Abstract
Earlier studies have demonstrated an unexplained depletion of the epidermal growth factor receptor (EGFR) protein expression in prostatic cancer. We now attribute this phenomenon to the presence of a variant EGFR (EGFRvIII) that is highly expressed in malignant prostatic neoplasms. In a retrospective study, normal, benign hyperplastic and malignant prostatic tissues were examined at the mRNA and protein levels for the presence of this mutant receptor. The results demonstrated that whilst EGFRvIII was not present in normal prostatic glands, the level of expression of this variant protein increased progressively with the gradual transformation of the tissues to the malignant phenotype. The selective association of high EGFRvIII levels with the cancer phenotype underlines the role that this mutant receptor may maintain in the initiation and progression of malignant prostatic growth, and opens the way for new approaches in the management of this disease including gene therapy. © 2000 Cancer Research Campaign
Keywords: tumour marker, stromal–epithelial interaction, EGFR, prostate/prognostic factors, hormone resistance
Full Text
The Full Text of this article is available as a PDF (569.1 KB).
Footnotes
This project is dedicated to Professor BO Osuntokun (beate memoriae) and Mr PT Doyle (beate memoriae).
These results were presented in part at the Schilling Research Conference, Hormones and Cancer in Santa Cruz, CA, 18–21 September 1997, and the International Symposium of the British Prostate Group in York, UK, 2–4 October 1997.
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Bartlett J. M., Langdon S. P., Simpson B. J., Stewart M., Katsaros D., Sismondi P., Love S., Scott W. N., Williams A. R., Lessells A. M. The prognostic value of epidermal growth factor receptor mRNA expression in primary ovarian cancer. Br J Cancer. 1996 Feb;73(3):301–306. doi: 10.1038/bjc.1996.53. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bostwick D. G., Pacelli A., Blute M., Roche P., Murphy G. P. Prostate specific membrane antigen expression in prostatic intraepithelial neoplasia and adenocarcinoma: a study of 184 cases. Cancer. 1998 Jun 1;82(11):2256–2261. doi: 10.1002/(sici)1097-0142(19980601)82:11<2256::aid-cncr22>3.0.co;2-s. [DOI] [PubMed] [Google Scholar]
- Cohen D. W., Simak R., Fair W. R., Melamed J., Scher H. I., Cordon-Cardo C. Expression of transforming growth factor-alpha and the epidermal growth factor receptor in human prostate tissues. J Urol. 1994 Dec;152(6 Pt 1):2120–2124. doi: 10.1016/s0022-5347(17)32335-2. [DOI] [PubMed] [Google Scholar]
- Cross M., Dexter T. M. Growth factors in development, transformation, and tumorigenesis. Cell. 1991 Jan 25;64(2):271–280. doi: 10.1016/0092-8674(91)90638-f. [DOI] [PubMed] [Google Scholar]
- Davies P., Eaton C. L., France T. D., Phillips M. E. Growth factor receptors and oncogene expression in prostate cells. Am J Clin Oncol. 1988;11 (Suppl 2):S1–S7. doi: 10.1097/00000421-198801102-00002. [DOI] [PubMed] [Google Scholar]
- Derynck R., Goeddel D. V., Ullrich A., Gutterman J. U., Williams R. D., Bringman T. S., Berger W. H. Synthesis of messenger RNAs for transforming growth factors alpha and beta and the epidermal growth factor receptor by human tumors. Cancer Res. 1987 Feb 1;47(3):707–712. [PubMed] [Google Scholar]
- Ekstrand A. J., Sugawa N., James C. D., Collins V. P. Amplified and rearranged epidermal growth factor receptor genes in human glioblastomas reveal deletions of sequences encoding portions of the N- and/or C-terminal tails. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4309–4313. doi: 10.1073/pnas.89.10.4309. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fong C. J., Sherwood E. R., Mendelsohn J., Lee C., Kozlowski J. M. Epidermal growth factor receptor monoclonal antibody inhibits constitutive receptor phosphorylation, reduces autonomous growth, and sensitizes androgen-independent prostatic carcinoma cells to tumor necrosis factor alpha. Cancer Res. 1992 Nov 1;52(21):5887–5892. [PubMed] [Google Scholar]
- Gleason D. F., Mellinger G. T. Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J Urol. 1974 Jan;111(1):58–64. doi: 10.1016/s0022-5347(17)59889-4. [DOI] [PubMed] [Google Scholar]
- Glynne-Jones E., Goddard L., Harper M. E. Comparative analysis of mRNA and protein expression for epidermal growth factor receptor and ligands relative to the proliferative index in human prostate tissue. Hum Pathol. 1996 Jul;27(7):688–694. doi: 10.1016/s0046-8177(96)90399-8. [DOI] [PubMed] [Google Scholar]
- Greig R., Dunnington D., Murthy U., Anzano M. Growth factors as novel therapeutic targets in neoplastic disease. Cancer Surv. 1988;7(4):653–674. [PubMed] [Google Scholar]
- Gullick W. J. Type I growth factor receptors: current status and future work. Biochem Soc Symp. 1998;63:193–198. [PubMed] [Google Scholar]
- Humphrey P. A., Wong A. J., Vogelstein B., Zalutsky M. R., Fuller G. N., Archer G. E., Friedman H. S., Kwatra M. M., Bigner S. H., Bigner D. D. Anti-synthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4207–4211. doi: 10.1073/pnas.87.11.4207. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Humphrey P. A., Wong A. J., Vogelstein B., Zalutsky M. R., Fuller G. N., Archer G. E., Friedman H. S., Kwatra M. M., Bigner S. H., Bigner D. D. Anti-synthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4207–4211. doi: 10.1073/pnas.87.11.4207. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hunts J., Ueda M., Ozawa S., Abe O., Pastan I., Shimizu N. Hyperproduction and gene amplification of the epidermal growth factor receptor in squamous cell carcinomas. Jpn J Cancer Res. 1985 Aug;76(8):663–666. [PubMed] [Google Scholar]
- Häggman M. J., Macoska J. A., Wojno K. J., Oesterling J. E. The relationship between prostatic intraepithelial neoplasia and prostate cancer: critical issues. J Urol. 1997 Jul;158(1):12–22. doi: 10.1097/00005392-199707000-00004. [DOI] [PubMed] [Google Scholar]
- Kristt D. A., Yarden Y. Differences between phosphotyrosine accumulation and Neu/ErbB-2 receptor expression in astrocytic proliferative processes. Implications for glial oncogenesis. Cancer. 1996 Sep 15;78(6):1272–1283. doi: 10.1002/(SICI)1097-0142(19960915)78:6<1272::AID-CNCR16>3.0.CO;2-Y. [DOI] [PubMed] [Google Scholar]
- Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
- Maddy S. Q., Chisholm G. D., Busuttil A., Habib F. K. Epidermal growth factor receptors in human prostate cancer: correlation with histological differentiation of the tumour. Br J Cancer. 1989 Jul;60(1):41–44. doi: 10.1038/bjc.1989.216. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Maddy S. Q., Chisholm G. D., Hawkins R. A., Habib F. K. Localization of epidermal growth factor receptors in the human prostate by biochemical and immunocytochemical methods. J Endocrinol. 1987 Apr;113(1):147–153. doi: 10.1677/joe.0.1130147. [DOI] [PubMed] [Google Scholar]
- Maygarden S. J., Strom S., Ware J. L. Localization of epidermal growth factor receptor by immunohistochemical methods in human prostatic carcinoma, prostatic intraepithelial neoplasia, and benign hyperplasia. Arch Pathol Lab Med. 1992 Mar;116(3):269–273. [PubMed] [Google Scholar]
- Mellon K., Thompson S., Charlton R. G., Marsh C., Robinson M., Lane D. P., Harris A. L., Horne C. H., Neal D. E. p53, c-erbB-2 and the epidermal growth factor receptor in the benign and malignant prostate. J Urol. 1992 Feb;147(2):496–499. doi: 10.1016/s0022-5347(17)37287-7. [DOI] [PubMed] [Google Scholar]
- Modjtahedi H., Hickish T., Nicolson M., Moore J., Styles J., Eccles S., Jackson E., Salter J., Sloane J., Spencer L. Phase I trial and tumour localisation of the anti-EGFR monoclonal antibody ICR62 in head and neck or lung cancer. Br J Cancer. 1996 Jan;73(2):228–235. doi: 10.1038/bjc.1996.40. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Morris G. L., Dodd J. G. Epidermal growth factor receptor mRNA levels in human prostatic tumors and cell lines. J Urol. 1990 Jun;143(6):1272–1274. doi: 10.1016/s0022-5347(17)40253-9. [DOI] [PubMed] [Google Scholar]
- Moscatello D. K., Holgado-Madruga M., Godwin A. K., Ramirez G., Gunn G., Zoltick P. W., Biegel J. A., Hayes R. L., Wong A. J. Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res. 1995 Dec 1;55(23):5536–5539. [PubMed] [Google Scholar]
- Moscatello D. K., Montgomery R. B., Sundareshan P., McDanel H., Wong M. Y., Wong A. J. Transformational and altered signal transduction by a naturally occurring mutant EGF receptor. Oncogene. 1996 Jul 4;13(1):85–96. [PubMed] [Google Scholar]
- Moscatello D. K., Ramirez G., Wong A. J. A naturally occurring mutant human epidermal growth factor receptor as a target for peptide vaccine immunotherapy of tumors. Cancer Res. 1997 Apr 15;57(8):1419–1424. [PubMed] [Google Scholar]
- Nagane M., Coufal F., Lin H., Bögler O., Cavenee W. K., Huang H. J. A common mutant epidermal growth factor receptor confers enhanced tumorigenicity on human glioblastoma cells by increasing proliferation and reducing apoptosis. Cancer Res. 1996 Nov 1;56(21):5079–5086. [PubMed] [Google Scholar]
- Newby J. C., Johnston S. R., Smith I. E., Dowsett M. Expression of epidermal growth factor receptor and c-erbB2 during the development of tamoxifen resistance in human breast cancer. Clin Cancer Res. 1997 Sep;3(9):1643–1651. [PubMed] [Google Scholar]
- Nishikawa R., Ji X. D., Harmon R. C., Lazar C. S., Gill G. N., Cavenee W. K., Huang H. J. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7727–7731. doi: 10.1073/pnas.91.16.7727. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Olapade-Olaopa E. O., MacKay E. H., Habib F. K. Variability of immunohistochemical reactivity on stored paraffin slides. J Clin Pathol. 1998 Dec;51(12):943–943. doi: 10.1136/jcp.51.12.943b. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Olapade-Olaopa E. O., MacKay E. H., Taub N. A., Sandhu D. P., Terry T. R., Habib F. K. Malignant transformation of human prostatic epithelium is associated with the loss of androgen receptor immunoreactivity in the surrounding stroma. Clin Cancer Res. 1999 Mar;5(3):569–576. [PubMed] [Google Scholar]
- Ozanne B., Richards C. S., Hendler F., Burns D., Gusterson B. Over-expression of the EGF receptor is a hallmark of squamous cell carcinomas. J Pathol. 1986 May;149(1):9–14. doi: 10.1002/path.1711490104. [DOI] [PubMed] [Google Scholar]
- Panneerselvam K., Kanakaraj P., Raj S., Das M., Bishayee S. Characterization of a novel epidermal-growth-factor-receptor-related 200-kDa tyrosine kinase in tumor cells. Eur J Biochem. 1995 Jun 15;230(3):951–957. doi: 10.1111/j.1432-1033.1995.tb20641.x. [DOI] [PubMed] [Google Scholar]
- Putz T., Culig Z., Eder I. E., Nessler-Menardi C., Bartsch G., Grunicke H., Uberall F., Klocker H. Epidermal growth factor (EGF) receptor blockade inhibits the action of EGF, insulin-like growth factor I, and a protein kinase A activator on the mitogen-activated protein kinase pathway in prostate cancer cell lines. Cancer Res. 1999 Jan 1;59(1):227–233. [PubMed] [Google Scholar]
- Ro J., North S. M., Gallick G. E., Hortobagyi G. N., Gutterman J. U., Blick M. Amplified and overexpressed epidermal growth factor receptor gene in uncultured primary human breast carcinoma. Cancer Res. 1988 Jan 1;48(1):161–164. [PubMed] [Google Scholar]
- Sainsbury J. R., Farndon J. R., Needham G. K., Malcolm A. J., Harris A. L. Epidermal-growth-factor receptor status as predictor of early recurrence of and death from breast cancer. Lancet. 1987 Jun 20;1(8547):1398–1402. doi: 10.1016/s0140-6736(87)90593-9. [DOI] [PubMed] [Google Scholar]
- Sakr W. A., Grignon D. J. Prostate cancer: indicators of aggressiveness. Eur Urol. 1997;32 (Suppl 3):15–23. [PubMed] [Google Scholar]
- Schmidt M., Reiser P., Hills D., Gullick W. J., Wels W. Expression of an oncogenic mutant EGF receptor markedly increases the sensitivity of cells to an EGF-receptor-specific antibody-toxin. Int J Cancer. 1998 Mar 16;75(6):878–884. doi: 10.1002/(sici)1097-0215(19980316)75:6<878::aid-ijc10>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
- Sherwood E. R., Van Dongen J. L., Wood C. G., Liao S., Kozlowski J. M., Lee C. Epidermal growth factor receptor activation in androgen-independent but not androgen-stimulated growth of human prostatic carcinoma cells. Br J Cancer. 1998 Mar;77(6):855–861. doi: 10.1038/bjc.1998.142. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thompson D. M., Gill G. N. The EGF receptor: structure, regulation and potential role in malignancy. Cancer Surv. 1985;4(4):767–788. [PubMed] [Google Scholar]
- Turkeri L. N., Sakr W. A., Wykes S. M., Grignon D. J., Pontes J. E., Macoska J. A. Comparative analysis of epidermal growth factor receptor gene expression and protein product in benign, premalignant, and malignant prostate tissue. Prostate. 1994 Oct;25(4):199–205. doi: 10.1002/pros.2990250405. [DOI] [PubMed] [Google Scholar]
- Ullrich A., Coussens L., Hayflick J. S., Dull T. J., Gray A., Tam A. W., Lee J., Yarden Y., Libermann T. A., Schlessinger J. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. 1984 May 31-Jun 6Nature. 309(5967):418–425. doi: 10.1038/309418a0. [DOI] [PubMed] [Google Scholar]
- Wikstrand C. J., Hale L. P., Batra S. K., Hill M. L., Humphrey P. A., Kurpad S. N., McLendon R. E., Moscatello D., Pegram C. N., Reist C. J. Monoclonal antibodies against EGFRvIII are tumor specific and react with breast and lung carcinomas and malignant gliomas. Cancer Res. 1995 Jul 15;55(14):3140–3148. [PubMed] [Google Scholar]
- Wong A. J., Bigner S. H., Bigner D. D., Kinzler K. W., Hamilton S. R., Vogelstein B. Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6899–6903. doi: 10.1073/pnas.84.19.6899. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wong A. J., Ruppert J. M., Bigner S. H., Grzeschik C. H., Humphrey P. A., Bigner D. S., Vogelstein B. Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2965–2969. doi: 10.1073/pnas.89.7.2965. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Xu Y. H., Richert N., Ito S., Merlino G. T., Pastan I. Characterization of epidermal growth factor receptor gene expression in malignant and normal human cell lines. Proc Natl Acad Sci U S A. 1984 Dec;81(23):7308–7312. doi: 10.1073/pnas.81.23.7308. [DOI] [PMC free article] [PubMed] [Google Scholar]