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[Cancer Research 62, 4558-4561, August 15, 2002]
© 2002 American Association for Cancer Research

Advances in Brief

No Effects of Smad2 (Madh2) Null Mutation on Malignant Progression of Intestinal Polyps in Apc{Delta}716 Knockout Mice1

Kazuaki Takaku, Jeffrey L. Wrana, Elizabeth J. Robertson and Makoto M. Taketo2

Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan [K. T., M. M. T.]; Laboratory of Biomedical Genetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan [K. T., M. M. T.]; Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada [J. L. W.]; and Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138 [E. J. R.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
The loss of heterozygosity (LOH) in human chromosome 18q21 is found at high frequencies in advanced pancreatic and colorectal cancers. Several candidate tumor suppressor genes, such as SMAD2, SMAD4, and DCC, are located in this region. The homologues of these genes in the mouse are also clustered on chromosome 18. Mutations in the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis, and we earlier constructed a mouse model for familial adenomatous polyposis, Apc{Delta}716. Although human APC is located on chromosome 5q, mouse Apc is on chromosome 18, 30 cM proximal to the Dcc-Smad4-Smad2 locus. Taking advantage of this fact, we constructed previously a cis-compound Apc{Delta}716 Smad4 mutant, the intestinal polyps of which progress to very invasive adenocarcinomas. To determine whether Smad2 mutations play similar roles in malignant progression, here we constructed compound mutant mice carrying Apc and Smad2 knockouts in the cis configuration. In contrast to the cis-compound Apc{Delta}716 Smad4 heterozygotes, the polyps in the cis-compound Apc{Delta}716 Smad2 heterozygotes showed no difference in the number, size, or histopathology from the polyps in the simple Apc{Delta}716 heterozygotes. These results suggest that, on human chromosome 18q21, the SMAD4 LOH plays a more significant role, and SMAD2 LOH is insufficient to cause malignant progression of colonic polyps.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
The molecular processes leading to colon cancer consist of sequential mutations in specific genes that transform the normal colonic epithelium to an adenomatous polyp and, ultimately, to carcinoma. In early colorectal adenomas, inactivating mutations in the APC3 gene are found, whereas in advanced stages of colorectal cancer, a high frequency of LOH is found in human chromosome 18q21 (1) . Several genes in this region encoding Smad2 (MADH2), Smad4 (MADH4 or DPC4) and DCC (DCC) have been proposed as candidates tumor suppressors (1, 2, 3) . Among them, DCC has been demonstrated to be a receptor for the axonal chemoattractant netrin-1, rather than a tumor suppressor (4) . Smad2 and Smad4 proteins belong to the evolutionarily conserved family of Smad proteins that are involved in the TGF-ß signal transduction pathway (5 , 6) . TGF-ß is a potent growth inhibitor of epithelial tissues, and loss of this negative regulation contributes to tumor development, especially invasive changes (7) . Tumors can become resistant to TGF-ß by various mechanisms. For example, inactivating mutations in the TGF-ß type II receptor gene (TGFBR2) have been found in many human colorectal carcinomas (8) . In addition, mutations and loss of heterozygosity in the SMAD4 (MADH4) gene or SMAD2 (MADH2) gene have been reported in colorectal carcinomas (2 , 9) .4

Earlier, we introduced a null mutation of the Smad4 (Madh4) gene (10) into the Apc{Delta}716 mouse strain (11) , a mouse model for human FAP. In the compound Apc{Delta}716 Smad4 mutant, the intestinal polyp adenomas progress to malignant adenocarcinomas, showing strong invasion (10) . These results indicate that inactivating mutations or deletions of SMAD4 (MADH4) play a significant role in the malignant progression of colorectal tumors.

On the other hand, missense mutations have been found in the SMAD2 (MADH2) gene only in small fractions of human colorectal carcinoma and other cancers (2 , 12) , and the effects of Smad2 loss or inactivating mutations in tumorigenesis remain to be determined. In the mouse, the Smad2 (Madh2) null homozygotes are embryonically lethal at the stage of perigastrulation, although the heterozygous Smad2 mice are viable, fertile, and appear normal (13) . Interestingly, mouse Smad2 has been also mapped to chromosome 18, tightly linked to Smad4 (14) . To determine whether a homozygous null mutation in Smad2 plays a similar role to that in Smad4, we have constructed cis-compound Apc{Delta}716 Smad2 heterozygotes according to the same strategy as used for the construction of the cis-compound Apc{Delta}716 Smad4 mutant (10) .


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Generation of cis-Compound Apc{Delta}716 Smad2 Heterozygous Mice.
Constructions of Apc{Delta}716 (11) and Smad2 (13) knockout mice have been described previously. Heterozygous Apc{Delta}716 and Smad2 mutants, respectively, have been backcrossed with C57BL/6J for generations; n = 13 for the Apc{Delta}716 mice and n = 3 for the Smad2+/- mice. We constructed the cis-compound Apc{Delta}716 Smad2 heterozygotes using the same strategy as used for constructing the cis-compound Apc{Delta}716 Smad4 heterozygotes (10) . Briefly, the Apc{Delta}716 males were mated with the Smad2+/- females to construct trans-Apc{Delta}716 Smad2 heterozygous mice. The compound heterozygous males were then backcrossed with C57BL/6J females to generate cis-compound Apc{Delta}716 Smad2 heterozygous mice. Offspring mice were genotyped by PCR, as described previously (11 , 13) .

Polyp Scoring.
The number and size of the polyps were scored by a single examiner (K. T.) as described (10) .

PCR Analysis for Apc and Smad4 LOH.
The smallest nascent adenomatous polyps identifiable under a dissection microscope were in the range of 0.2 mm in diameter. The normal epithelium covering these smallest polyps was removed by peeling it off very carefully under a dissection microscope, as described previously (11) . Genomic DNA was prepared from these nascent polyps, as described previously (10 , 11) . The PCR primers and conditions for Apc and Smad2 LOH determinations have been described previously (11 , 13) .

Histopathology.
cis-compound Apc{Delta}716 Smad2 heterozygous mice and Apc{Delta}716 controls were sacrificed and necropsied, and intestinal samples were prepared for histopathology as described previously (10 , 11) .


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
LOH at Both Apc and Smad2 Loci in the Polyp Epithelium of the cis-Compound Apc{Delta}716 Smad2 Heterozygotes.
We earlier constructed a mouse strain carrying a knockout mutation in the Apc gene (Apc{Delta}716; Ref. 11 ). These mice develop numerous polyps in the intestines and can serve as a model for human FAP. Although human APC is located on 5q21, its mouse homologue Apc is on chromosome 18, at ~15th cM from the centromere (10) . On the other hand, human SMAD2 (MADH2) is on 18q21, and its mouse homologue Smad2 (Madh2) has been also mapped to chromosome 18, tightly linked to Smad4 (14) . Accordingly, the mouse Apc and Smad2/Smad4 loci are located on the same chromosome separated by 33 cM, although their human homologues are on separate chromosomes. We therefore constructed compound heterozygotes whose Apc and Smad2 mutations were brought onto the same chromosome in the cis configuration and determined the effects of the homozygous Smad2 knockout mutation in the Apc{Delta}716 mutant polyps. This was achieved by the same strategy as used for the construction of the cis-compound Apc{Delta}716 Smad4 mutants (10) ; i.e., we first crossed the Apc{Delta}716 mice with the Smad2 heterozygotes and obtained trans-compound Apc{Delta}716 Smad2 heterozygous mice. The compound heterozygous males were then backcrossed with C57BL/6J females to generate cis-compound Apc{Delta}716 Smad2 heterozygous mice by meiotic recombination. Their offspring contained not only simple heterozygotes (51 Apc+/{Delta}716 and 35 Smad2+/- pups) but also compound heterozygotes in the cis configuration (26 pups) and the wild-type mice (24 pups). This recombination frequency of 36.8% [(26 + 24)/(26 + 24 + 51 + 35)] matches their linkage distance, because the Apc and Smad2 genes are separated by ~33 cM (14) .

As we demonstrated earlier (11) , the formation of both small intestinal and colonic polyps in the Apc{Delta}716 knockout mice is always associated with LOH in the Apc locus from a very early stage on. The early LOH was confirmed in the polyp microadenomas of the cis-compound Apc{Delta}716 Smad2 heterozygotes as well. As shown in Fig. 1Citation , the PCR band for the wild-type Apc allele was lost in the polyp epithelial cells (T1–T4), whereas it remained in the normal intestinal epithelium adjacent to the polyps (N1–N3). Likewise, the band for the full-length wild-type Smad2 was also missing in the polyps (T1–T4), although it remained in the normal intestinal epithelium (N1–N3), showing LOH in the Smad2 locus as well. These results strongly suggest that a wide range of mouse chromosome 18, including the wild-type Apc and Smad2 alleles, is lost in the polyp adenoma epithelium in the cis-compound Apc{Delta}716 Smad2 heterozygotes, as in the cis-compound Apc{Delta}716 Smad4 heterozygotes (10) .



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  		Fig. 1. LOH at the Apc and Smad2 loci in the cis-compound Apc{Delta}716 Smad2 heterozygous mouse intestinal polyps. The Apc (top) and Smad2 (bottom) genotypes were determined by PCR for the dissected nascent polyp epithelial (T1–T4) and normal intestinal (N1–N3) samples. The samples were obtained from three mice. The positions of the amplified bands for Apc and Smad2 are shown on the right, respectively. WT, wild-type alleles; KO, knockout alleles.

 
No Increase in the Intestinal Polyp Number or Size in the cis-Compound Apc{Delta}716 Smad2 Heterozygotes.
As shown in Table 1Citation , the polyp numbers in the small intestine of the cis-compound Apc{Delta}716 Smad2 heterozygotes were similar to those in the simple Apc{Delta}716 heterozygotes at 6, 14, and 20 weeks of age, respectively. These results suggest that homozygous inactivation of the Smad2 gene does not affect the frequency of LOH in the Apc gene. Moreover, the size distribution of the small intestinal polyps in the cis-compound Apc{Delta}716 Smad2 heterozygotes showed essentially the same pattern as that of the simple Apc{Delta}716 controls at all ages examined (Fig. 2)Citation . Likewise, the number and size distribution of the colonic polyps in the cis-compound Apc{Delta}716 Smad2 heterozygotes were not significantly different from those in the simple Apc{Delta}716 heterozygotes (data not shown). These results are in sharp contrast to the phenotype of the cis-compound Apc{Delta}716 Smad4 heterozygotes, whose polyps are much larger than those of the Apc{Delta}716 controls (10) .


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  		Table 1 Polyp numbers of cis-compound Apc{Delta}716 Smad2 and Apc{Delta}716 heterozygotes

 


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  		Fig. 2. Comparison of intestinal polyp size distribution between the Apc{Delta}716 controls (left) and cis-compound Apc{Delta}716 Smad2 heterozygotes (right). The bar patterns for the respective size classes are shown on the right ({Phi}, diameter in mm), whereas the ages are shown on the bottom. The mean values from 6 mice/group are shown as percentages for the respective size classes.

 
No Difference in the Polyp Histopathology between the cis-Compound Apc{Delta}716 Smad2 Heterozygotes and Simple Apc{Delta}716 Heterozygotes.
As shown in Fig. 3, A and BCitation , the histopathology of the small intestinal polyps was not different between the cis-compound Apc{Delta}716 Smad2 heterozygotes and littermate Apc{Delta}716 controls. The colonic polyp histopathology was also indistinguishable between the cis-compound Apc{Delta}716 Smad2 and Apc{Delta}716 heterozygotes (Fig. 3, C and D)Citation . None of 6 cis-compound Apc{Delta}716 Smad2 heterozygotes contained any invasive polyps at 20 weeks of age. These results indicate that a homozygous null mutation in the Smad2 gene does not affect the formation or malignant progression of the Apc{Delta}716 polyps. Although the cis-compound Apc{Delta}716 Smad4 heterozygotes show additional lesions as skin epidermoid cysts and/or adenocarcinomas in the ampullary region of the pancreatic duct (10) , we did not find any such phenotypes in the cis-compound Apc{Delta}716 Smad2 heterozygotes.



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  		Fig. 3. Histopathology of the intestinal polyps in the cis-compound Apc{Delta}716 Smad2 heterozygotes (left) compared with those in the Apc{Delta}716 controls (right). A and B, representative small intestinal polyps. C and D, representative colonic polyps. All mice were littermates, 20 weeks of age. H&E. Bars, 500 µm.

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
Biallelic loss of 18q21 is found at a high frequency in advanced stages of colorectal cancer (1) . Some genes in this region, such as SMAD2 (MADH2), SMAD4 (MADH4), and DCC, have been proposed to be candidate tumor suppressors. Among them, DCC has been demonstrated to be a netrin-1 receptor, rather than a tumor suppressor (4) ; i.e., in the cis-compound ApcMin Dcc heterozygotes, constructed by the same strategy as used for the cis-compound Apc{Delta}716 Smad2 and Apc{Delta}716 Smad4 heterozygote constructions, a null mutation in Dcc does not affect the intestinal polyp initiation, the average size, or the morphology of the adenoma (4) . On the other hand, a null mutation in Smad4 (Madh4) develops invasive adenocarcinomas in the Apc{Delta}716 mice (10) . To assess the possible tumor suppressor activity of the Smad2 (Madh2) gene, we have constructed cis-compound Apc{Delta}716 Smad2 heterozygotes and compared the number, size, and morphology of their polyps with those in the simple Apc{Delta}716 controls. Unlike the Smad4 mutation, however, the Smad2 null mutation did not affect the intestinal tumorigenesis in the Apc{Delta}716 mice significantly. These results collectively indicate that loss of Smad4 is most responsible for the malignant progression of adenomas, among these three genes examined by the same genetic strategy. Accordingly, it is possible that effects of 18q21 LOH in human cancer are caused essentially by the inactivation of a single gene, SMAD4, although loss of other genes in the locus may play additional roles.

It is worth noting that some Smad2 missense mutations have been reported in small fractions of colorectal and lung cancers (2 , 12) . One such mutant, Smad2.P445E, suppresses the TGF-ß-induced growth arrest in epithelial cells by dominant-negative inhibition of the wild-type Smad2 for its nuclear accumulation (15) . Another mutant Smad2.D450E does not affect TGF-ß-mediated growth arrest but rather induces cellular invasion in a TGF-ß-dependent manner (16) . In this context, it is interesting that such effects of the TGF-ß signaling as growth arrest is independent of Smad4, because it is not affected in Smad4-deficient cells (17 , 18) .

The roles of Smad2 and Smad3 in the canonical TGF-ß signaling pathway have been established (5 , 6) , and both Smad2 and Smad3 mRNAs are expressed in the Apc{Delta}716 polyps at similar levels to those in the normal mucosa of the small intestine and colon (data not shown). Although Smad2 homozygotes are embryonically lethal, homozygous Smad3 mice are viable and survive for 4–6 months. One of the Smad3 mutants can develop colon carcinomas that metastasize to the regional lymph nodes (19) . However, other Smad3-/- mutations do not cause any colorectal tumors, but they die of chronic inflammation in several organs as a consequence of impaired immune functions (20 , 21) . These findings suggest that the colorectal tumors in the Smad3 null mice may be similar to those found in the TGF-ß1 knockout mice (22) and those in human inflammatory bowel diseases. It is conceivable that the tumor suppressor activity of Smad3 and/or Smad4 may be interfered by some missense mutations in Smad2, although not by its null mutation.

In conclusion, loss of Smad4 appears to play the most important role in colorectal tumor progression in the deletions in the DCC-SMAD4-SMAD2 gene cluster on 18q21.


   ACKNOWLEDGMENTS
 
We thank Drs. K. Hioki and N. Shimozawa (Central Institute for Experimental Animals) for the breeding mice and S. Hagiwara, S. Iwasaki, M. Sonoshita, and Dr. N. Sasaki (University of Tokyo, Tokyo, Japan) 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 This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology, and from the Organization for Pharmaceutical Safety and Research, Japan. Back

2 To whom requests for reprints should be addressed, at Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida-Konoé-cho, Sakyo-ku, Kyoto 606-8501, Japan. Phone: 81-75-753-4391; Fax: 81-75-753-4402; E-mail: taketo{at}mfour.med.kyoto-u.ac.jp Back

3 The abbreviations used are: APC, adenomatous polyposis coli; LOH, loss of heterozygosity; DCC, deleted in colon cancer; TGF, transforming growth factor; FAP, familial adenomatous polyposis. Back

4 Although official gene symbols assigned by the Committees for Smad2 and Smad4 proteins in the human/mouse are MADH2/Madh2 and MADH4/Madh4, respectively, SMAD2/Smad2 and SMAD4/Smad4 are used here because they are widely used, with the official symbols in parentheses whenever appropriate. In contrast, their protein products are shown in roman. Back

Received 6/27/02. Accepted 7/12/02.


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 Introduction
 Materials and Methods
 Results
 Discussion
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