Sequential and morphological analyses of aberrant crypt foci formation in mice of differing susceptibility to azoxymethane-induced colon carcinogenesis
Alexandros Papanikolaou2,
Qian-Shu Wang,
Demetrios Papanikolaou,
Herbert E. Whiteley1 and
Daniel W. Rosenberg2,3
Department of Pharmaceutical Sciences and
1 Department of Pathobiology, University of Connecticut, Storrs, CT 062692092, USA
 |
Abstract
|
---|
Aberrant crypt foci (ACF), putative preneoplastic lesions, are early morphological changes induced by the colon carcinogen azoxymethane (AOM). Although inbred mice differ markedly in their susceptibility to AOM carcinogenesis, we have previously shown that ACF develop in both resistant and sensitive mouse strains after AOM treatment. The purpose of this study was to examine the sequential development and identify the morphological characteristics of ACF induced by AOM in the distal colon of sensitive and resistant mice. A/J (highly susceptible), SWR/J (relatively susceptible) and AKR/J (resistant) mice were treated with 10 mg/kg AOM or saline i.p. once a week for 6 weeks and were killed at 1, 2, 4, 6, 9 and 24 weeks after the last injection. The distal colons were stained with methylene blue and the numbers of ACF and tumors determined. Tumors were present as early as 4 weeks after AOM exposure in SWR/J and A/J mice and increased in frequency throughout the study in both strains. No tumors developed in the AKR/J mice. ACF, however, formed in all strains of mice. The greatest difference between susceptible and resistant strains was in the number of large ACF that developed at later time points. Furthermore, morphometric analysis revealed that A/J mice had the highest percentage of dysplastic ACF, followed by SWR/J mice. These data indicate that the difference in cancer risk from AOM may be due to the lack of progression of smaller ACF in the resistant mice and to the development of dysplasia in a higher percentage of ACF from susceptible strains.
Abbreviations: ACF, aberrant crypt foci; AOM, azoxymethane; DMH, 1,2-dimethylhydrazine; FAA, focal areas of atypism; H&E, hematoxylin and eosin.
 |
Introduction
|
---|
Repetitive treatment with the methylating carcinogen azoxymethane (AOM) produces colon tumors in mice that exhibit many of the pathological features associated with sporadic forms of the disease (1). As in human populations, the genetic background of mice is a significant component of organ-specific carcinogenesis. We have identified a panel of inbred mouse lines that differ markedly in their susceptibility to AOM (2). SWR/J and A/J mice are susceptible to AOM, although SWR/J develop significantly fewer tumors than A/J mice, whereas AKR/J mice are virtually resistant to the carcinogenic properties of this agent (2). The cellular basis of this differential response has not been established.
Aberrant crypt foci (ACF) are early morphological changes induced by colon-specific carcinogens in rodents (37). They are also observed at a higher frequency in the colons of patients with sporadic and inherited forms of colon cancer (8,9). ACF are considered putative preneoplastic lesions because they share many morphological and biochemical characteristics with tumors, including a comparable increase in cell proliferation, higher expression of tumor-associated antigens and dysplasia (1012). A number of mutations within important tumor-related genes have also been identified within these lesions, including K-ras and APC (13,14). ACF have been classified as hyperplastic (non-dysplastic) or dysplastic, based primarily on morphological characteristics (15). It has further been proposed that only dysplastic ACF progress to adenomas and adenocarcinomas (16).
Previous studies from our laboratory have shown that ACF are readily formed in both tumor susceptible and resistant mice exposed to AOM, but only progress to tumors in the sensitive strains (2). However, it is unknown whether sequential development of ACF may vary between each of the strains. Furthermore, it is not clear whether the morphological characteristics of the ACF in each strain are different. Therefore, in the following experiment the sequential development of ACF was examined in AKR/J, SWR/J and A/J mice. At various time points after treatment with AOM, the number, size and morphological characteristics of ACF were evaluated to determine whether any of these properties may explain the lack of progression of these lesions to tumors in resistant mice.
 |
Materials and methods
|
---|
Materials
AOM, 10% buffered formalin, methylene blue and all other analytical reagents were purchased from Sigma Chemical Co. (St Louis, MO). Harris hematoxylin and eosin (H&E) were obtained from Shandon Co. (Pittsburgh, PA).
Treatment of animals
SWR/J, A/J and AKR/J mice, purchased from the Jackson Laboratories (Bar Harbor, ME), were housed in a ventilated, temperature controlled (23 ± 1°C) room with a 12 h light/dark cycle. Mice were allowed access to laboratory rodent chow (Laboratory Rodent Diet 5001; PMI Nutrition International, Richmond, IN) and water ad libitum up to the time of death. Starting at 6 weeks of age, mice were injected i.p. once a week for a total of 6 weeks with 10 mg/kg AOM. Control animals received saline as the vehicle control. The mice were killed 1, 2, 4, 6, 9 and 24 weeks after the last injection. A total of six treated and four control animals were evaluated for each strain at each of the first five time points. Eight treated and six controls from each strain were tested at the final time point. Only tumors were counted at 24 weeks, because the tissue is dramatically altered at this late time point thus making the identification of ACF more difficult.
Identification and characterization of ACF and tumors
Immediately after death the entire colon was removed, divided into two approximately equal sections (proximal and distal), gently flushed with ice-cold phosphate-buffered saline, opened longitudinally and fixed flat between filter paper in 10% buffered formalin. After fixation, distal colons were stained with 0.2% methylene blue and tumors and ACF were visualized by stereo microscopy. Tumors were identified and counted in whole colon mounts but were not further classified. ACF were identified using a published set of criteria which distinguishes these lesions from normal crypts: they are larger; they have an increased pericryptal area; they have greater staining intensity due to the thickened layer of epithelial cells; they are microscopically elevated above the adjacent normal crypts; they have abnormally shaped lumina, often slit-shaped in appearance (3). The total number of ACF, as well as the number of crypts per foci, were quantified in the distal colon. The mucosa in the direct vicinity of lymphoid nodules was not evaluated because of the natural occurrence of aberrant crypt-like structures in untreated animals (personal observations).
After all the necessary observations were made using the whole tissue, ACF of different sizes were removed along with surrounding normal tissue and embedded in paraffin for histological examination. ACF from each strain were assessed for the presence and degree of dysplasia. Two tissue sections ~50 µm apart were evaluated for each ACF. The degree of dysplasia assigned to each ACF in the present study was determined by the crypt exhibiting the highest degree of dysplasia. The grading was based on criteria described previously (9,12,1719). ACF having atypia/hyperplasia without dysplasia may be defined as showing an increase in the number of cells per crypt but having normal differentiation and goblet cell formation and relatively normal nuclear morphology. ACF with mild to moderate dysplasia show hypercellularity of cells with dark, elongated nuclei, nuclear stratification and only moderate loss of goblet cell differentiation. ACF with moderate to severe dysplasia show clear distortion of crypt architecture. They also have enlarged nuclei in the epithelium and extensive nuclear pleomorphism. Furthermore, they have more discernible nuclear elongation and stratification, loss of cell polarity and complete loss of goblet cell differentiation.
Statistical analysis
Stastitical analysis was performed using analysis of variance (ANOVA), followed by NewmanKeuls post hoc test (Statistica Software; Statsoft, Tulsa, OK). P < 0.05 was considered statistically significant.
2 analysis was performed to determine significant differences in the morphology of ACF between the strains.
 |
Results
|
---|
Identification of tumors
Tumors were present as early as 6 weeks after AOM exposure in SWR/J and A/J mice and increased in frequency throughout the study in both strains (Figure 1
). The number of tumors was significantly higher in A/J than SWR/J mice at all time points examined (8.7-fold higher at 6 weeks, 6.1-fold at 9 weeks and 7.0-fold at 24 weeks, P < 0.05). No tumors were observed in the AKR/J mice throughout the entire study period.

View larger version (17K):
[in this window]
[in a new window]
|
Fig. 1. Induction of tumors in the distal colon of mice after six weekly injections of AOM. The number of tumors was determined in methylene blue stained whole mounts of distal colons. Since control mice did not develop any tumors, only data for AOM-treated mice are shown. Each datum point represents the mean ± SEM of 68 animals.
|
|
Sequential formation of ACF
The number and size of ACF were determined in methylene blue stained, whole mount distal colons of SWR/J, AKR/J and A/J mice beginning 1 week after the last injection of AOM. As predicted by earlier studies (2), administration of the carcinogen resulted in the formation of ACF in all three strains of mice. The total number of ACF, shown in Figure 2
, included those classified as small (12 crypts/focus), medium (34 crypts) and large (
5 crypts). There was no significant difference in the frequency of ACF formation between AKR/J and SWR/J mice at any of the time points examined. However, the number of ACF in A/J colon was significantly higher (P < 0.05) than in the other two strains at 9 weeks after AOM treatment. A general downward trend, though not statistically significant, was evident in all strains of mice 4 weeks after AOM and was followed by a rebound in the number of ACF.
The most dramatic difference between susceptible and resistant mouse strains was apparent in the number of large ACF (Figure 3
). There was a significantly higher number of large ACF in A/J and SWR/J mice compared with AKR/J mice beginning 4 and 6 weeks after the last dose of AOM, respectively. Nine weeks after treatment the number of large ACF in A/J mice was also significantly higher than in SWR/J. Comparing the number of large ACF measured as a percentage of total ACF provides an important insight into strain specificity. For example, in AKR/J mice only 9.4% of identifiable lesions were classified as large ACF at week 9. The majority of ACF (69.8%) in the resistant strain (AKR/J) were small, consisting of 12 aberrant crypts/focus. On the other hand, the percentage of large ACF in A/J and SWR/J (33.5 and 32.7%, respectively) was ~3.5-fold higher than in AKR/J mice. This indicates that the majority of ACF that formed in response to AOM in the resistant AKR/J mice failed to progress to larger lesions.
Morphological characteristics of ACF
After all the necessary observations were made with the whole mount distal colons, ACF of different sizes were removed along with surrounding normal tissue and embedded in paraffin for histological examination. Tissue from weeks 2 and 9 were used for ACF characterization. Based on established histological criteria (9,12,1719), ACF were classified as having either atypia/hyperplasia without dysplasia, mild to moderate dysplasia or moderate to severe dysplasia. In general, the majority of ACF with dysplastic characteristics were large ACF, although a limited number of small ACF also showed signs of dysplasia. Photomicrographs of representative sections are shown in Figure 4
. A histological section of a small ACF (1 crypt) from an AKR/J mouse is shown in Figure 4A
. There is a lack of goblet cell differentiation, thickening of the epithelium and nuclear elongation and stratification indicative of moderate to severe dysplasia. In Figure 4B
another small ACF from an AKR/J mouse displaying somewhat different characteristics is shown. Hyperchromatic nuclei and moderate loss of goblet cell differentiation indicate that this crypt is hyperplastic but not dysplastic. A medium sized ACF involving three crypts from an SWR/J mouse is shown in Figure 4C
. A severely dysplastic morphology, including nuclear stratification and elongation, is evident. In addition, there is evidence of nuclear pleomorphism and loss of cell polarity. Finally, a large ACF from an A/J mouse involving 10 crypts shows a wide range of morphological characteristics among each of the crypts within the focus, ranging from hyperplasia to severe dysplasia (Figure 4D
).

View larger version (167K):
[in this window]
[in a new window]
|
Fig. 4. Morphological evaluation of ACF in susceptible and resistant mouse strains. ACF of different size were removed along with surrounding normal tissue and embedded for histological examination using H&E staining. ACF from each strain were assessed for the presence and degree of dysplasia. (A) Small ACF (1 crypt) from AKR/J mouse (400x). There is a lack of goblet cell differentiation, thickened epithelium and nuclear elongation and stratification indicative of severe dysplasia. (B) Small ACF from AKR/J mouse (400x). Hyperchromatic nuclei and moderate loss of goblet cell differentiation indicate this crypt to be non-dysplastic. (C) Medium size ACF involving 3 crypts from an SWR/J mouse (400x). A severely dysplastic morphology, including nuclear stratification and elongation is evident. There is also evidence of nuclear pleomorphism and loss of cell polarity. (D) Large ACF from an A/J mouse involving 10 crypts (200x). Characteristics vary between each of the crypts within the focus, ranging from hyperplasia to dysplasia.
|
|
Table I
shows the percentage of ACF with varying degrees of dysplasia 2 weeks after AOM treatment. AKR/J mice had the highest percentage (88.5%) of non-dysplastic ACF (P < 0.05). There was no significant difference in the number of mildly to moderately dysplastic ACF between any of the strains. However, even at this early time point after AOM treatment a percentage of ACF from A/J and SWR/J mice displayed moderate to severe dysplasia. The resistant strain actually did not develop any ACF with this level of dysplasia.
The morphology of ACF at 9 weeks after AOM administration was also evaluated (Table II
). The greatest percentage of ACF with dysplasia was found in the highly susceptible A/J strain. Furthermore, A/J mice also developed the highest percentage of ACF with moderate to severe dysplasia (31.9%). Although SWR/J mice had a lower percentage of dysplastic crypts relative to A/J mice, the frequency was still higher than that found in AKR/J mice (21.0 versus 10.0%, P < 0.05).
 |
Discussion
|
---|
There is a difference in susceptibility to carcinogen-induced tumor formation between strains of inbred mice (2,20). The underlying mechanisms that may account for this phenotypic variability are unknown, but may involve differences in initiation of normal cells, promotion of initiated cells to preneoplastic lesions or progression of lesions to neoplasms. In this study we have examined the development of ACF, putative preneoplastic lesions, in mice with different susceptibility to AOM-induced colon carcinogenesis. The sequential formation and morphological characteristics of ACF were examined at various time points after AOM administration.
AOM produced ACF in both the susceptible and resistant strains. Furthermore, the total number of ACF was not significantly different between the different strains at each of the early time points examined. Only in A/J mice, the most susceptible strain, was there a significantly higher number of ACF at the last time point evaluated. Interestingly, a general downward trend in ACF frequency was observed 4 weeks after AOM, followed by a rebound in ACF number throughout the remaining time points. This trend was seen in all three strains of mice. McLellan et al. (21) also reported a comparable transient decrease in total ACF frequency produced by AOM in rats. Both of these findings suggest that ACF are dynamic entities, undergoing regression and rebuilding after carcinogen exposure.
Other studies have reported the presence of abnormal foci in tumor-resistant mice. James et al. (22) studied morphological changes induced by 1,2-dimethylhydrazine (DMH) in tumor susceptible C57BL/Ha and resistant ICR/Ha mice. A number of dysplastic foci within the colonic mucosa were observed in resistant ICR/Ha mice, prompting these investigators to suggest that the observed differences in tumorigenesis between strains was a result of differences in the rate of progression from initiated cells to tumors. In another study, hybrid crosses were made between SWR/J and AKR/J mice and F1, F2 and reciprocal backcrosses were treated with DMH (23). The authors found what they described as `focal areas of atypism' (FAA) in histological sections even within the colons of resistant AKR/J mice. No difference, however, was found in the number of FAA induced in the backcross resistant or backcross susceptible mice, whereas a difference was found in the number of tumors. It was concluded that AKR/J mice imparted a degree of protection to offspring of crosses derived from the sensitive strain. Consistent with the findings of these earlier studies, our laboratory has also observed the formation of abnormal foci (ACF) in the colons of resistant AKR/J mice following repetitive exposures to AOM (2,24).
Interestingly, AKR mice are resistant to the development of intestinal tumorigenesis even when crossed with Min (multiple intestinal neoplasia) mice, which spontaneously develop hundreds of intestinal adenomas (25,26). Introduction of the Min mutation onto the AKR background significantly decreases tumor incidence and multiplicity in the small intestine and completely abrogates tumor development in the colon (25,26). A modifier locus, modifier of Min 1 (Mom1), that affects intestinal tumor number has been identified in AKR mice (25,27). This locus may also be important for resistance to chemically induced colon cancer (28).
The finding of a significant number of ACF within the colons of the resistant AKR/J mice raises the question as to whether ACF truly represent precursor lesions in the process of tumorigenesis. Other investigators have raised the same question. In a study by Moen et al. (29), differences in susceptibility to ACF and adenoma formation between recombinant congenic CcS/Dem strains and their parental strains, BALB/cHeA and STS/A, were determined after exposure to DMH. Although there was a correlation between ACF and tumor formation within some of the congenic strains, the authors concluded that the formation of ACF is under a different set of genetic controls than tumor formation. However, a limitation with this and other studies which question the validity of ACF as a precancerous change is that they do not take into consideration the heterogeneity of ACF populations. Numerous studies in rodents and humans have provided evidence that only a small subpopulation of ACF have the potential to progress to tumors (3032). The present study evaluated both the growth and morphological characteristics of ACF to better define the types of ACF which form in the different strains of mice. Our studies demonstrate that both A/J and SWR/J mice generally develop a higher frequency of large ACF than similarly treated AKR/J mice, particularly at the later time points. Our data further indicate that the greatest percentage of dysplastic ACF are found in the highly susceptible A/J strain, which also has the highest percentage of moderately to severely dysplastic ACF. SWR/J mice, which are intermediate in susceptibility, show a lower percentage of dysplastic crypts, but a higher frequency than that found in AKR/J mice. Thus, despite the limitations inherent in the present study, whereby only ACF that are readily apparent in methylene blue stained whole colon mounts can be further analyzed, a strong association was found between ACF with dysplasia and tumor susceptibility.
The data described in this study may have important implications regarding our understanding of tumor progression in the human colon. ACF are commonly found in human colons, in both people with and without colorectal cancer (8,9,32,33). One recent study found ACF in as many as 65% of normal subjects between the ages of 60 and 69 years (33). Analogous to the situation in AOM-treated inbred mice, susceptibility to colorectal cancer in human populations may therefore be dependent on mechanisms or factors which control the progression of ACF to frank cancer.
One set of possible factors includes tumor modifiers that could theoretically limit progression of ACF (25,27,28). Another possible factor is dietary fat. Although the precise carcinogenic mechanisms through which dietary fat may affect tumorigenesis is not known, evidence does indicate that it may act as a promoter of colon cancer at the post-initiation phase (34). Thus, a high fat diet may contribute to the development of colon cancer because many people may already have ACF. Future studies will address the importance of tumor modifiers and the effects of dietary fat composition on tumor progression in susceptible and resistant mice.
 |
Notes
|
---|
2 Present address: Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-3101, USA 
3 To whom correspondence should be addressed Email: rosenberg{at}nso2.uchc.edu 
 |
Acknowledgments
|
---|
The authors would like to thank Andrew Bolt and Ken Crary for their technical assistance. These studies were supported in part by NIH grant DK49805-01, NIEHS Training Grant 1T32ES07163 and NIH grant CA 81428-01.
 |
References
|
---|
-
Druckrey,H. (1970) Production of colonic carcinomas by 1,2-dialkyhydrazines and azoxyalkanes. In Burdette,W.J. (ed.) Carcinoma of the Colon and Antecedent Epithelium. Thomas Books, Springfield, IL, pp. 267279.
-
Papanikolaou,A., Wang,Q.-S., Delker,D.A. and Rosenberg,D.W. (1998) Azoxymethane-induced tumors and aberrant crypt foci in mice of different tumor susceptibility. Cancer Lett., 130, 2934.[ISI][Medline]
-
Bird,R.P. (1987) Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings. Cancer Lett., 37, 147151.[ISI][Medline]
-
McLellan,E.A. and Bird,R.P. (1988) Aberrant crypts: potential preneoplastic lesions in the murine colon. Cancer Res., 48, 61876192.[Abstract]
-
McLellan,E.A. and Bird,R.P. (1988) Specificity study to evaluate induction of aberrant crypts in murine colons. Cancer Res., 48, 61836186.[Abstract]
-
Kristiansen,E. (1996) The role of aberrant crypt foci induced by the two heterocyclic amines 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP) in the development of colon cancer in mice. Cancer Lett., 110, 187192.[ISI][Medline]
-
Whiteley,L.O., Hudson,L. and Pretlow,T.P. (1996) Aberrant crypt foci in the colonic mucosa of rats treated with a genotoxic and nongenotoxic colon carcinogen. Toxicol. Pathol., 24, 681689.[ISI][Medline]
-
Pretlow,T.P., O'Riordan,M., Pretlow,T.G. and Stellato,T.A. (1992) Aberrant crypts in human colonic mucosa: putative preneoplastic lesions. J. Cell. Biochem., 16G (suppl.), 5562.
-
Roncucci,L., Stamp,D., Medline,A., Cullen,J.B. and Bruce,W.R. (1991) Identification and quantification of aberrant crypt foci and microadenomas in the human colon. Hum. Pathol., 22, 287295.[ISI][Medline]
-
Pretlow,T.P., Cheyer,C. and O'Riordan,M. (1994) Aberrant crypt foci and colon tumors in F344 rats have similar increases in proliferative activity. Int. J. Cancer, 56, 599602.[ISI][Medline]
-
Pretlow,T.P., Roukhadze,E.V., O'Riordan,M.A., Chan,J.C., Amini,S.B. and Stellato,T.A. (1994) Carcinoembryonic antigen in human colonic aberrant crypt foci. Gastroenterology, 107, 17191725.[ISI][Medline]
-
Siu,I.-M., Pretlow,T.G., Amini,S.B. and Pretlow,T.P. (1997) Identification of dysplasia in human colonic aberrant crypt foci. Am. J. Pathol., 150, 18051813.[Abstract]
-
Smith,A.J., Stern,H.S., Penner,M., Hay,K., Mitri,A., Bapat,B.V. and Gallinger,S. (1994) Somatic APC and K-ras codon 12 mutations in aberrant crypt foci from human colons. Cancer Res., 54, 55275530.[Abstract]
-
Bolt,A.B., Papanikolaou,A., Delker,D.A., Wang,Q.-S. and Rosenberg,D.W. (1999) Azoxymethane induces K-ras activation in the tumor resistant AKR/J mouse colon. Mol. Carcinog., 27, 210218.[ISI]
-
Nucci,M.R., Robinson,C.R., Longo,P., Campbell,P. and Hamilton,S.R. (1997) Phenotypic and genotypic characteristics of aberrant crypt foci in human colorectal mucosa. Hum. Pathol., 28, 13961407.[ISI][Medline]
-
Jen,J., Powell,S.M., Papadopoulos,N., Smith,K.J., Hamilton,S.R., Vogelstein,B. and Kinzler,K.W. (1994) Molecular determinants of dysplasia in colorectal lesions. Cancer Res., 54, 55235526.[Abstract]
-
Thorup,I. (1997) Histomorphological and immunohistochemical characterization of colonic aberrant crypt foci in rats: relationship to growth factor expression. Carcinogenesis, 18, 465472.[Abstract]
-
Shpitz,B., Bomstein,Y., Mekori,Y., Cohen,R., Kaufman,Z., Neufeld,D., Galkin,M. and Bernheim,J. (1998) Aberrant crypt foci in human colons: distribution and histomorphologic characteristics. Hum. Pathol., 29, 469475.[ISI][Medline]
-
Whiteley,L.O., Anver,M.R., Botts,S. and Jokinen,M.P. (1996) Proliferative lesions of the intestine, salivary glands, oral cavity and esophagus in rats. In Guides for Toxicologic Pathology. STP/ARP/AFIP, Washington, DC, pp. 118.
-
Diwan,B.A., Meier,H. and Blackman,K.E. (1977) Genetic differences in the induction of colorectal tumors by 1,2-dimethylhydrazine in inbred mice. J. Natl Cancer Inst., 59, 455458.[ISI]
-
McLellan,E.A., Medline,A. and Bird,R.P. (1991) Sequential analyses of the growth and morphological characteristics of aberrant crypt foci: putative preneoplastic lesions. Cancer Res., 51, 52705274.[Abstract]
-
James,J.T., Shamsuddin,A.M. and Trump,B.F. (1983) Comparative study of the morphologic, histochemical and proliferative changes induced in the large intestine of ICR/Ha and C57BL/Ha mice. J. Natl Cancer Inst., 71, 955964.[ISI][Medline]
-
Deschner,E.E., Long,F.C. and Hakissian,M. (1988) Susceptibility to 1,2-dimethylhydrazine-induced colonic tumors and epithelial cell proliferation characteristics of F1, F2 and reciprocal backcrosses derived from SWR/J and AKR/J parental mouse strains. Cancer, 61, 478482.[ISI][Medline]
-
Delker,D.A., Wang,Q.-S., Papanikolaou,A., Whiteley,H.E. and Rosenberg,D.W. (1999) Quantitative assessment of azoxymethane-induced aberrant crypt foci in inbred mice. Exp. Mol. Pathol., 65, 141149.[ISI][Medline]
-
McPhee,M., Chepenik,K.P., Liddell,R.A., Nelson,K.K., Siracusa,L.D. and Buchberg,A.M. (1995) The secretory phospholipase A2 gene is a candidate for the Mom1 locus, a major modifier of ApcMin-induced intestinal neoplasia. Cell, 81, 957966.[ISI][Medline]
-
Shoemaker,A.R., Moser,A.R., Midgley,C.A., Clipson,L., Newton,M.A. and Dove,W.F. (1998) A resistant genetic background leading to incomplete penetrance of intestinal neoplasia and reduced loss of heterozygosity in ApcMin/+ mice. Proc. Natl Acad. Sci. USA, 95, 1082610831.[Abstract/Free Full Text]
-
Dietrich,W.F., Lander,E.S., Smith,J.S., Moser,A.R., Gould,K.A., Luongo,C., Borenstein,N. and Dove,W.F. (1993) Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal multiple neoplasia in the mouse. Cell, 75, 631639.[ISI][Medline]
-
Papanikolaou,A., Wang,Q.-S., Mulherkar,R., Bolt,A. and Rosenberg,D.W. (2000) Expression analysis of the group IIA secretory phospholipase A2 in mice with differential susceptibility to azoxymethane-induced colon tumorigenesis. Carcinogenesis, 21, 133138.[Abstract/Free Full Text]
-
Moen,C.J.A., van der Valk,M.A., Bird,R.P., Hart,A.A.M. and Demant,P. (1996) Different genetic susceptibility to aberrant crypts and colon adenomas in mice. Cancer Res., 56, 23822386.[Abstract]
-
Park,H.-S., Goodlad,R.A. and Wright,N.A. (1997) The incidence of aberrant crypt foci and colonic carcinoma in dimethylhydrazine-treated rats varies in a site-specific manner and depends on tumor histology. Cancer Res., 57, 45074510.[Abstract]
-
Shpitz,B., Hay,K., Medline,A., Bruce,W.R., Bull,S.B., Gallinger,S. and Stern,H. (1996) Natural history of aberrant crypt foci. A surgical approach. Dis. Colon Rectum, 39, 763767.[ISI][Medline]
-
Bouzourene,H., Chaubert,P., Seelentag,W., Bosman,F.T. and Saraga,E. (1999) Aberrant crypt foci in patients with neoplastic and nonneoplastic colonic desease. Hum. Pathol., 30, 6671.[ISI][Medline]
-
Takayama,T., Katsuki,S., Takahashi,Y., Ohi,M., Nojiri,S., Sakamaki,S., Kato,J., Kogawa,K., Miyake,H. and Niitsu,Y. (1998) Aberrant crypt foci of the colon as precursors of adenoma and cancer. N. Engl. J. Med., 339, 12771284.[Abstract/Free Full Text]
-
Lipkin,M., Reddy,B., Newmark,H. and Lamprecht,S.A. (1999) Dietary factors in human colorectal cancer. Annu. Rev. Nutr., 19, 545586.[ISI][Medline]
Received December 23, 1999;
revised April 27, 2000;
accepted May 4, 2000.