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[Cancer Research 62, 6367-6370, November 15, 2002]
© 2002 American Association for Cancer Research

Advances in Brief

Microadenomatous Lesions Involving Loss of Apc Heterozygosity in the Colon of Adult ApcMin/+ Mice1

Yasuhiro Yamada2, Kazuya Hata, Yoshinobu Hirose, Akira Hara, Shigeyuki Sugie, Toshiya Kuno, Naoki Yoshimi, Takuji Tanaka and Hideki Mori

Department of Pathology, Gifu University School of Medicine, Gifu 500-8705 [Y. Y., K. H., Y. H., A. H., S. S., T. K., H. M.]; and Department of Pathology, Faculty of Medicine, University of the Ryukyus, Okinawa 903-0213 [N. Y.]; and Department of Pathology, Kanazawa Medical University, Ishikawa 920-0293 [T. T.], Japan


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Mutations in the human adenomatous polyposis coli (APC) gene are causative for familial adenomatous polyposis (FAP), a rare condition in which numerous colonic polyps arise during puberty and, if left untreated, lead to colon cancer. Mouse model for human FAP, ApcMin/+ mouse, contains a truncating mutation in the Apc gene and spontaneously develops intestinal adenomas. However, the distribution of tumors along the intestine found in ApcMin/+ mice is different from that in human FAP. A majority of intestinal polyps in the ApcMin/+ mice is known to be located in the small intestine but rarely detected in the colon. We report here that adult ApcMin/+ mice develop dozens of microadenomatous lesions in the colon (>20 lesions/colon). Surprisingly, the vast majority of such adenomatous lesions consisting of colonic crypts were <300 µm in their greatest dimension, whereas lesions in the small intestine showed various sizes. The allelic loss analysis revealed that these adenomatous crypts in the colon have already lost the remaining allele of Apc. Such findings suggest that, in contrast to tumorigenesis in the small intestine, loss of heterozygosity of the Apc gene is not sufficient for tumor development in the colon of ApcMin/+ mice. Our results may give an account for the low incidence of colonic tumors in ApcMin/+ mice.


   Introduction
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 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
The colorectal carcinogenesis is known to have multistep processes (1) . Because of its gradual evolution toward malignancy, colorectal cancer might serve as an excellent paradigm to examine the genes involved in tumorigenesis. In humans, APC,3 ß-catenin (CTNNB1), Ki-ras (KRAS1) oncogene, and p53 (TP53) genes play important roles at different stages of colorectal carcinogenesis (2 , 3) . Of these, mutations in APC gene found in the earliest stages of the adenoma-carcinoma pathway are considered to play a gate-keeping role in tumor formation and progression (4) . Moreover, germ-line mutations in the APC gene are recognized to be responsible for FAP, a dominantly inherited autosomal condition characterized by formation of multiple colonic adenomatous polyps with a high likelihood to develop colon carcinomas (5 , 6) . Somatic APC mutations are also implicated in most of the colonic tumors (4 , 7) and other neoplasms in the digestive tracts (8) .

Mutant mouse lineage being predisposed to Min is regarded as one of the models for colorectal tumorigenesis (9) . Originally, this lineage was established from an ethylnitrosourea-treated C57BL/6J (B6) male mouse, and its phenotype is a fully penetrate autosomal dominant trait. The dominant mutation is known to be located in Apc, the mouse homologue of the human APC gene, resulting in truncation of the gene product at amino acid 850 (10) . It is suggested that, although homozygous ApcMin/Min mice die as embryos, ApcMin/+ mice develop multiple intestinal neoplasias in the intestinal tracts within a few weeks after birth. APC is now recognized as a recessive tumor suppressor gene, and its inactivation of both alleles is considered to be necessary for tumor formation (11) . In mice heterozygous for a mutant allele of Apc, the loss of Apc function occurs almost exclusively by LOH (12 , 13) .

Although it appears to be true that inactivation of both APC alleles is necessary for tumorigenesis, it is still not clear whether such mutations are sufficient. We have assumed that many precursors of colonic tumor could be recognized in the colonic mucosa of aged ApcMin/+ mice if the inactivation of both Apc alleles were insufficient for the tumorigenesis. To test this possibility, we screened intramucosal colonic lesions of aged ApcMin/+ mice by analysis using en face and serial histological sections. In such analysis, we have reported the presence of newly identified early appearing lesions of colon cancer, which are hard to be detected in whole mount preparations (14 , 15) . Because it is known that a majority of ApcMin/+ mice live no longer than 150 days, ApcMin/+ mice >20 weeks of age were examined in this study. LMM and LPC were used to analyze allelic loss of the Apc gene.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Experimental Procedure.
ApcMin/+ mice were obtained from The Jackson Laboratory (Bar Harbor, ME). They were bred and maintained on a basal diet, CE-2 (CLEA Japan Inc., Tokyo, Japan), until termination of the study. Sixteen ApcMin/+ mice (9 males and 7 females) and 7 Apc+/+ mice (4 males and 3 females), which were >20 weeks of age (20–33 weeks of age), were used in the present study. The colons were removed, cut open along their longitudinal axis, and fixed flat in 10% buffered formalin for 24 h at room temperature. Colon tumors identified macroscopically were also fixed in 10% buffered formalin and processed for histopathological evaluation by routine procedures (16) . To identify small tumors, mucosal surface with methylene blue staining was observed under a microscope. In brief, fixed colons were placed in 0.5% solution of methylene blue in distilled water. They were then placed mucosal side up on a microscope slide and observed through a light microscope at a magnification of x40.

Tissue Preparation.
To identify intramucosal lesions, colonic mucosa was examined in histological sections. Colons (the length of 6 cm from the anal ring) were divided into three segments and were embedded in paraffin. The middle part of the small intestine was also cut into small segments and embedded in paraffin. A total of 69 segments from the colon and 23 segments from the small intestine were examined by using an en face preparation and 3–5-µm thick serial sections (14 , 15 , 17) . For each case, 10–20 serial sections were used to investigate the intramucosal lesions.

LMM and LPC.
In the current study, DNA for the analysis of the Apc allelic loss was extracted from cells isolated with LMM and LPC (zref18). For laser capturing, the slides were put into xylene for 30 min to dissolve the paraffin that otherwise interferes with LMM. Next, the slides were washed for 10 min in 100% ethanol. After staining with H&E, sections were dehydrated in 100% ethanol, incubated 2 min in xylene, and dried at room temperature. Sections were captured in one session using the PALM Robot-MicroBeam system (P.A.L.M. Mikrolaser Technology AG, Bernried, Germany). The LPC-collected cells were solved in 20 µl of lysis buffer.

Apc Allelic Loss Analysis.
A total of 62 microdissected tissues (28 normal-appearing crypts, 14 microadenomatous lesions in the colon, 5 tumors in the small intestine, 10 colonic tumors in ApcMin/+ mice, and 5 normal crypts in Apc+/+ mice) were selected at random. They were digested overnight at 50° in 20 µl of lysis buffer containing 500 µg/ml proteinase K, 10 mmol/liter Tris-HCl (pH 8.0), 50 mmol/liter KCl, 0.45% NP40, and 0.45% Tween 20. The proteinase K was heat inactivated (10 min at 95°). The tubes were centrifuged for 5 min, and the supernatant was transferred to new tubes. LOH of the Apc gene was checked using PCR with mismatched primers, as described previously (12) . Briefly, the amplification of the ApcMin allele resulted in a 155-bp PCR product with one HindIII site, whereas the 155-bp product from the Apc+ allele contained two HindIII sites. HindIII digestion of PCR-amplified DNA from ApcMin/+ heterozygous tissue resulted in a 123-bp product from the Apc+ allele and a 144-bp product from the ApcMin allele. Therefore, PCR products from tissue with LOH displayed only one band (144-bp) from the ApcMin allele. Samples were assayed at least twice, independently.


   Results
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Microadenomatous Lesions in the Colon of ApcMin/+ Mice.
Unlike the frequency of tumors in the small intestine (30–60 tumors/small intestine), only small numbers of tumors (0–5 tumors/colon) were evident in the colon of adult ApcMin/+ mice. Histological sections of these colonic tumors were examined for tumor types, and they were classified as adenomas or adenocarcinomas. In the sections stained with H&E, dysplastic crypts were detected frequently in the colonic mucosa of all of the ApcMin/+ mice (Fig. 1A)Citation , whereas the lesions were absent in the colons of Apc+/+ mice. Adult ApcMin/+ mice developed at least 20 lesions/colon. The histological features of such dysplastic crypts resembled those of adenomas; the crypts bore basophilic cytoplasm and hyperchromatic nuclei, and they were associated with an increase of the nuclear:cytoplasmic ratio (Fig. 1, C–E)Citation . Mucin production was almost absent in the microadenomatous crypts (Fig. 1E)Citation . Interestingly, the vast majority (>95%) of the adenomatous lesions in the colon were <300 µm in their greatest dimension (Fig. 1ACitation ; Fig. 2Citation ). Most of such lesions consisted of one to six adenomatous crypts. The greatest dimensions of the adenomatous lesions, including microadenomatous lesions, adenomas, and adenocarcinomas, in both colon and small intestine are summarized in Fig. 2Citation . In contrast to the colon, adult ApcMin/+ mice developed a number of adenomatous lesions with a variety of sizes in the small intestine (Fig. 1, B and FCitation ; Fig. 2Citation ). The numbers of the lesion/area in the colon and small intestine were 17.85 ± 9.86/cm2 and 8.07 ± 3.06/cm2, respectively (Table 1)Citation . The incidence of colonic lesions was significantly higher than that of the small intestine (P < 0.001). The mean dimensions of colonic lesions and small intestinal lesions were 176.04 ± 410.84 µm and 1286.96 ± 1069.78 µm, respectively (Table 1)Citation . The size of colonic lesions was smaller than that of the small intestine (P < 0.001).



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  		Fig. 1. Microadenomatous lesions found in the colon of aged ApcMin/+ mice. A, at lower magnification of en face sections, intramucosal adenomatous crypts are frequently detectable in the colonic mucosa of aged ApcMin/+ mice (arrowheads). Note that all lesions are <300 µm in their greatest dimension. B, in the small intestine, various sizes of adenomatous lesions are seen in cross-sections. C–E, higher magnifications of microadenomatous crypts in the colon. The crypts bear basophilic cytoplasm and hyperchromatic nuclei. Mucin production is almost absent in those crypts. F, a cross-section of a single adenomatous crypt in the small intestine, which have been described as the earliest lesion in the small intestine (13 , 24) . Bars, 300 µm (A and B), 100 µm (C, D, and F), 50 µm (E)

 


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  		Fig. 2. Size distribution of adenomatous lesions in the colon and small intestine. Representative example of each greatest dimension of adenomatous lesions including tumors is shown.

 

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  		Table 1 Adenomatous lesions in the colon and small intestine

 
Apc Allelic Loss in Colonic Lesions.
Twenty-eight normal-appearing crypts, 14 microadenomatous lesions in the colon, and 15 intestinal tumors were randomly selected, and picked individually from the histological sections of adult ApcMin/+ mice. Fig. 3Citation represents the results of nondenatured acrylamide gel electrophoresis. After HindIII digestion of PCR-amplified DNA, two DNA bands (144-bp and 123-bp) appeared on gels from phenotypically normal crypts of ApcMin/+ mice, whereas only one band at 123-bp was evident in normal crypts of the Apc+/+ mice (Fig. 3)Citation . All of the PCR products from tumors revealed a single band (144-bp) deriving from the ApcMin allele (Fig. 3Citation ; Table 2Citation ). Remarkably, the majority of microadenomatous lesions (12 of 14 lesions) showed a single band at 144 bp, suggesting that such small lesions have lost Apc+ allele already (Fig. 3Citation ; Table 2Citation ).



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  		Fig. 3. Apc allelic loss assay. Two DNA bands (144-bp and 123-bp) appear on gels from phenotypically normal crypts of ApcMin/+ mice, whereas only one band at 123-bp is evident in normal crypts of the Apc+/+ mice. PCR products from tumors revealed a single band (144-bp), which were derived from the ApcMin allele. Remarkably, microadenomatous lesions also showed a single band at 144 bp, suggesting that such crypts already have lost Apc+ allele.

 

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  		Table 2 Apc allelic loss in the ApcMin/+ mouse

 

   Discussion
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
Min mice are heterozygous for a nonsense mutation in the Apc gene. They develop spontaneously Mins similarly to the FAP syndrome in humans. However, it is well demonstrated that the distributing pattern of intestinal tumors in ApcMin/+ mice is different from that in human FAP. Most adenomatous polyps in FAP patients arise in the colon and, if left untreated, lead to colonic cancers. In contrast, the highest frequency of tumors in ApcMin/+ mice is seen in the small intestine, whereas lower numbers are located in the colon (19) . In the current study, we found that there are many microadenomatous lesions that are hardly identified in the whole mount preparations in the colonic mucosa of the ApcMin/+ mice. It is noteworthy that adult ApcMin/+ mice developed a number of lesions not only in the small intestine but also in the colon.

It has been demonstrated that loss of Apc function plays a pivotal role in colorectal carcinogenesis. It is also known that all of the intestinal tumors in mice heterozygous for a mutant allele of Apc have lost the Apc function by LOH (12 , 13) . In this study, microadenomatous crypts in the colon were found to have lost the remaining allele of Apc, indicating that loss of Apc function has already occurred in such crypts. Accordingly, it seems to be reasonable to apply Knudson’s "two-hit" theory (20) to the formation of microadenomatous lesions in the colon of ApcMin/+ mice. Importantly, in this study, the number of colonic adenomatous lesions per area was much higher than that of lesions in the small intestine, suggesting that LOH of the Apc occurs frequently in the colonic crypts as well as epithelium in the small intestine.

It is also interesting that almost all of the intramucosal adenomatous lesions in the colon were <300 µm in their greatest dimension. Because ApcMin/+ mice used in this experiment were >20 weeks of age, such microadenomatous crypts are suggested to be self-limiting lesions and not grow into colonic tumors. Conditional knockout mice of the Apc are reported to develop only 6.7 colon tumors on average, although numerous colonic cells in the mice ought to be lacking in both alleles of Apc (21) . The results in the present study, together with previous findings, suggest that inactivation of the Apc is not sufficient for development of colonic tumors. It is noteworthy that mutation of K-ras seems to be correlated with the development of large, dysplastic adenomatous polyps in humans (1 , 22) . K-ras mutation may be associated with the tumor development in the colon of ApcMin/+ mice. However, no ras mutations have been found in intestinal tumors of ApcMin/+ mice (23) , indicating that the mutational activation of K- or H-ras is not a common event in the formation of intestinal adenomas in ApcMin/+ mice. Therefore, it is possible that another genetic and/or epigenetic event except ras mutations occurs in those colonic tumors.

In contrast to colonic lesions, it is quite interesting to note that the adenomatous lesions in the small intestine had various sizes, and the mean size of the lesions was significantly larger than in the colon. We detected different adenomatous lesions, which have been reported in the stages of polyp development (13 , 24) , including a single adenomatous crypt. It has been demonstrated that loss of the Apc gene is also involved in the earliest lesions in the small intestine of mice heterozygous for a mutant allele of Apc (13) . It is possible that, in the small intestine, a dominant-negative mechanism by the loss of function of Apc is directly responsible for the formation of microadenomas that could develop into intestinal tumors. Thus, our results may explain why the ApcMin/+ mouse develops intestinal tumors preferably in the small intestine and suggest that mechanisms of tumorigenesis involved in the small intestine may differ from those in the colon.

In conclusion, it was shown that there are a number of microadenomatous lesions together with a few tumors in the colon of aged ApcMin/+ mice. Such microadenomatous lesions have already lost the remaining allele of Apc, indicating that LOH of the Apc gene has occurred in the crypts. These findings suggest that loss of Apc function is responsible for the formation of microadenomatous lesions in the colon but is not sufficient for the development of colonic tumors in ApcMin/+ mice.


   ACKNOWLEDGMENTS
 
We thank Misato Yasuda for steady and highly capable technical assistance in the allelic loss assay. We also thank Kyoko Takahashi, Tomoko Kajita, Hisae Shibazaki, and Yoshitaka Kinjyo for assistance.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported in part by Grants-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare and the Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan. Back

2 To whom requests for reprints should be addressed, at Department of Pathology, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705, Japan. Phone: 81-58-267-2235; Fax: 81-58 -265-9005; E-mail: y-yamada{at}cc.gifu-u.ac.jp Back

3 The abbreviations used are: APC, adenomatous polyposis coli; FAP, familial adenomatous polyposis; Min, multiple intestinal neoplasm; LMM, laser microbeam microdissection; LPC, laser pressure catapulting; LOH, loss of heterozygosity. Back

Received 8/ 5/02. Accepted 10/ 2/02.


   REFERENCES
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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