Regional distribution of carcinogen‐induced colonic neoplasia in the rat

Holt, Peter R.; Mokuolu, Adedayo O.; Distler, Peter; Liu, Thomas T.; Reddy, Bandaru S.

doi:10.1080/01635589609514435

Cited by 47 publications

(22 citation statements)

References 25 publications

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“…5 Epidemiological evidence suggests that high-fat diets possibly increase the risk of colorectal cancer 19 and high-fat diets in which fat is provided by corn oil have been demonstrated to increase colon carcinogenesis in F344 rats and Min/1 mice. 6,[20][21][22] In our experiments, on the contrary, ACF were not affected by the high-fat diet. While high-fat diets containing saturated fats have been demonstrated to increase ACF in rodents, 23,24 the effect of corn oil on ACF is more controversial, since it has been reported to increase ACF 25,26 or to have no effect by others.…”

Section: Discussionmentioning

confidence: 49%

Mucin‐depleted foci are modulated by dietary treatments and show deregulation of proliferative activity in carcinogen‐treated rodents

Femia

Caderni

Bottini

et al. 2007

Intl Journal of Cancer

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The correlation between mucin-depleted foci (MDF) and colon carcinogenesis was studied in F344 rats initiated with 1,2-dimethylhydrazine and treated with a chemopreventive regimen (polyethylene glycol, PEG) or with a promoting diet (high-corn oil). High corn oil diet increased MDF, while PEG reduced them. The expression of p27 and p16, inhibitors of cyclin-dependent kinases, which inhibit the progression of the cell cycle, was studied by immunohistochemistry in MDF and in aberrant crypt foci (ACF) of control rats. In both MDF and ACF, the nuclear expression of p27 was markedly reduced, while p16 was reduced to a lower extent. Mitotic activity was higher in MDF and ACF than in normal mucosa of control rats. MDF were also identified in azoxymethane-initiated SWR/J mice. These results further confirm that MDF are preneoplastic lesions and could be useful biomarkers of colon carcinogenesis. ' 2007 Wiley-Liss, Inc.Key words: colon carcinogenesis; preneoplastic lesions; mucindepleted foci; colon proliferative activity Mucin-depleted foci (MDF) were recently described by our group as dysplastic lesions that occur in the colon of carcinogentreated rats and are easily recognizable in unsectioned colon as foci of crypts with defective mucous production.1 The number of MDF/colon increases in rats treated with promoters of colon carcinogenesis, such as cholic acid, while it is decreased by chemopreventive agents.1,2 MDF are induced dose-dependently by the specific colon carcinogen 1,2-dimethylhydrazine (DMH) and progressively increase in size after carcinogen administration.3 Recently, we showed that MDF carry alterations in the Wnt signaling pathway and mutations in the b-catenin gene, 3 2 characteristic phenomena in colon tumorigenesis.4 Therefore, MDF are suspected preneoplastic lesions.To obtain further data on the preneoplastic nature of MDF, we studied MDF in 2 different experimental settings in which DMHinitiated rats were treated with an inhibitor of colon carcinogenesis (polyethylene glycol, PEG), 5 or with a promoter (a high-fat diet). 6In the same rats, we also determined aberrant crypt foci (ACF), routinely used as an endpoint in short-term carcinogenesis studies. 5Since deregulation of the cell cycle is an important mechanism for uncontrolled growth in most preneoplastic lesions and cancers, we also studied the mitotic index (MI) in MDF and ACF and the expression of p27 and p16, 2 inhibitors of cyclin-dependent kinases (CKI).7 Progression through the cell cycle is regulated by cyclin-dependent kinases and their inhibitors, either the cip/kip family (p27) or the INK4 family (p16), which inhibit cyclin/cyclin kinase complexes and block the cell cycle.7 The CKI and MI studies were also carried out in ACF identified in the same rats. Moreover, since MDF have been so far described only in rats, we investigated whether similar lesions would be present in the colon of SWR/J mice treated with the specific colon carcinogen azoxymethane (AOM). Materials and methods1,2-Dimethylhydrazine (DMH) and azoxymethane (AOM) were o...

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Section: Discussionmentioning

confidence: 49%

Mucin‐depleted foci are modulated by dietary treatments and show deregulation of proliferative activity in carcinogen‐treated rodents

Femia

Caderni

Bottini

et al. 2007

Intl Journal of Cancer

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“…Similar to the regional distribution of tumors in the human colon, AOM treatment induces colon tumors predominantly in the distal colon [Holt et al, 1996]. AOM treatment also induces oncogene mutations at codon 12 of Kand H-Ras and increases in the expression of the ras family of proto-oncogenes have been causally associated with colon tumor development [Singh et al, 1994[Singh et al, , 1997.…”

Section: Preclinical Models For Colon Cancermentioning

confidence: 97%

Studies with the azoxymethane–rat preclinical model for assessing colon tumor development and chemoprevention

Reddy

2004

Environ and Mol Mutagen

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100

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During recent years, multidisciplinary studies in epidemiology and molecular biology have contributed to our understanding of the etiology of colorectal cancer; more importantly they have enabled us to approach its prevention. An impressive body of epidemiological data suggests an inverse relationship between colorectal cancer risk and consumption of diets rich in omega (omega)-3 fatty acids (n-3 PUFAs) or the regular use of nonsteroidal antiinflammatory drugs (NSAIDs), including aspirin. The development of strategies for the chemoprevention of colorectal cancer have been facilitated by the use of relevant animal models mimicking the neoplastic processes that occur in humans, including similarities in histopathology and molecular and genetic lesions during both the early and promotion/progression stages of carcinogenesis. Studies with the azoxymethane-F344 rat model indicate that diets rich in n-3 PUFAs, NSAIDs, selective cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) inhibitors, and curcumin can reduce the incidence of colon cancer. Advances in the knowledge of the mechanisms by which chemopreventive agents act offer opportunities to use combinations of specific chemopreventive agents, having clinically beneficial aggregate activity with minimal toxicity. This approach is extremely important when a promising chemopreventive agent demonstrates apparent efficacy but may produce toxic effects at high doses. Our studies show that a combination of very low doses of piroxicam (NSAID) and difluoromethylornithine, a specific inhibitor of ornithine decarboxylase, or very low doses of COX-2 and HMG-CoA reductase inhibitors are more effective in inhibiting colon carcinogenesis than administration of these compounds as single agents even at higher levels. The natural history of colorectal cancer, from dysplastic aberrant crypts to adenomas and adenocarcinomas, offers multiple opportunities for assessment and intervention. Of further importance is to identify whether the molecular targets that are critical in the growth and survival of the malignant colorectal cell are modulated by n-3 PUFAs, NSAIDs, or COX-2 and iNOS inhibitors.

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“…4) As regards adenocarcinomas, 63% of AOM-induced tumors were found in the distal half of the colon in one experiment in rats. 12) However, in humans, more than half arise in the proximal colon 14) and increasing numbers were reported in the cecal 23) and ascending colon. 24) To explain the discrepancy between animal models and the human cases, our system using PhIP appears to have major advantages.…”

Section: Discussionmentioning

confidence: 99%

Development and Distribution of 2‐Amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]‐pyridine (PhIP)‐induced Aberrant Crypt Foci in the Rat Large Intestine

Tsukamoto

Kozaki

Nishikawa

et al. 1999

Japanese Journal of Cancer Research

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Aberrant crypt foci (ACF) are generally considered to be preneoplastic lesions for colon cancer. To assess their induction by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a colon carcinogen, we performed a sequential study of ACF morphology and localization. F344 male rats were given PhIP, and methylene blue-stained colon epithelium and isolated crypts were analyzed at weeks 12, 25, 50, and 75. Each crypt was classified into 2 groups, "single" with round bottoms and "bifurcating" displaying V-shaped clefts (indicating proliferation). In combination with the number of crypts in an ACF, this classification was a good indicator for the generation of ACF in line with the fission mechanism of growth. Increasing numbers of crypts in ACF through weeks 12 to 75 and decreased percentages of ACF with bifurcating crypts at the late time points indicated that proliferation of crypts occurs predominantly during the early stages. The distribution pattern showed a significant shift (P< < < <0.000005) from the distal to the proximal part of the large intestine between weeks 25 and 50. Adenocarcinomas were first found to develop at week 50 in the ascending colon and cecum where bifurcating crypts were generally lacking at weeks 12 and 25. These data suggest the existence of (1) proliferating ACF which contains bifurcating crypt(s) and (2) quiescent or senescent ACF which consists of only single crypts.

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Regional distribution of carcinogen‐induced colonic neoplasia in the rat

Cited by 47 publications

References 25 publications

Mucin‐depleted foci are modulated by dietary treatments and show deregulation of proliferative activity in carcinogen‐treated rodents

Mucin‐depleted foci are modulated by dietary treatments and show deregulation of proliferative activity in carcinogen‐treated rodents

Studies with the azoxymethane–rat preclinical model for assessing colon tumor development and chemoprevention

Development and Distribution of 2‐Amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]‐pyridine (PhIP)‐induced Aberrant Crypt Foci in the Rat Large Intestine

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