Azoxymethane-induced colon tumors and aberrant crypt foci in mice of different genetic susceptibility

Παπανικολάου, Αλέξανδρος; Wang, Qian‐Shu; Delker, Don A.; Rosenberg, Daniel W.

doi:10.1016/s0304-3835(98)00101-3

Cited by 75 publications

(59 citation statements)

References 8 publications

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“…1). Significant numbers of ACF were observed in colons of both strains, although in A/J, a higher percentage of ACF was dysplastic (5,10,20). Hyperplastic ACF from both strains showed increased crypt size, moderate loss of goblet cell differentiation, low crypt multiplicity, and mild to moderate anisokaryosis (Fig.…”

Section: Resultsmentioning

confidence: 92%

“…The criteria used for histologic grading of ACF have been adapted from previous studies (10,(27)(28)(29) as follows: (1) hyperplastic; small (1 to 5 crypts/focus), moderately hypercellular, normal cellular differentiation with Ͻ30% loss of goblet cell differentiation, slight variation in crypt diameter relative to normal, basally arranged and slightly hyperchromatic nucleus; (2) dysplastic; moderate size (5 to 10 crypts/focus), markedly hypercellular, Ͼ50% loss of goblet cell differentiation; enlarged, often tortuous crypts with slit-shaped lumina, loss of polarity, dark, elongate to oval, hyperchromatic nuclei with pseudostratification and mitotic figures of 0 to 1/high power field; (3) microadenoma; large size (Ͼ10 crypts/focus) but not visible by the naked eye, severely hypercellular, complete loss of goblet cell differentiation, enlarged tortuous crypts; loss of cellular polarity, moderate nuclear anisokaryosis and mitotic figures of 1 to 2/high power field. ACF are defined as high-or low-risk based on established strain sensitivity to azoxymethane (5,20).…”

Section: Animal Treatment and Laser Capture Microdissected (Lcm)mentioning

confidence: 99%

“…ACF, although not yet fully committed to neoplasia, are stratified into two broad classes, hyperplastic and dysplastic, based on morphology and predicted biological behavior (4,5). Histomorphologic grading of ACF, in terms of size and dysplasia, represent one of the few biomarkers of colorectal cancer risk (6 -10).…”

Section: Introductionmentioning

confidence: 99%

“…For example, A/J mice develop 10 to 20 tumors in distal colon, whereas tumors in AKR/J mice are rare (10,11,20). Interestingly, initiation of ACF upon carcinogen exposure is a feature common to both strains (5,10,18). However, a higher percentage of dysplastic ACF form in A/J colons compared with AKR/J.…”

Section: Introductionmentioning

confidence: 99%

“…ACF are comprised of aggregates of abnormal crypts and characterized by hyperproliferation, increased size, expanded pericryptal zones, and elongated or slit-like crypt lumina (5,10,21,22). A number of studies support the contention that only limited subsets of ACF have the potential to progress, whereas most lesions remain behaviorally benign (10).…”

Section: Introductionmentioning

confidence: 99%

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Genetic signatures of High- and Low-Risk Aberrant Crypt Foci in a Mouse Model of Sporadic Colon Cancer

et al. 2004

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To determine whether cancer risk is related to histopathological features of preneoplastic aberrant crypt foci (ACF), gene expression analysis was performed on ACF from two mouse strains with differing tumor sensitivity to the colonotropic carcinogen, azoxymethane. ACF from sensitive A/J mice were considered at high risk, whereas ACF from resistant AKR/J mice were considered at low risk for tumorigenesis. A/J and AKR/J mice received weekly injections of azoxymethane (10 mg/kg body weight), and frozen colon sections were prepared 6 weeks later. Immunohistochemistry was performed using biomarkers associated with colon cancer, including adenomatous polyposis coli, ␤-catenin, p53, c-myc, cyclin D1, and proliferating cell nuclear antigen. Hyperplastic ACF, dysplastic ACF, microadenomas, adjacent normal-appearing epithelium, and vehicle-treated colons were laser captured, and RNA was linearly amplified (LCM-LA) and subjected to cDNA microarray-based expression analysis. Patterns of gene expression were identified using adaptive centroid algorithm. ACF from low-and high-risk colons were not discriminated by immunohistochemistry, with the exception of membrane staining of ␤-catenin. To develop genetic signatures that predict cancer risk, LCM-LA RNA from ACF was hybridized to cDNA arrays. Of 4896 interrogated genes, 220 clustered into six broad clusters. A total of 226 and 202 genes was consistently altered in lesions from A/J and AKR/J mice, respectively. Although many alterations were common to both strains, expression profiles stratified high-and low-risk lesions. These data demonstrate that ACF with distinct tumorigenic potential have distinguishing molecular features. In addition to providing insight into colon cancer promotion, our data identify potential biomarkers for determining colon cancer risk in humans.

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Section: Resultsmentioning

confidence: 92%

Section: Animal Treatment and Laser Capture Microdissected (Lcm)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genetic signatures of High- and Low-Risk Aberrant Crypt Foci in a Mouse Model of Sporadic Colon Cancer

et al. 2004

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Azoxymethane induces KI-ras activation in the tumor resistant AKR/J mouse colon

et al. 2000

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A differential susceptibility phenotype to the organotropic colon carcinogen azoxymethane (AOM) has been described in mice. The following studies were undertaken to test the hypothesis that intraspecific susceptibility can be accounted for by the specific complement of genetic alterations acquired by precancerous colon lesions referred to as aberrant crypt foci (ACF). As an initial approach to this question, mutations in codons 12 and 13 of the Ki-ras proto-oncogene were assessed in ACF, normal-appearing AOM-treated colonic epithelium, and tumors from A/J and SWR/J (susceptible) as well as AKR/J (resistant) mice. Four-week-old male mice were injected intraperitonealy, with AOM once a week for a total of 6 wk and killed 4 and 24 wk after the last injection. DNA was isolated from microdissected tissue, and polymerase chain reaction (PCR)-amplified products of Ki-ras exon 1 (codons 12 and 13) were directly sequenced from microdissected tissues. At 4 wk after AOM exposure, there was no significant difference in the frequency of Ki-ras activation (20-33%) between the three strains. Ki-ras mRNA expression was also evaluated by reverse transcription (RT)-PCR analysis and was comparably reduced (40-50%) in all three strains at the 4 wk time point. However, Ki-ras expression returned to normal by 24 wk after treatment. Finally, to gain further insight into the molecular pathogenesis underlying this experimental tumor model, analysis of the adenomatous polyposis coli (APC) protein within the colonic epithelium was undertaken by using an immunohistochemical approach. Although the APC protein was lost to a varying extent in tumors from A/J and SWR/J mice, the full-length form of the protein was still present in precancerous ACF isolated from each of the three strains, regardless of the degree of dysplasia of the lesion. A further molecular genetic analyses of ACF will be required to gain a more complete understanding of the molecular basis of tumor susceptibility phenotype in this murine model.

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Differential Expression of p16INK4a in Azoxymethane-Induced Mouse Colon Tumorigenesis

et al. 2000

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Azoxymethane-induced colon tumors and aberrant crypt foci in mice of different genetic susceptibility

Cited by 75 publications

References 8 publications

Genetic signatures of High- and Low-Risk Aberrant Crypt Foci in a Mouse Model of Sporadic Colon Cancer

Genetic signatures of High- and Low-Risk Aberrant Crypt Foci in a Mouse Model of Sporadic Colon Cancer

Azoxymethane induces KI-ras activation in the tumor resistant AKR/J mouse colon

Differential Expression of p16INK4a in Azoxymethane-Induced Mouse Colon Tumorigenesis

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