Abstract
Metastasis is the major cause of death for cancer patients. The presence of metastatic tumors often indicates the late stage of the disease progression in which the tumor cells have undergone multiple genetic changes that may have contributed to resistance to radiation and chemotherapy treatment. To treat the elusive metastatic tumors, an efficient systemic delivery system that carries the therapeutic payload to multiple tumor targets in a patient would be needed. The therapeutic agent has to be powerful enough to inhibit the tumor growth or to eliminate it. In this chapter, we focus the discussion on our experience using adenovirus E1A (Ad.E1A) as a therapeutic gene in cancer gene therapy treatment for metastatic tumors. Finally, we describe our findings that show the antitumor and antimetastasis activities of a novel therapeutic gene, p202, and its potential use against metastatic tumors.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Ben-Israel, H. and Kleinberger, T. (2002) Adenovirus and cell cycle control. Front. Biosci. 7, d1369–1395.
Frisch, S. M. and Mymryk, J. S. (2002) Adenovirus-5 E1A: paradox and paradigm. Nat. Rev. Mol. Cell Biol. 3, 441–452.
Frisch, S. M. (1996) Reversal of malignancy by the adenovirus E1a gene. Mutat. Res. 350, 261–266.
Houweling, A., van den Elsen, P. J., and van der Eb, A. J. (1980) Partial transformation of primary rat cells by the leftmost 4.5% fragment of adenovirus 5 DNA. Virology 105, 537–550.
Howe, J. A., Mymryk, J. S., Egan, C., Branton, P. E., and Bayley, S. T. (1990) Retinoblastoma growth suppressor and a 300-kDa protein appear to regulate cellular DNA synthesis. Proc. Natl. Acad. Sci. USA 87, 5883–5887.
Ruley, H. E. (1983) Adenovirus early region 1A enables viral and cellular transforming genes to transform primary cells in culture. Nature 304, 602–606.
Pozzatti, R., McCormick, M., Thompson, M. A., and Khoury, G. (1988) The E1a gene of adenovirus type 2 reduces the metastatic potential of ras-transformed rat embryo cells. Mol. Cell. Biol. 8, 2984–2988.
Steeg, P. S., Bevilacqua, G., Pozzatti, R., Liotta, L. A., and Sobel, M. E. (1988) Altered expression of NM23, a gene associated with low tumor metastatic potential, during adenovirus 2 Ela inhibition of experimental metastasis. Cancer Res. 48, 6550–6554.
Pozzatti, R., McCormick, M., Thompson, M. A., Garbisa, S., Liotta, L., and Khoury, G. (1988) Regulation of the metastatic phenotype by the E1A gene of adenovirus-2. Adv. Exp. Med. Biol. 233, 293–301.
Yu, D., Hamada, J., Zhang, H., Nicolson, G. L., and Hung, M. C. (1992) Mechanisms of c-erbB2/neu oncogene-induced metastasis and repression of metastatic properties by adenovirus 5 E1A gene products. Oncogene 7, 2263–2270.
Frisch, S. M., Reich, R., Collier, I. E., Genrich, L. T., Martin, G., and Goldberg, G. I. (1990) Adenovirus E1A represses protease gene expression and inhibits metastasis of human tumor cells. Oncogene 5, 75–83.
Frisch, S. M. (1994) E1a induces the expression of epithelial characteristics. J. Cell Biol. 127, 1085–1096.
Hennig, G., Behrens, J., Truss, M., Frisch, S., Reichmann, E., and Birchmeier, W. (1995) Progression of carcinoma cells is associated with alterations in chromatin structure and factor binding at the E-cadherin promoter in vivo. Oncogene 11, 475–484.
Santoro, M., Battaglia, C., Zhang, L., et al. (1994) Cloning of the rat tissue inhibitor of metalloproteinases type 2 (TIMP-2) gene: analysis of its expression in normal and transformed thyroid cells. Exp. Cell Res. 213, 398–403.
Offringa, R., Smits, A. M., Houweling, A., Bos, J. L., and van der Eb, A. J. (1988) Similar effects of adenovirus E1A and glucocorticoid hormones on the expression of the metalloprotease stromelysin. Nucleic Acids Res. 16, 10,973–10,984.
Linder, S., Popowicz, P., Svensson, C., Marshall, H., Bondesson, M., and Akusjarvi, G. (1992) Enhanced invasive properties of rat embryo fibroblasts transformed by adenovirus E1A mutants with deletions in the carboxy-terminal exon. Oncogene 7, 439–443.
Garbisa, S., Pozzatti, R., Muschel, R. J., et al. (1987) 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. 47, 1523–1528.
Offringa, R., Gebel, S., van Dam, H., et al. (1990) A novel function of the transforming domain of E1a: repression of AP-1 activity. Cell 62, 527–538.
Bernhard, E. J., Muschel, R. J., and Hughes, E. N. (1990) Mr 92,000 gelatinase release correlates with the metastatic phenotype in transformed rat embryo cells. Cancer Res. 50, 3872–3877.
Bernhard, E. J., Hagner, B., Wong, C., Lubenski, I., and Muschel, R. J. (1995) The effect of E1A transfection on MMP-9 expression and metastatic potential. Int. J. Cancer 60, 718–724.
Hofmann, M., Rudy, W., Gunthert, U., et al. (1993) A link between ras and metastatic behavior of tumor cells: ras induces CD44 promoter activity and leads to low-level expression of metastasis-specific variants of CD44 in CREF cells. Cancer Res. 53, 1516–1521.
Yu, D., Shi, D., Scanlon, M., and Hung, M. C. (1993) Reexpression of neu-encoded oncoprotein counteracts the tumor-suppressing but not the metastasis-suppressing function of E1A. Cancer Res. 53, 5784–5790.
Yu, D. H., Scorsone, K., and Hung, M. C. (1991) Adenovirus type 5 E1A gene products act as transformation suppressors of the neu oncogene. Mol. Cell. Biol. 11, 1745–1750.
Chen, H., Yu, D., Chinnadurai, G., Karunagaran, D., and Hung, M. C. (1997) Mapping of adenovirus 5 E1A domains responsible for suppression of neu-mediated transformation via transcriptional repression of neu. Oncogene 14, 1965–1971.
Deng, J., Xia, W., and Hung, M. C. (1998) Adenovirus 5 E1A-mediated tumor suppression associated with E1A-mediated apoptosis in vivo. Oncogene 17, 2167–2175.
Frisch, S. M. (1991) Antioncogenic effect of adenovirus E1A in human tumor cells. Proc. Natl. Acad. Sci. USA 88, 9077–9081.
Yu, D., Wolf, J. K., Scanlon, M., Price, J. E., and Hung, M. C. (1993) Enhanced c-erbB-2/neu expression in human ovarian cancer cells correlates with more severe malignancy that can be suppressed by E1A. Cancer Res. 53, 891–898.
Frisch, S. M. and Dolter, K. E. (1995) Adenovirus E1a-mediated tumor suppression by a c-erbB-2/neu-independent mechanism. Cancer Res. 55, 5551–5555.
Dickopp, A., Esche, H., Swart, G., Seeber, S., Kirch, H. C., and Opalka, B. (2000) Transformation-defective adenovirus 5 E1A mutants exhibit antioncogenic properties in human BLM melanoma cells. Cancer Gene Ther. 7, 1043–1050.
Chinnadurai, G. (1992) Adenovirus E1a as a tumor-suppressor gene. Oncogene 7, 1255–1258.
Mymryk, J. S. (1996) Tumour suppressive properties of the adenovirus 5 E1A oncogene. Oncogene 13, 1581–1589.
Yu, D. and Hung, M. C. (1998) The erbB2 gene as a cancer therapeutic target and the tumor-and metastasis-suppressing function of E1A. Cancer Metastasis Rev. 17, 195–202.
Yan, D.-H., Shao, R., and Hung, M.-C. (2001) E1A cancer gene therapy. In Gene Therapy of Cancer, 2nd ed. (Lattime, E. C. and Gerson, S. L., eds.), Academic Press, San Diego, CA, 2001.
Ueno, N. T., Yu, D., and Hung, M. C. (2001) E1A: tumor suppressor or oncogene? Preclinical and clinical investigations of E1A gene therapy. Breast Cancer 8, 285–293.
Chang, J. Y., Xia, W., Shao, R., et al. (1997) The tumor suppression activity of E1A in HER-2/neu-overexpressing breast cancer. Oncogene 14, 561–568.
Zhang, Y., Yu, D., Xia, W., and Hung, M. C. (1995) HER-2/neu-targeting cancer therapy via adenovirus-mediated E1A delivery in an animal model. Oncogene 10, 1947–1954.
Yu, D., Matin, A., Xia, W., Sorgi, F., Huang, L., and Hung, M. C. (1995) Liposome-mediated in vivo E1A gene transfer suppressed dissemination of ovarian cancer cells that overexpress HER-2/neu. Oncogene 11, 1383–1388.
Chang, J. Y., Xia, W., Shao, R., and Hung, M. C. (1996) Inhibition of intratracheal lung cancer development by systemic delivery of E1A. Oncogene 13, 1405–1412.
Nevins, J. R., Imperiale, M. J., Feldman, L. T., and Kao, H. T. (1984) Role of the adenovirus transforming gene (E1A) in the general control of gene expression. Transplant. Proc. 16, 438–440.
Nevins, J. R. (1995) Adenovirus E1A: transcription regulation and alteration of cell growth control. Curr. Top. Microbiol. Immunol. 199, 25–32.
Slamon, D. J., Clark, G. M., Wong, S. G., Levin, W. J., Ullrich, A., and McGuire, W. L. (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 177–182.
Slamon, D. J. and Clark, G. M. (1988) Amplification of c-erbB-2 and aggressive human breast tumors? Science 240, 1795–1798.
McCann, A. H., Dervan, P. A., O’Regan, M., et al. (1991) Prognostic significance of c-erbB-2 and estrogen receptor status in human breast cancer. Cancer Res. 51, 3296–3303.
Gusterson, B. A., Gelber, R. D., Goldhirsch, A., et al. (1992) Prognostic importance of c-erbB-2 expression in breast cancer. International (Ludwig) Breast Cancer Study Group. J. Clin. Oncol. 10, 1049–1056.
Slamon, D. J., Godolphin, W., Jones, L. A., et al. (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244, 707–712.
Berchuck, A., Kamel, A., Whitaker, R., et al. (1990) Overexpression of Her-2/neu is associated with poor survival in advanced epithelial ovarian cancer. Cancer Res. 50, 4087–4091.
Zhang, X., Silva, E., Gershenson, D., and Hung, M. C. (1989) Amplification and rearrangement of c-erb B proto-oncogenes in cancer of human female genital tract. Oncogene 4, 985–989.
Schneider, P. M., Hung, M. C., Chiocca, S. M., et al. (1989) Differential expression of the c-erbB-2 gene in human small cell and non-small cell lung cancer. Cancer Res. 49, 4968–4971.
Weiner, D. B., Nordberg, J., Robinson, R., et al. (1990) Expression of the neu gene-encoded protein (p185neu) in human non-small cell carcinomas of the lung. Cancer Res. 50, 421–425.
Yokota, J., Yamamoto, T., Miyajima, N., et al. (1988) Genetic alterations of the c-erbB-2 oncogene occur frequently in tubular adenocarcinoma of the stomach and are often accompanied by amplification of the v-erbA homologue. Oncogene 2, 283–287.
Zhau, H. E., Zhang, X., von, E. A., Scorsone, K., Babaian, R. J., Ro, J. Y., and Hung, M. C. (1990) Amplification and expression of the c-erb B-2/neu proto-oncogene in human bladder cancer. Mol. Carcinog. 3, 254–257.
Hou, L., Shi, D., Tu, S. M., Zhang, H. Z., Hung, M. C., and Ling, D. (1992) Oral cancer progression and c-erbB-2/neu proto-oncogene expression. Cancer Lett. 65, 215–220.
Xia, W. Y., Lau, Y. K., Zhang, H. Z., et al. (1997) Strong correlation between c-Erbb-2 overexpression and overall survival of patients with oral squamous cell carcinoma. Clin. Cancer Res. 3, 3–9.
Xia, W., Lau, Y. K., Zhang, H. Z., et al. (1999) Combination of EGFR, HER-2/neu, and HER-3 is a stronger predictor for the outcome of oral squamous cell carcinoma than any individual family members. Clin. Cancer Res. 5, 4164–4174.
Eccles, S. A. (2001) The role of c-erbB-2/HER2/neu in breast cancer progression and metastasis. J. Mammary Gland Biol. Neoplasia 6, 393–406.
Menard, S., Tagliabue, E., Campiglio, M., and Pupa, S. M. (2000) Role of HER2 gene overexpression in breast carcinoma. J. Cell. Physiol. 182, 150–162.
Revillion, F., Bonneterre, J., and Peyrat, J. P. (1998) ERBB2 oncogene in human breast cancer and its clinical significance. Eur. J. Cancer 34, 791–808.
Yu, D., Wang, S. S., Dulski, K. M., Tsai, C. M., Nicolson, G. L., and Hung, M. C. (1994) c-erbB-2/neu overexpression enhances metastatic potential of human lung cancer cells by induction of metastasis-associated properties. Cancer Res. 54, 3260–3266.
Tan, M., Yao, J., and Yu, D. (1997) Overexpression of the c-erbB-2 gene enhanced intrinsic metastasis potential in human breast cancer cells without increasing their transformation abilities. Cancer Res. 57, 1199–1205.
Hung, M.-C., Wang, S.-C., and Hortobagyi, G. (1999) Targeting HER-2/neu-overexpressing cancer cells with transcriptional repressor genes delivered by cationic liposome. In Nonviral Vectors for Gene Therapy (Hung, M.-C., Huang, L., and Wagner, E., eds.), Academic Press, New York, pp. 357–375.
Yu, D. and Hung, M.-C. (2000) Therapeutic resistance of erbB-2-overexpressing cancers and strategies to overcome this resistance. In DNA Alterations in Cancer (Ehrlich, M., ed.), Eaton, Natick, MA, pp. 457–470.
Slamon, D., Leyland-Jones, B., Shak, S., et al. (1998) Addition of Herceptinâ„¢ (humanized anti-HER2 antibody) to first line chemotherapy for HER2 overexpressing metastatic breast cancer (HER2+/MBC) markedly increase anticancer activity: a randomized, multinational controlled phase III trial. Proc. Annu. Meet. Am. Soc. Clin. Oncol., 376.
Yu, D., Suen, T. C., Yan, D. H., Chang, L. S., and Hung, M. C. (1990) Transcriptional repression of the neu protooncogene by the adenovirus 5 E1A gene products. Proc. Natl. Acad. Sci. USA 87, 4499–4503.
Yan, D. H., Chang, L. S., and Hung, M. C. (1991) Repressed expression of the HER-2/c-erbB-2 proto-oncogene by the adenovirus E1a gene products. Oncogene 6, 343–345.
Gao, X. and Huang, L. (1991) A novel cationic liposome reagent for efficient transfection of mammalian cells. Biochem. Biophys. Res. Commun. 179, 280–285.
Xing, X., Zhang, S., Chang, J. Y., et al. (1998) Safety study and characterization of E1A-liposome complex gene delivery in an ovarian cancer model. Gene Ther. 5, 1538–1544.
Xing, X., Liu, V., Xia, W., et al. (1997) Safety studies of the intraperitoneal injection of E1A—liposome complex in mice. Gene Ther. 4, 238–243.
Shao, R., Hu, M. C., Zhou, B. P., et al. (1999) E1A sensitizes cells to tumor necrosis factor-induced apoptosis through inhibition of IkappaB kinases and nuclear factor kappaB activities. J. Biol. Chem. 274, 21,495–21,498.
Hortobagyi, G. N., Ueno, N. T., Xia, W., et al. (2001) Cationic liposome-mediated E1A gene transfer to human breast and ovarian cancer cells and its biologic effects: a phase I clinical trial. J. Clin. Oncol. 19, 3422–3433.
Yoo, G. H., Hung, M. C., Lopez-Berestein, G., et al. (2001) Phase I trial of intratumoral liposome E1A gene therapy in patients with recurrent breast and head and neck cancer. Clin. Cancer Res. 7, 1237–1245.
Villaret, D., Glisson, B., Kenady, D., et al. (2002) A multicenter phase II study of tgDCC-E1A for the intratumoral treatment of patients with recurrent head and neck squamous cell carcinoma. Head Neck 24, 661–669.
Lengyel, P., Choubey, D., Li, S.-J., and Datta, B. (1995) The interferon-activatable gene 200 cluster: from structure toward function. Semin. Virol. 6, 203–213.
Landolfo, S., Gariglio, M., Gribaudo, G., and Lembo, D. (1998) The Ifi 200 genes: an emerging family of IFN-inducible genes. Biochimie 80, 721–728.
Rozzo, S. J., Allard, J. D., Choubey, D., et al. (2001) Evidence for an interferon-inducible gene, Ifi202, in the susceptibility to systemic lupus. Immunity 15, 435–443.
Choubey, D. and Lengyel, P. (1995) Binding of an interferon-inducible protein (p202) to the retinoblastoma protein. J. Biol. Chem. 270, 6134–6140.
Choubey, D., Li, S.-J., Datta, B., Gutterman, J. U., and Lengyel, P. (1996) Inhibition of E2F-mediated transcription by p202. EMBO J. 15, 5668–5678.
Choubey, D. and Gutterman, J. U. (1997) Inhibition of E2F-4/DP-1-stimulated transcription by p202. Oncogene 15, 291–301.
Datta, B., Li, B., Choubey, D., Nallur, G., and Lengyel, P. (1996) p202, an interferon-inducible modulator of transcription, inhibits transcriptional activation by the p53 tumor suppressor protein, and a segment from the p53-binding protein 1 that binds to p202 overcomes this inhibition. J. Biol. Chem. 271, 27,544–27,555.
Wang, H., Liu, C., Lu, Y., et al. (2000) The interferon-and differentiation-inducible p202a protein inhibits the transcriptional activity of c-Myc by blocking its association with Max. J. Biol. Chem. 275, 27,377–27,385.
Datta, B., Min, W., Burma, S., and Lengyel, P. (1998) Increase in p202 expression during skeletal muscle differentiation: inhibition of MyoD protein expression and activity by p202. Mol. Cell. Biol. 18, 1074–1083.
Min, W., Ghosh, S., and Lengyel, P. (1996) The interferon-inducible p202 protein as a modulator of transcription: inhibition of NFkB, c-Fos, and c-Jun activities. Mol. Cell. Biol. 16, 359–368.
Wen, Y., Yan, D.-H., Wang, B., et al. (2001) p202, an interferon-inducible protein, mediates multiple anti-tumor activities in human pancreatic cancer xenograft models. Cancer Res. 61, 7142–7147.
Wen, Y., Yan, D. H., Spohn, B., Deng, J., Lin, S. Y., and Hung, M. C. (2000) Tumor suppression and sensitization to tumor necrosis factor alpha-induced apoptosis by an interferon-inducible protein, p202, in breast cancer cells. Cancer Res. 60, 42–46.
Choubey, D. and Gutterman, J. U. (1996) The interferon-inducible growth-inhibitory p202 protein: DNA binding properties and identification of a DNA binding domain. Biochem. Biophys. Res. Commun. 221, 396–401.
Gutterman, J. U. and Choubey, D. (1999) Retardation of cell proliferation after expression of p202 accompanies an increase in p21(WAF1/CIP1). Cell Growth Differ. 10, 93–100.
Yan, D.-H., Wen, Y., Spohn, B., Choubey, D., Gutterman, J. U., and Hung, M.-C. (1999) Reduced growth rate and transformation phenotype of the prostate cancer cells by an interferon-inducible protein, p202. Oncogene 18, 807–811.
Ding, Y., Wen, Y., Spohn, B., et al. (2002) Pro-apoptotic and anti-tumor activities of adenovirus-mediated p202 gene transfer. Clin. Cancer Res. 8, 3290–3297.
Zou, Y., Peng, H., Zhou, B., et al. (2002) Systemic tumor suppression by the proapoptotic gene bik. Cancer Res. 62, 8–12.
Nishikawa, M. and Huang, L. (2001) Nonviral vectors in the new millennium: delivery barriers in gene transfer. Hum. Gene Ther. 12, 861–870.
Landis, S. H., Murray, T., Bolden, S., and Wingo, P. A. (1999) Cancer statistics, 1999. CA Cancer J. Clin. 49, 8–31.
Rosewicz, S. and Wiedenmann, B. (1997) Pancreatic carcinoma. Lancet 349, 485–489.
Staley, C. A., Lee, J. E., Cleary, K. R., et al. (1996) Preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for adenocarcinoma of the pancreatic head. Am. J. Surg. 171, 118–124; discussion, 124-115.
Hanahan, D. and Folkman, J. (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353–364.
DeLisser, H. M., Newman, P. J., and Albelda, S. M. (1993) Platelet endothelial cell adhesion molecule (CD31). Curr. Top. Microbiol. Immunol. 184, 37–45.
Reynolds, T. C., Alberts, D., Gershenson, D., et al. (2000) Activity of E1A in human clinical trials. In ASCO, abstract no. 1809.
Shao, R., Karunagaran, D., Zhou, B. P., et al. (1997) Inhibition of nuclear factor-kappaB activity is involved in E1A-mediated sensitization of radiation-induced apoptosis. J. Biol. Chem. 272, 32,739–32,742.
Baldwin, A. S. J. (1996) The NF-kB and IkB proteins: new discoveries and insights. Annu. Rev. Immunol. 14, 649–681.
Pahl, H. L. (1999) Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 18, 6853–6866.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2005 Humana Press Inc., Totowa, NJ
About this chapter
Cite this chapter
Yan, DH., Rau, KM., Hung, MC. (2005). Antimetastasis. In: Curiel, D.T., Douglas, J.T. (eds) Cancer Gene Therapy. Contemporary Cancer Research. Humana Press. https://doi.org/10.1007/978-1-59259-785-7_19
Download citation
DOI: https://doi.org/10.1007/978-1-59259-785-7_19
Publisher Name: Humana Press
Print ISBN: 978-1-58829-213-1
Online ISBN: 978-1-59259-785-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)