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. 1993 Jul 15;90(14):6523–6527. doi: 10.1073/pnas.90.14.6523

Metastatic conversion of cells by expression of human papillomavirus type 16 E6 and E7 genes.

L Chen 1, S Ashe 1, M C Singhal 1, D A Galloway 1, I Hellström 1, K E Hellström 1
PMCID: PMC46964  PMID: 8341664

Abstract

The human papillomavirus type 16 (HPV-16) is a DNA tumor virus highly associated with cervical carcinoma. Viral DNA from HPV-16 is found in primary tumors and their metastatic lesions. To investigate the role of HPV-16 oncoproteins in the development of cancer metastasis, the E6 and E7 genes from HPV-16 were inserted into retrovirus and introduced into nonmetastatic mouse cell lines. Expression of either of the viral genes from HPV-16 made the cells metastatic in nude mice. In contrast, expression of the E6 and E7 genes of HPV type 6 (HPV-6b), which is frequently found in nonmalignant HPV-associated diseases, did not. The metastatic ability of cells transduced with viral genes of HPV-16 did not correlate with their growth rate or sensitivity to destruction by natural killer cells. Our results demonstrate that expression of oncogenic proteins of HPV-16 can cause tumor metastasis and implicate HPV-16 in an important role regarding the progression of HPV-associated human cancers.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aoyama A., Klemenz R. Oncogene-mediated effects on cellular gene expression. Crit Rev Oncog. 1993;4(1):53–94. [PubMed] [Google Scholar]
  2. Chambers A. F., Tuck A. B. Ras-responsive genes and tumor metastasis. Crit Rev Oncog. 1993;4(2):95–114. [PubMed] [Google Scholar]
  3. Chen L. P., Thomas E. K., Hu S. L., Hellström I., Hellström K. E. Human papillomavirus type 16 nucleoprotein E7 is a tumor rejection antigen. Proc Natl Acad Sci U S A. 1991 Jan 1;88(1):110–114. doi: 10.1073/pnas.88.1.110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chen L., Ashe S., Brady W. A., Hellström I., Hellström K. E., Ledbetter J. A., McGowan P., Linsley P. S. Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell. 1992 Dec 24;71(7):1093–1102. doi: 10.1016/s0092-8674(05)80059-5. [DOI] [PubMed] [Google Scholar]
  5. Chen L., Mizuno M. T., Singhal M. C., Hu S. L., Galloway D. A., Hellström I., Hellström K. E. Induction of cytotoxic T lymphocytes specific for a syngeneic tumor expressing the E6 oncoprotein of human papillomavirus type 16. J Immunol. 1992 Apr 15;148(8):2617–2621. [PubMed] [Google Scholar]
  6. Claas E. C., Melchers W. J., van der Linden H. C., Lindeman J., Quint W. G. Human papillomavirus detection in paraffin-embedded cervical carcinomas and metastases of the carcinomas by the polymerase chain reaction. Am J Pathol. 1989 Oct;135(4):703–709. [PMC free article] [PubMed] [Google Scholar]
  7. Crook T., Morgenstern J. P., Crawford L., Banks L. Continued expression of HPV-16 E7 protein is required for maintenance of the transformed phenotype of cells co-transformed by HPV-16 plus EJ-ras. EMBO J. 1989 Feb;8(2):513–519. doi: 10.1002/j.1460-2075.1989.tb03405.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Crook T., Storey A., Almond N., Osborn K., Crawford L. Human papillomavirus type 16 cooperates with activated ras and fos oncogenes in the hormone-dependent transformation of primary mouse cells. Proc Natl Acad Sci U S A. 1988 Dec;85(23):8820–8824. doi: 10.1073/pnas.85.23.8820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Desaintes C., Hallez S., Van Alphen P., Burny A. Transcriptional activation of several heterologous promoters by the E6 protein of human papillomavirus type 16. J Virol. 1992 Jan;66(1):325–333. doi: 10.1128/jvi.66.1.325-333.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. DiPaolo J. A., Woodworth C. D., Popescu N. C., Notario V., Doniger J. Induction of human cervical squamous cell carcinoma by sequential transfection with human papillomavirus 16 DNA and viral Harvey ras. Oncogene. 1989 Apr;4(4):395–399. [PubMed] [Google Scholar]
  11. Fuchs P. G., Girardi F., Pfister H. Human papillomavirus 16 DNA in cervical cancers and in lymph nodes of cervical cancer patients: a diagnostic marker for early metastases? Int J Cancer. 1989 Jan 15;43(1):41–44. doi: 10.1002/ijc.2910430110. [DOI] [PubMed] [Google Scholar]
  12. Galehouse D., Jenison E., DeLucia A. Differences in the integration pattern and episomal forms of human papillomavirus type 16 DNA found within an invasive cervical neoplasm and its metastasis. Virology. 1992 Jan;186(1):339–341. doi: 10.1016/0042-6822(92)90093-5. [DOI] [PubMed] [Google Scholar]
  13. Galloway D. A., McDougall J. K. Human papillomaviruses and carcinomas. Adv Virus Res. 1989;37:125–171. doi: 10.1016/s0065-3527(08)60834-9. [DOI] [PubMed] [Google Scholar]
  14. Girardi F., Fuchs P., Haas J. Prognostic importance of human papillomavirus type 16 DNA in cervical cancer. Cancer. 1992 May 15;69(10):2502–2504. doi: 10.1002/1097-0142(19920515)69:10<2502::aid-cncr2820691019>3.0.co;2-7. [DOI] [PubMed] [Google Scholar]
  15. Gissmann L., Jochmus-Kudielka I. Immune response to papillomavirus infections. Curr Probl Dermatol. 1989;18:162–167. doi: 10.1159/000416852. [DOI] [PubMed] [Google Scholar]
  16. Grisoni M., Meneguzzi G., de Lapeyrière O., Binétruy B., Rassoulzadegan M., Cuzin F. The transformed phenotype in culture and tumorigenicity of Fischer rat fibroblast cells (FR3T3) transformed with bovine papilloma virus type 1. Virology. 1984 Jun;135(2):406–416. doi: 10.1016/0042-6822(84)90196-x. [DOI] [PubMed] [Google Scholar]
  17. Halbert C. L., Demers G. W., Galloway D. A. The E6 and E7 genes of human papillomavirus type 6 have weak immortalizing activity in human epithelial cells. J Virol. 1992 Apr;66(4):2125–2134. doi: 10.1128/jvi.66.4.2125-2134.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Halbert C. L., Demers G. W., Galloway D. A. The E7 gene of human papillomavirus type 16 is sufficient for immortalization of human epithelial cells. J Virol. 1991 Jan;65(1):473–478. doi: 10.1128/jvi.65.1.473-478.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Howley P. M. Role of the human papillomaviruses in human cancer. Cancer Res. 1991 Sep 15;51(18 Suppl):5019s–5022s. [PubMed] [Google Scholar]
  20. Ikenberg H., Teufel G., Schmitt B., Kommoss F., Stanimirovic B., Pfleiderer A. Human papillomavirus DNA in distant metastases of cervical cancer. Gynecol Oncol. 1993 Jan;48(1):56–60. doi: 10.1006/gyno.1993.1009. [DOI] [PubMed] [Google Scholar]
  21. King L. A., Tase T., Twiggs L. B., Okagaki T., Savage J. E., Adcock L. L., Prem K. A., Carson L. F. Prognostic significance of the presence of human papillomavirus DNA in patients with invasive carcinoma of the cervix. Cancer. 1989 Mar 1;63(5):897–900. doi: 10.1002/1097-0142(19890301)63:5<897::aid-cncr2820630517>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
  22. Lancaster W. D., Castellano C., Santos C., Delgado G., Kurman R. J., Jenson A. B. Human papillomavirus deoxyribonucleic acid in cervical carcinoma from primary and metastatic sites. Am J Obstet Gynecol. 1986 Jan;154(1):115–119. doi: 10.1016/0002-9378(86)90405-9. [DOI] [PubMed] [Google Scholar]
  23. Lewandowski G., Delgado G., Holloway R. W., Farrell M., Jenson A. B., Lancaster W. D. The use of in situ hybridization to show human papillomavirus deoxyribonucleic acid in metastatic cancer cells within lymph nodes. Am J Obstet Gynecol. 1990 Oct;163(4 Pt 1):1333–1337. doi: 10.1016/0002-9378(90)90715-j. [DOI] [PubMed] [Google Scholar]
  24. Liotta L. A., Steeg P. S., Stetler-Stevenson W. G. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell. 1991 Jan 25;64(2):327–336. doi: 10.1016/0092-8674(91)90642-c. [DOI] [PubMed] [Google Scholar]
  25. Macri C. I., Cook N. S., Walker J. L., Berman M. L., Patton T. J., Jr, Wilczynski S. P. Analysis of fine-needle aspirates for HPV by PCR may be useful in diagnosis of metastatic gynecologic malignancies. Gynecol Oncol. 1992 Sep;46(3):372–376. doi: 10.1016/0090-8258(92)90235-b. [DOI] [PubMed] [Google Scholar]
  26. Marcante M. L., Venuti A. Human papillomavirus DNA as a possible index of invasiveness in female genital tract carcinomas. Eur J Cancer. 1991;27(2):187–190. doi: 10.1016/0277-5379(91)90484-u. [DOI] [PubMed] [Google Scholar]
  27. Phelps W. C., Yee C. L., Münger K., Howley P. M. The human papillomavirus type 16 E7 gene encodes transactivation and transformation functions similar to those of adenovirus E1A. Cell. 1988 May 20;53(4):539–547. doi: 10.1016/0092-8674(88)90570-3. [DOI] [PubMed] [Google Scholar]
  28. Riou G., Favre M., Jeannel D., Bourhis J., Le Doussal V., Orth G. Association between poor prognosis in early-stage invasive cervical carcinomas and non-detection of HPV DNA. Lancet. 1990 May 19;335(8699):1171–1174. doi: 10.1016/0140-6736(90)92693-c. [DOI] [PubMed] [Google Scholar]
  29. Rose B. R., Thompson C. H., Chantrill L. A., Tattersall M. H., Cossart Y. E. Prevalence and distribution of human papillomavirus type-16 DNA in pelvic lymph nodes of patients with cervical cancer and in women with no history of cervical abnormality. Int J Cancer. 1992 Sep 9;52(2):225–228. doi: 10.1002/ijc.2910520212. [DOI] [PubMed] [Google Scholar]
  30. Rubin A. L., Yao A., Rubin H. Relation of spontaneous transformation in cell culture to adaptive growth and clonal heterogeneity. Proc Natl Acad Sci U S A. 1990 Jan;87(1):482–486. doi: 10.1073/pnas.87.1.482. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. SANFORD K. K., MERWIN R. M., HOBBS G. L., YOUNG J. M. Clonal analysis of variant cell lines transformed to malignant cells in tissue culture. J Natl Cancer Inst. 1959 Nov;23:1035–1059. [PubMed] [Google Scholar]
  32. Sillman F. H., Sedlis A. Anogenital papillomavirus infection and neoplasia in immunodeficient women: an update. Dermatol Clin. 1991 Apr;9(2):353–369. [PubMed] [Google Scholar]
  33. Smotkin D., Prokoph H., Wettstein F. O. Oncogenic and nononcogenic human genital papillomaviruses generate the E7 mRNA by different mechanisms. J Virol. 1989 Mar;63(3):1441–1447. doi: 10.1128/jvi.63.3.1441-1447.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Walboomers J. M., Fokke H. E., Polak M., Volkers H., Houthoff H. J., Barents J., van der Noordaa J., ter Schegget J. In situ localization of human papilloma virus type 16 DNA in a metastasis of an endocervical adenocarcinoma. Intervirology. 1987;27(2):81–85. doi: 10.1159/000149723. [DOI] [PubMed] [Google Scholar]
  35. Yasumoto S., Burkhardt A. L., Doniger J., DiPaolo J. A. Human papillomavirus type 16 DNA-induced malignant transformation of NIH 3T3 cells. J Virol. 1986 Feb;57(2):572–577. doi: 10.1128/jvi.57.2.572-577.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Yasumoto S., Doniger J., DiPaolo J. A. Differential early viral gene expression in two stages of human papillomavirus type 16 DNA-induced malignant transformation. Mol Cell Biol. 1987 Jun;7(6):2165–2172. doi: 10.1128/mcb.7.6.2165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. zur Hausen H. Papillomaviruses in anogenital cancer as a model to understand the role of viruses in human cancers. Cancer Res. 1989 Sep 1;49(17):4677–4681. [PubMed] [Google Scholar]
  38. zur Hausen H. Viruses in human cancers. Science. 1991 Nov 22;254(5035):1167–1173. doi: 10.1126/science.1659743. [DOI] [PubMed] [Google Scholar]

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