Abstract
We have previously demonstrated that second-passage rat embryo cells transformed by the ras oncogene alone are both tumorigenic and highly metastatic when injected into nude mice. In contrast, rat embryo cells cotransformed with the ras oncogene and the adenovirus type 2 (Ad2) E1a gene are tumorigenic but either fail to metastasize or exhibit a very low metastatic potential. In this report, we demonstrate that transfection of the Ad2 E1a gene into four independent ras-transformed rat embryo cell lines results in a dramatic reduction in metastatic potential relative to that of the parental cell line. Transfection of cDNAs for the 12S and 13S E1a transcripts showed that the 12S cDNA was highly effective in reducing the metastatic potential of ras-transformed cell lines, while the 13S cDNA showed an effect in only one of the two cell lines tested. This effect is specific to the Ad2 E1a gene, since ras-transformed cell lines expressing the Ad12 E1a gene maintained their high metastatic potential. We hypothesize that the Ad2 E1a gene may regulate the expression of one or more cellular genes that contribute to the metastatic phenotype.
Full text
PDF




Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- 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]
- Bernards R., Van der Eb A. J. Adenovirus: transformation and oncogenicity. Biochim Biophys Acta. 1984 Dec 14;783(3):187–204. doi: 10.1016/0167-4781(84)90029-0. [DOI] [PubMed] [Google Scholar]
- Cook J. L., Lewis A. M., Jr Differential NK cell and macrophage killing of hamster cells infected with nononcogenic or oncogenic adenovirus. Science. 1984 May 11;224(4649):612–615. doi: 10.1126/science.6710160. [DOI] [PubMed] [Google Scholar]
- Cook J. L., Walker T. A., Lewis A. M., Jr, Ruley H. E., Graham F. L., Pilder S. H. Expression of the adenovirus E1A oncogene during cell transformation is sufficient to induce susceptibility to lysis by host inflammatory cells. Proc Natl Acad Sci U S A. 1986 Sep;83(18):6965–6969. doi: 10.1073/pnas.83.18.6965. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fidler I. J., Kripke M. L. Metastasis results from preexisting variant cells within a malignant tumor. Science. 1977 Aug 26;197(4306):893–895. doi: 10.1126/science.887927. [DOI] [PubMed] [Google Scholar]
- Garbisa S., Pozzatti R., Muschel R. J., Saffiotti U., Ballin M., Goldfarb R. H., Khoury G., Liotta L. A. Secretion of type IV collagenolytic protease and metastatic phenotype: induction by transfection with c-Ha-ras but not c-Ha-ras plus Ad2-E1a. Cancer Res. 1987 Mar 15;47(6):1523–1528. [PubMed] [Google Scholar]
- Gilardi P., Perricaudet M. The E4 transcriptional unit of Ad2: far upstream sequences are required for its transactivation by E1A. Nucleic Acids Res. 1984 Oct 25;12(20):7877–7888. doi: 10.1093/nar/12.20.7877. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gorman C., Padmanabhan R., Howard B. H. High efficiency DNA-mediated transformation of primate cells. Science. 1983 Aug 5;221(4610):551–553. doi: 10.1126/science.6306768. [DOI] [PubMed] [Google Scholar]
- Graham F. L., van der Eb A. J. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. doi: 10.1016/0042-6822(73)90341-3. [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]
- Hurwitz D. R., Chinnadurai G. Evidence that a second tumor antigen coded by adenovirus early gene region E1a is required for efficient cell transformation. Proc Natl Acad Sci U S A. 1985 Jan;82(1):163–167. doi: 10.1073/pnas.82.1.163. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Imperiale M. J., Feldman L. T., Nevins J. R. Activation of gene expression by adenovirus and herpesvirus regulatory genes acting in trans and by a cis-acting adenovirus enhancer element. Cell. 1983 Nov;35(1):127–136. doi: 10.1016/0092-8674(83)90215-5. [DOI] [PubMed] [Google Scholar]
- Jochemsen A. G., Bernards R., van Kranen H. J., Houweling A., Bos J. L., van der Eb A. J. Different activities of the adenovirus types 5 and 12 E1A regions in transformation with the EJ Ha-ras oncogene. J Virol. 1986 Sep;59(3):684–691. doi: 10.1128/jvi.59.3.684-691.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Land H., Chen A. C., Morgenstern J. P., Parada L. F., Weinberg R. A. Behavior of myc and ras oncogenes in transformation of rat embryo fibroblasts. Mol Cell Biol. 1986 Jun;6(6):1917–1925. doi: 10.1128/mcb.6.6.1917. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Land H., Parada L. F., Weinberg R. A. Cellular oncogenes and multistep carcinogenesis. Science. 1983 Nov 18;222(4625):771–778. doi: 10.1126/science.6356358. [DOI] [PubMed] [Google Scholar]
- Land H., Parada L. F., Weinberg R. A. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature. 1983 Aug 18;304(5927):596–602. doi: 10.1038/304596a0. [DOI] [PubMed] [Google Scholar]
- Liotta L. A., Abe S., Robey P. G., Martin G. R. Preferential digestion of basement membrane collagen by an enzyme derived from a metastatic murine tumor. Proc Natl Acad Sci U S A. 1979 May;76(5):2268–2272. doi: 10.1073/pnas.76.5.2268. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liotta L. A., Tryggvason K., Garbisa S., Hart I., Foltz C. M., Shafie S. Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature. 1980 Mar 6;284(5751):67–68. doi: 10.1038/284067a0. [DOI] [PubMed] [Google Scholar]
- Montell C., Courtois G., Eng C., Berk A. Complete transformation by adenovirus 2 requires both E1A proteins. Cell. 1984 Apr;36(4):951–961. doi: 10.1016/0092-8674(84)90045-x. [DOI] [PubMed] [Google Scholar]
- Moran E., Grodzicker T., Roberts R. J., Mathews M. B., Zerler B. Lytic and transforming functions of individual products of the adenovirus E1A gene. J Virol. 1986 Mar;57(3):765–775. doi: 10.1128/jvi.57.3.765-775.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nicolson G. L., Poste G. Tumor implantation and invasion at metastatic sites. Int Rev Exp Pathol. 1983;25:77–181. [PubMed] [Google Scholar]
- Nowell P. C. The clonal evolution of tumor cell populations. Science. 1976 Oct 1;194(4260):23–28. doi: 10.1126/science.959840. [DOI] [PubMed] [Google Scholar]
- Poste G., Doll J., Fidler I. J. Interactions among clonal subpopulations affect stability of the metastatic phenotype in polyclonal populations of B16 melanoma cells. Proc Natl Acad Sci U S A. 1981 Oct;78(10):6226–6230. doi: 10.1073/pnas.78.10.6226. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Poste G., Tzeng J., Doll J., Greig R., Rieman D., Zeidman I. Evolution of tumor cell heterogeneity during progressive growth of individual lung metastases. Proc Natl Acad Sci U S A. 1982 Nov;79(21):6574–6578. doi: 10.1073/pnas.79.21.6574. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pozzatti R., Muschel R., Williams J., Padmanabhan R., Howard B., Liotta L., Khoury G. Primary rat embryo cells transformed by one or two oncogenes show different metastatic potentials. Science. 1986 Apr 11;232(4747):223–227. doi: 10.1126/science.3456644. [DOI] [PubMed] [Google Scholar]
- Rassoulzadegan M., Cowie A., Carr A., Glaichenhaus N., Kamen R., Cuzin F. The roles of individual polyoma virus early proteins in oncogenic transformation. Nature. 1982 Dec 23;300(5894):713–718. doi: 10.1038/300713a0. [DOI] [PubMed] [Google Scholar]
- Rassoulzadegan M., Naghashfar Z., Cowie A., Carr A., Grisoni M., Kamen R., Cuzin F. Expression of the large T protein of polyoma virus promotes the establishment in culture of "normal" rodent fibroblast cell lines. Proc Natl Acad Sci U S A. 1983 Jul;80(14):4354–4358. doi: 10.1073/pnas.80.14.4354. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rowe D. T., Branton P. E., Yee S. P., Bacchetti S., Graham F. L. Establishment and characterization of hamster cell lines transformed by restriction endonuclease fragments of adenovirus 5. J Virol. 1984 Jan;49(1):162–170. doi: 10.1128/jvi.49.1.162-170.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sawada Y., Föhring B., Shenk T. E., Raska K., Jr Tumorigenicity of adenovirus-transformed cells: region E1A of adenovirus 12 confers resistance to natural killer cells. Virology. 1985 Dec;147(2):413–421. doi: 10.1016/0042-6822(85)90143-6. [DOI] [PubMed] [Google Scholar]
- Schrier P. I., Bernards R., Vaessen R. T., Houweling A., van der Eb A. J. Expression of class I major histocompatibility antigens switched off by highly oncogenic adenovirus 12 in transformed rat cells. 1983 Oct 27-Nov 2Nature. 305(5937):771–775. doi: 10.1038/305771a0. [DOI] [PubMed] [Google Scholar]
- Schwab M., Varmus H. E., Bishop J. M. Human N-myc gene contributes to neoplastic transformation of mammalian cells in culture. Nature. 1985 Jul 11;316(6024):160–162. doi: 10.1038/316160a0. [DOI] [PubMed] [Google Scholar]
- Spandidos D. A., Wilkie N. M. Malignant transformation of early passage rodent cells by a single mutated human oncogene. Nature. 1984 Aug 9;310(5977):469–475. doi: 10.1038/310469a0. [DOI] [PubMed] [Google Scholar]
- Svensson C., Akusjärvi G. Adenovirus 2 early region 1A stimulates expression of both viral and cellular genes. EMBO J. 1984 Apr;3(4):789–794. doi: 10.1002/j.1460-2075.1984.tb01886.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thorgeirsson U. P., Turpeenniemi-Hujanen T., Liotta L. A. Cancer cells, components of basement membranes, and proteolytic enzymes. Int Rev Exp Pathol. 1985;27:203–234. [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]

