7%) PhIP/DSSinduced adenocarcinomas showed evidence of submucosal invasion at week 10.…”

Section: Discussionsupporting

confidence: 76%

“…In the past decades, dozens of experimental rodent models have been developed to investigate the pathogenesis of CRC (De Robertis et al, 2011;Rosenberg et al, 2009). However, the most popular and widely studied of these models employed genetic manipulation (eg, Apc min mutants) or synthetic chemicals, such as azoxymethane (AOM) and/or dextran sodium sulfate (DSS).…”

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confidence: 99%

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From the Cover: PhIP/DSS-Induced Colon Carcinogenesis in CYP1A-Humanized Mice and the Possible Role of Lgr5+ Stem Cells

et al. 2016

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In the past decades, experimental rodent models developed to study the pathogenesis of human colorectal cancer (CRC) generally employed synthetic chemical carcinogens or genetic manipulation. Our lab, in order to establish a more physiologically relevant CRC model, recently developed a colon carcinogenesis model induced by the meat-derived dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), and promoted by dextran sodium sulfate (DSS)-induced colitis in the cytochrome P450 1A-humanized (hCYP1A) mice. The resulting colon tumors shared many histologic and molecular features of human colon cancer. In this study, we characterized the early stages of PhIP/DSS-induced colon carcinogenesis. We found that PhIP/DSS treatments caused rapid destruction of the colon mucosa with severe inflammation, followed by the presence of reactive changes and low-grade dysplastic lesions, and then manifestation of high-grade dysplastic lesions and finally adenocarcinomas. Molecular analysis of the early time-points (ie, days 1, 3, 7, 11, 14, and 21 after DSS exposure) indicates Ctnnb1/b-catenin mutations and b-catenin nuclear accumulation in the high-grade dysplastic lesions, but not low-grade dysplastic lesions or adjacent normal tissues. In addition, we investigated the role of Lgr5þ colon stem cells in the PhIP/DSS-induced colon carcinogenesis and found the presence of Lgr5-enhance green fluorescent protein-expressing cells amidst some ulcerated mucosa, high-grade dysplastic lesions and adenocarcinomas, suggesting a possible role of Lgr5þ stem cells in this dietary carcinogen-induced, inflammation-promoted colon carcinogenesis model. Overall, the findings suggest that PhIP/DSS-induced colon carcinogenesis is likely initiated by dominant active Ctnnb1/b-catenin mutation in residual epithelial cells, which when promoted by colitis, developed into high-grade dysplasia and adenocarcinoma.

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Section: Discussionsupporting

confidence: 76%

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confidence: 99%

From the Cover: PhIP/DSS-Induced Colon Carcinogenesis in CYP1A-Humanized Mice and the Possible Role of Lgr5+ Stem Cells

et al. 2016

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“…To date, no in vivo model of CRC has demonstrated predictable and reproducible distant metastatic outgrowth within relevant target organs from an orthotopically-established primary colorectal tumour [2][3][4][5] . The lack of available models has precluded investigations into the route(s) of metastatic spread to distant organs.…”

Section: Resultsmentioning

confidence: 99%

“…Investigations into CRC metastatic routes, however, have been precluded by the lack of availability of relevant in vivo metastatic models of CRC. Indeed, despite the wide availability of xenograft, chemical-induced and genetically-engineered mouse models of CRC [2][3][4][5] , tumours in these models fail to reproducibly metastasize to the regional intestinal lymph nodes and liver-the target organs relevant to human CRC.…”

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confidence: 99%

Lymph node-independent liver metastasis in a model of metastatic colorectal cancer

Enquist¹,

Good²,

Jubb³

et al. 2014

Nat Commun

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Deciphering metastatic routes is critically important as metastasis is a primary cause of cancer mortality. In colorectal cancer (CRC), it is unknown whether liver metastases derive from cancer cells that first colonize intestinal lymph nodes, or whether such metastases can form without prior lymph node involvement. A lack of relevant metastatic CRC models has precluded investigations into metastatic routes. Here we describe a metastatic CRC mouse model and show that liver metastases can manifest without a lymph node metastatic intermediary. Colorectal tumours transplanted onto the colonic mucosa invade and metastasize to specific target organs including the intestinal lymph nodes, liver and lungs. Importantly, this metastatic pattern differs from that observed following caecum implantation, which invariably involves peritoneal carcinomatosis. Anti-angiogenesis inhibits liver metastasis, yet anti-lymphangiogenesis does not impact liver metastasis despite abrogating lymph node metastasis. Our data demonstrate direct hematogenous spread as a dissemination route that contributes to CRC liver malignancy.

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“…AOM metabolized in the liver to methylazoxymethanol (MAM) by phase I detoxification enzymes such as CYP2E1. MAM then readily yields the ultimate carcinogenic metabolite, high reactive methyldiazonium ions for the methylation of DNA (Rosenberg et al, 2009). Thereafter, phase II detoxification enzymes conjugate and guide these ions from the body (Sunkara et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Dietary Aloe Vera Gel Powder and Extract Inhibit Azoxymethane-induced Colorectal Aberrant Crypt Foci in Mice Fed a High-fat Diet

Chihara

Shimpo

Kaneko

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Aloe vera gel exhibits protective effects against insulin resistance as well as lipid-lowering and anti-diabetic effects. The anti-diabetic compounds in this gel were identified as Aloe-sterols. Aloe vera gel extract (AVGE) containing Aloe-sterols has recently been produced using a new procedure. We previously reported that AVGE reduced large-sized intestinal polyps in Apc-deficient Min mice fed a high fat diet (HFD), suggesting that Aloe vera gel may protect against colorectal cancer. In the present study, we examined the effects of Aloe vera gel powder (AVGP) and AVGE on azoxymethane-induced colorectal preneoplastic aberrant crypt foci (ACF) in mice fed a HFD. Male C57BL/6J mice were given a normal diet (ND), HFD, HFD containing 0.5% carboxymethyl cellulose solution, which was used as a solvent for AVGE (HFDC), HFD containing 3% or 1% AVGP, and HFDC containing 0.0125% (H-) or 0.00375% (L-) AVGE. The number of ACF was significantly lower in mice given 3% AVGP and H-AVGE than in those given HFD or HFDC alone. Moreover, 3% AVGP, H-AVGE and L-AVGE significantly decreased the mean Ki-67 labeling index, assessed as a measure of cell proliferation in the colonic mucosa. In addition, hepatic phase II enzyme glutathione S-transferase mRNA levels were higher in the H-AVGE group than in the HFDC group. These results suggest that both AVGP and AVGE may have chemopreventive effects on colorectal carcinogenesis under the HFD condition. Furthermore, the concentration of Aloe-sterols was similar between 3% AVGP and H-AVGE, suggesting that Aloe-sterols were the main active ingredients in this experiment.

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Mouse models for the study of colon carcinogenesis

Cited by 367 publications

References 192 publications

From the Cover: PhIP/DSS-Induced Colon Carcinogenesis in CYP1A-Humanized Mice and the Possible Role of Lgr5+ Stem Cells

From the Cover: PhIP/DSS-Induced Colon Carcinogenesis in CYP1A-Humanized Mice and the Possible Role of Lgr5+ Stem Cells

Lymph node-independent liver metastasis in a model of metastatic colorectal cancer

Dietary Aloe Vera Gel Powder and Extract Inhibit Azoxymethane-induced Colorectal Aberrant Crypt Foci in Mice Fed a High-fat Diet

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