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. 1995 Aug;147(2):245–250.

Coexpression of transforming growth factor-alpha and épidermal growth factor receptor in capillary hemangioblastomas of the central nervous system.

G Reifenberger 1, J Reifenberger 1, T Bilzer 1, W Wechsler 1, V P Collins 1
PMCID: PMC1869821  PMID: 7639324

Abstract

The expression of epidermal growth factor receptor (EGFR) and the pre-pro form of one of its ligands, transforming growth factor-alpha (TGF-alpha), was studied by Northern blotting in a series of 14 capillary hemangioblastomas of the central nervous system. A constant coexpression of EGFR and pre-pro-TGF-alpha mRNAs was found. Immunocytochemical investigation of an extended series of 51 capillary hemangioblastomas revealed that the stromal cells in these tumors showed immunoreactivity with monoclonal antibodies to EGFR and TGF-alpha. Analysis of gene dosage by Southern blotting in 20 tumors indicated a normal gene copy number of EGFR and TGF alpha in all cases. Our findings suggest that autocrine and/or juxtacrine growth stimulation via the EGFR may contribute to tumor growth in capillary hemangioblastomas.

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Selected References

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

  1. Aaronson S. A. Growth factors and cancer. Science. 1991 Nov 22;254(5035):1146–1153. doi: 10.1126/science.1659742. [DOI] [PubMed] [Google Scholar]
  2. Becker I., Paulus W., Roggendorf W. Histogenesis of stromal cells in cerebellar hemangioblastomas. An immunohistochemical study. Am J Pathol. 1989 Feb;134(2):271–275. [PMC free article] [PubMed] [Google Scholar]
  3. Brachmann R., Lindquist P. B., Nagashima M., Kohr W., Lipari T., Napier M., Derynck R. Transmembrane TGF-alpha precursors activate EGF/TGF-alpha receptors. Cell. 1989 Feb 24;56(4):691–700. doi: 10.1016/0092-8674(89)90591-6. [DOI] [PubMed] [Google Scholar]
  4. Crossey P. A., Foster K., Richards F. M., Phipps M. E., Latif F., Tory K., Jones M. H., Bentley E., Kumar R., Lerman M. I. Molecular genetic investigations of the mechanism of tumourigenesis in von Hippel-Lindau disease: analysis of allele loss in VHL tumours. Hum Genet. 1994 Jan;93(1):53–58. doi: 10.1007/BF00218913. [DOI] [PubMed] [Google Scholar]
  5. Derynck R. Transforming growth factor alpha. Cell. 1988 Aug 26;54(5):593–595. doi: 10.1016/s0092-8674(88)80001-1. [DOI] [PubMed] [Google Scholar]
  6. Di Fiore P. P., Pierce J. H., Fleming T. P., Hazan R., Ullrich A., King C. R., Schlessinger J., Aaronson S. A. Overexpression of the human EGF receptor confers an EGF-dependent transformed phenotype to NIH 3T3 cells. Cell. 1987 Dec 24;51(6):1063–1070. doi: 10.1016/0092-8674(87)90592-7. [DOI] [PubMed] [Google Scholar]
  7. Ekstrand A. J., James C. D., Cavenee W. K., Seliger B., Pettersson R. F., Collins V. P. Genes for epidermal growth factor receptor, transforming growth factor alpha, and epidermal growth factor and their expression in human gliomas in vivo. Cancer Res. 1991 Apr 15;51(8):2164–2172. [PubMed] [Google Scholar]
  8. Frank T. S., Trojanowski J. Q., Roberts S. A., Brooks J. J. A detailed immunohistochemical analysis of cerebellar hemangioblastoma: an undifferentiated mesenchymal tumor. Mod Pathol. 1989 Nov;2(6):638–651. [PubMed] [Google Scholar]
  9. Gnarra J. R., Tory K., Weng Y., Schmidt L., Wei M. H., Li H., Latif F., Liu S., Chen F., Duh F. M. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet. 1994 May;7(1):85–90. doi: 10.1038/ng0594-85. [DOI] [PubMed] [Google Scholar]
  10. Gomella L. G., Anglard P., Sargent E. R., Robertson C. N., Kasid A., Linehan W. M. Epidermal growth factor receptor gene analysis in renal cell carcinoma. J Urol. 1990 Jan;143(1):191–193. doi: 10.1016/s0022-5347(17)39908-1. [DOI] [PubMed] [Google Scholar]
  11. Jhappan C., Stahle C., Harkins R. N., Fausto N., Smith G. H., Merlino G. T. TGF alpha overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas. Cell. 1990 Jun 15;61(6):1137–1146. doi: 10.1016/0092-8674(90)90076-q. [DOI] [PubMed] [Google Scholar]
  12. Kanno H., Kondo K., Ito S., Yamamoto I., Fujii S., Torigoe S., Sakai N., Hosaka M., Shuin T., Yao M. Somatic mutations of the von Hippel-Lindau tumor suppressor gene in sporadic central nervous system hemangioblastomas. Cancer Res. 1994 Sep 15;54(18):4845–4847. [PubMed] [Google Scholar]
  13. Latif F., Tory K., Gnarra J., Yao M., Duh F. M., Orcutt M. L., Stackhouse T., Kuzmin I., Modi W., Geil L. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993 May 28;260(5112):1317–1320. doi: 10.1126/science.8493574. [DOI] [PubMed] [Google Scholar]
  14. Luetteke N. C., Lee D. C. Transforming growth factor alpha: expression, regulation and biological action of its integral membrane precursor. Semin Cancer Biol. 1990 Aug;1(4):265–275. [PubMed] [Google Scholar]
  15. Marquardt H., Hunkapiller M. W., Hood L. E., Twardzik D. R., De Larco J. E., Stephenson J. R., Todaro G. J. Transforming growth factors produced by retrovirus-transformed rodent fibroblasts and human melanoma cells: amino acid sequence homology with epidermal growth factor. Proc Natl Acad Sci U S A. 1983 Aug;80(15):4684–4688. doi: 10.1073/pnas.80.15.4684. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Massagué J. Epidermal growth factor-like transforming growth factor. II. Interaction with epidermal growth factor receptors in human placenta membranes and A431 cells. J Biol Chem. 1983 Nov 25;258(22):13614–13620. [PubMed] [Google Scholar]
  17. McGeady M. L., Kerby S., Shankar V., Ciardiello F., Salomon D., Seidman M. Infection with a TGF-alpha retroviral vector transforms normal mouse mammary epithelial cells but not normal rat fibroblasts. Oncogene. 1989 Nov;4(11):1375–1382. [PubMed] [Google Scholar]
  18. Morii K., Tanaka R., Washiyama K., Kumanishi T., Kuwano R. Expression of vascular endothelial growth factor in capillary hemangioblastoma. Biochem Biophys Res Commun. 1993 Jul 30;194(2):749–755. doi: 10.1006/bbrc.1993.1885. [DOI] [PubMed] [Google Scholar]
  19. Mydlo J. H., Michaeli J., Cordon-Cardo C., Goldenberg A. S., Heston W. D., Fair W. R. Expression of transforming growth factor alpha and epidermal growth factor receptor messenger RNA in neoplastic and nonneoplastic human kidney tissue. Cancer Res. 1989 Jun 15;49(12):3407–3411. [PubMed] [Google Scholar]
  20. Nemes Z. Fibrohistiocytic differentiation in capillary hemangioblastoma. Hum Pathol. 1992 Jul;23(7):805–810. doi: 10.1016/0046-8177(92)90351-3. [DOI] [PubMed] [Google Scholar]
  21. Neumann H. P., Eggert H. R., Weigel K., Friedburg H., Wiestler O. D., Schollmeyer P. Hemangioblastomas of the central nervous system. A 10-year study with special reference to von Hippel-Lindau syndrome. J Neurosurg. 1989 Jan;70(1):24–30. doi: 10.3171/jns.1989.70.1.0024. [DOI] [PubMed] [Google Scholar]
  22. Petrides P. E., Bock S., Bovens J., Hofmann R., Jakse G. Modulation of pro-epidermal growth factor, pro-transforming growth factor alpha and epidermal growth factor receptor gene expression in human renal carcinomas. Cancer Res. 1990 Jul 1;50(13):3934–3939. [PubMed] [Google Scholar]
  23. Reifenberger G., Liu L., Ichimura K., Schmidt E. E., Collins V. P. Amplification and overexpression of the MDM2 gene in a subset of human malignant gliomas without p53 mutations. Cancer Res. 1993 Jun 15;53(12):2736–2739. [PubMed] [Google Scholar]
  24. Rosenthal A., Lindquist P. B., Bringman T. S., Goeddel D. V., Derynck R. Expression in rat fibroblasts of a human transforming growth factor-alpha cDNA results in transformation. Cell. 1986 Jul 18;46(2):301–309. doi: 10.1016/0092-8674(86)90747-6. [DOI] [PubMed] [Google Scholar]
  25. Sandgren E. P., Luetteke N. C., Qiu T. H., Palmiter R. D., Brinster R. L., Lee D. C. Transforming growth factor alpha dramatically enhances oncogene-induced carcinogenesis in transgenic mouse pancreas and liver. Mol Cell Biol. 1993 Jan;13(1):320–330. doi: 10.1128/mcb.13.1.320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Schultz G., Rotatori D. S., Clark W. EGF and TGF-alpha in wound healing and repair. J Cell Biochem. 1991 Apr;45(4):346–352. doi: 10.1002/jcb.240450407. [DOI] [PubMed] [Google Scholar]
  27. Shuin T., Kondo K., Torigoe S., Kishida T., Kubota Y., Hosaka M., Nagashima Y., Kitamura H., Latif F., Zbar B. Frequent somatic mutations and loss of heterozygosity of the von Hippel-Lindau tumor suppressor gene in primary human renal cell carcinomas. Cancer Res. 1994 Jun 1;54(11):2852–2855. [PubMed] [Google Scholar]
  28. Velu T. J., Beguinot L., Vass W. C., Willingham M. C., Merlino G. T., Pastan I., Lowy D. R. Epidermal-growth-factor-dependent transformation by a human EGF receptor proto-oncogene. Science. 1987 Dec 4;238(4832):1408–1410. doi: 10.1126/science.3500513. [DOI] [PubMed] [Google Scholar]
  29. Watanabe S., Lazar E., Sporn M. B. Transformation of normal rat kidney (NRK) cells by an infectious retrovirus carrying a synthetic rat type alpha transforming growth factor gene. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1258–1262. doi: 10.1073/pnas.84.5.1258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Wong S. T., Winchell L. F., McCune B. K., Earp H. S., Teixidó J., Massagué J., Herman B., Lee D. C. The TGF-alpha precursor expressed on the cell surface binds to the EGF receptor on adjacent cells, leading to signal transduction. Cell. 1989 Feb 10;56(3):495–506. doi: 10.1016/0092-8674(89)90252-3. [DOI] [PubMed] [Google Scholar]

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