Abstract
To understand the pathogenesis that may be induced by human adenovirus type 12 (Ad12), we have generated transgenic mice carrying the Ad12 early region 1 under control of the mouse mammary tumor virus long terminal repeat. Eleven of 11 male founder mice, but only 2 of 12 females, died between 3 to 4 mo of age. Death was associated with presence of tumors at or near the squamocolumnar junction of the stomach. Microscopically, these multifocal tumors appeared to arise from hyperplastic epithelium and showed features consistent with adenocarcinoma or adenosquamous carcinoma. High levels of expression of both the Ad12 E1A and E1B genes were seen in the tumor-bearing stomach. Various levels of expression were also detected in other tissues, although the stomach was the only organ with detectable pathology. These observations suggest an organ-specific action of the Ad12 early region 1 gene products. This transgenic mouse model provides an experimental system for studying the development of human carcinomas at sites of transition from squamous to columnar epithelium.
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Selected References
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- Bernards R., Houweling A., Schrier P. I., Bos J. L., Van der Eb A. J. Characterization of cells transformed by Ad5/Ad12 hybrid early region I plasmids. Virology. 1982 Jul 30;120(2):422–432. doi: 10.1016/0042-6822(82)90042-3. [DOI] [PubMed] [Google Scholar]
- Bernards R., Schrier P. I., Houweling A., Bos J. L., van der Eb A. J., Zijlstra M., Melief C. J. Tumorigenicity of cells transformed by adenovirus type 12 by evasion of T-cell immunity. 1983 Oct 27-Nov 2Nature. 305(5937):776–779. doi: 10.1038/305776a0. [DOI] [PubMed] [Google Scholar]
- Bos J. L., ten Wolde-Kraamwinkel H. C. The E1b promoter of Ad12 in mouse L tk- cells is activated by adenovirus region E1a. EMBO J. 1983;2(1):73–76. doi: 10.1002/j.1460-2075.1983.tb01383.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Byrd P., Brown K. W., Gallimore P. H. Malignant transformation of human embryo retinoblasts by cloned adenovirus 12 DNA. Nature. 1982 Jul 1;298(5869):69–71. doi: 10.1038/298069a0. [DOI] [PubMed] [Google Scholar]
- Choi Y. W., Henrard D., Lee I., Ross S. R. The mouse mammary tumor virus long terminal repeat directs expression in epithelial and lymphoid cells of different tissues in transgenic mice. J Virol. 1987 Oct;61(10):3013–3019. doi: 10.1128/jvi.61.10.3013-3019.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gallimore P. H., McDougall J. K., Chen L. B. In vitro traits of adenovirus-transformed cell lines and their relevance to tumorigenicity in nude mice. Cell. 1977 Apr;10(4):669–678. doi: 10.1016/0092-8674(77)90100-3. [DOI] [PubMed] [Google Scholar]
- Gallimore P. H. Viral DNA in transformed cells. II. A study of the sequences of adenovirus 2 DNA IN NINE LINES OF TRANSFORMED RAT CELLS USING SPECIFIC FRAGMENTS OF THE VIRAL GENOME;. J Mol Biol. 1974 Oct 15;89(1):49–72. doi: 10.1016/0022-2836(74)90162-4. [DOI] [PubMed] [Google Scholar]
- HUEBNER R. J., ROWE W. P., LANE W. T. Oncogenic effects in hamsters of human adenovirus types 12 and 18. Proc Natl Acad Sci U S A. 1962 Dec 15;48:2051–2058. doi: 10.1073/pnas.48.12.2051. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Harwood L. M., Gallimore P. H. A study of the oncogenicity of adenovirus type 2 transformed rat embryo cells. Int J Cancer. 1975 Sep 15;16(3):498–508. doi: 10.1002/ijc.2910160317. [DOI] [PubMed] [Google Scholar]
- Houweling A., van den Elsen P. J., van der Eb A. J. Partial transformation of primary rat cells by the leftmost 4.5% fragment of adenovirus 5 DNA. Virology. 1980 Sep;105(2):537–550. doi: 10.1016/0042-6822(80)90054-9. [DOI] [PubMed] [Google Scholar]
- Kelly F., Boccara M. Susceptibility of teratocarcinoma cells to adenovirus type 2. Nature. 1976 Jul 29;262(5567):409–411. doi: 10.1038/262409a0. [DOI] [PubMed] [Google Scholar]
- Kress M., Liu W. Y., Jay E., Khoury G., Jay G. Comparison of class I (H-2) gene sequences. Derivation of unique probes for members of this multigene family. J Biol Chem. 1983 Nov 25;258(22):13929–13936. [PubMed] [Google Scholar]
- Lee F., Mulligan R., Berg P., Ringold G. Glucocorticoids regulate expression of dihydrofolate reductase cDNA in mouse mammary tumour virus chimaeric plasmids. Nature. 1981 Nov 19;294(5838):228–232. doi: 10.1038/294228a0. [DOI] [PubMed] [Google Scholar]
- Nerenberg M., Hinrichs S. H., Reynolds R. K., Khoury G., Jay G. The tat gene of human T-lymphotropic virus type 1 induces mesenchymal tumors in transgenic mice. Science. 1987 Sep 11;237(4820):1324–1329. doi: 10.1126/science.2888190. [DOI] [PubMed] [Google Scholar]
- Nevins J. R. Mechanism of activation of early viral transcription by the adenovirus E1A gene product. Cell. 1981 Oct;26(2 Pt 2):213–220. doi: 10.1016/0092-8674(81)90304-4. [DOI] [PubMed] [Google Scholar]
- POPE J. H., ROWE W. P. IMMUNOFLUORESCENT STUDIES OF ADENOVIRUS 12 TUMORS AND OF CELLS TRANSFORMED OR INFECTED BY ADENOVIRUSES. J Exp Med. 1964 Oct 1;120:577–588. doi: 10.1084/jem.120.4.577. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sinn E., Muller W., Pattengale P., Tepler I., Wallace R., Leder P. Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: synergistic action of oncogenes in vivo. Cell. 1987 May 22;49(4):465–475. doi: 10.1016/0092-8674(87)90449-1. [DOI] [PubMed] [Google Scholar]
- Spechler S. J., Goyal R. K. Barrett's esophagus. N Engl J Med. 1986 Aug 7;315(6):362–371. doi: 10.1056/NEJM198608073150605. [DOI] [PubMed] [Google Scholar]
- Starzinski-Powitz A., Schulz M., Esche H., Mukai N., Doerfler W. The adenovirus type 12 - mouse cell system: permissivity and analysis of integration patterns of viral DNA in tumor cells. EMBO J. 1982;1(4):493–497. doi: 10.1002/j.1460-2075.1982.tb01196.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stewart T. A., Hollingshead P. G., Pitts S. L. Multiple regulatory domains in the mouse mammary tumor virus long terminal repeat revealed by analysis of fusion genes in transgenic mice. Mol Cell Biol. 1988 Jan;8(1):473–479. doi: 10.1128/mcb.8.1.473. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stewart T. A., Pattengale P. K., Leder P. Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes. Cell. 1984 Oct;38(3):627–637. doi: 10.1016/0092-8674(84)90257-5. [DOI] [PubMed] [Google Scholar]
- TRENTIN J. J., YABE Y., TAYLOR G. The quest for human cancer viruses. Science. 1962 Sep 14;137(3533):835–841. doi: 10.1126/science.137.3533.835. [DOI] [PubMed] [Google Scholar]
- Tanaka K., Isselbacher K. J., Khoury G., Jay G. Reversal of oncogenesis by the expression of a major histocompatibility complex class I gene. Science. 1985 Apr 5;228(4695):26–30. doi: 10.1126/science.3975631. [DOI] [PubMed] [Google Scholar]
- Tanaka K., Yoshioka T., Bieberich C., Jay G. Role of the major histocompatibility complex class I antigens in tumor growth and metastasis. Annu Rev Immunol. 1988;6:359–380. doi: 10.1146/annurev.iy.06.040188.002043. [DOI] [PubMed] [Google Scholar]
- Van den Elsen P., Houweling A., Van der Eb A. Expression of region E1b of human adenoviruses in the absence of region E1a is not sufficient for complete transformation. Virology. 1983 Jul 30;128(2):377–390. doi: 10.1016/0042-6822(83)90264-7. [DOI] [PubMed] [Google Scholar]
- Weinberg R. A. The action of oncogenes in the cytoplasm and nucleus. Science. 1985 Nov 15;230(4727):770–776. doi: 10.1126/science.2997917. [DOI] [PubMed] [Google Scholar]
- Whyte P., Buchkovich K. J., Horowitz J. M., Friend S. H., Raybuck M., Weinberg R. A., Harlow E. Association between an oncogene and an anti-oncogene: the adenovirus E1A proteins bind to the retinoblastoma gene product. Nature. 1988 Jul 14;334(6178):124–129. doi: 10.1038/334124a0. [DOI] [PubMed] [Google Scholar]
- Woodworth C. D., Isom H. C. Transformation of differentiated rat hepatocytes with adenovirus and adenovirus DNA. J Virol. 1987 Nov;61(11):3570–3579. doi: 10.1128/jvi.61.11.3570-3579.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wu L., Rosser D. S., Schmidt M. C., Berk A. A TATA box implicated in E1A transcriptional activation of a simple adenovirus 2 promoter. Nature. 1987 Apr 2;326(6112):512–515. doi: 10.1038/326512a0. [DOI] [PubMed] [Google Scholar]