Virchows Archiv B

, Volume 53, Issue 1, pp 146–152 | Cite as

Immunohistochemical evaluation of ras oncogene expression in pulmonary and pleural neoplasms

  • Inchul Lee
  • Victor E. Gould
  • James A. Radosevich
  • Ann Thor
  • Yixing Ma
  • Jeffrey Schlom
  • Steven T. Rosen


We undertook an immunohistochemical analysis of human bronchopulmonary epithelial neoplasms and pleural mesotheliomas using a monoclonal antibody which recognizes ras oncogene products (p21ras). The monoclonal antibody, RAP-5, recognizes both unaltered and certain mutated p21ras. Formalin fixed and paraffin embedded tissue samples of 187 lung epithelial tumors and 27 pleural mesotheliomas were investigated; normal and bronchiectatic lungs were similarly studied. Normal lung and pleural tissue did not immunostain except for occasional type II pneumocytes. Reactive type II pneumocytes adjacent to carcinomas and bronchiectasis immunostained consistently. Twenty four/34 (71%) squamous carcinomas immunostained. Only 8/50 (16%) adenocarcinomas immunostained focally and weakly whereas 19/24 (79%) bronchioloalveolar carcinomas immunostained. Eleven/18 (61%) large cell carcinomas immunostained with variable intensity. Eleven/13 (85%) carcinoids, 6/7 (85%) well differentiated neuroendocrine carcinomas, and 18/21 (86%) intermediate cell neuroendocrine carcinomas immunostained while none of 20 small cell neuroendocrine carcinomas immunostained. Only a few mesotheliomas were immunostained focally. Two/14 (14%) epithelial type and 1/9 (11%) biphasic type mesotheliomas immunostained weakly; none of 4 spindle cell mesotheliomas immuno stained.

We conclude that while at least occasional cases of most types of pulmonary epithelial neoplasms express p21ras, the frequency and intensity of the expression are distinctly greater in certain tumor types such as squamous, bronchioloalveolar, and neuroendocrine neoplasm except for the small cell type. Contrary to these lung epithelial neoplasms, most mesotheliomas did not immunostain for p21ras. Whether the enhanced p21ras expression may point to a different mechanism of transformation or may merely reflect differentiation features remains undetermined.

Key words

Ras onogene, p21 Immunohistochemistry Lung carcinomas Mesotheliomas 


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  1. Bishop JM (1983) Cellular oncogenes and retroviruses. Annu Rev Biochem 52:301–354PubMedCrossRefGoogle Scholar
  2. Blair DG, Oskarsson M, Wood TG, McClements WL, Fischinger PJ (1981) Activation of the transforming potential of a normal cell sequence: a molecular model for oncogenesis. Science 212:941–943PubMedCrossRefGoogle Scholar
  3. Blobel GA, Gould VE, Moll R, Lee I, Huszar M, Geiger B, Franke WW (1985) Coexpression of neuroendocrine markers and epithelial cytoskeletal proteins in bronchopulmonary neuroendocrine neoplasms. Lab Invest 52:39–51PubMedGoogle Scholar
  4. Blobel GA, Moll R, Franke WW, Kayser KW, Gould VE (1985) The intermediate filament cytoskeleton of malignant mesotheliomas and its diagnostic significance. Am J Pathol 121: 235–247PubMedGoogle Scholar
  5. Blobel GA, Moll R, Franke WW, Vogt-Mykopf I, Gould VE (1987) Cytoskeletal characterization of normal and transformed lung epithelial cells: Improved histodiagnosis of carcinomas of the lung. Klin Wochenschr (in press)Google Scholar
  6. Carter D, Eggleston J (1979) Tumors of the lower respiratory tract. Atlas of tumor pathology, Fascicle 17, Armed Forces Institute of Pathology, Washington DC, USAGoogle Scholar
  7. DeFeo D, Gonda MA, Young HA, Chang EH, Lowy DR, Scolnick EM, Ellis RW (1981) Analysis of two different rat genomic clones homologous to the transforming gene of Harvey murine sarcoma virus. Proc Natl Acad Sci (USA) 78: 3328–3332CrossRefGoogle Scholar
  8. Der CJ, Cooper GM (1983) Altered gene products are associated with activation of cellular ras genes in human lung and colon carcinomas. Cell 32:201–208PubMedCrossRefGoogle Scholar
  9. Fujita J, Srivastava S, Kraus M, Rhim J, Tronick S, Aaronson S (1984) Frequency of molecular alteration affecting ras proto-oncogenes in human urinary tract tumors. Proc Natl Acad Sci (USA) 82:3849–3853CrossRefGoogle Scholar
  10. Gallick GE, Kurzrock R, Kloetzer WS, Arlinghaus RB, Gutterman JU (1985) Expression of p21ras in fresh primary and metastatic human colorectal tumors. Proc Natl Acad Sci (USA) 82:1795–1799CrossRefGoogle Scholar
  11. Gould VE, Linnoila RL, Memoli VA, Warren WH (1983) Neuroendocrine components of the bronchopulmonary tract: hyperplasias, dysplasias, and neoplasms. Lab Invest 49:5, 519–537Google Scholar
  12. Gould VE, Linnoila RI, Memoli VA, Warren WH (1983) Neuroendocrine cells and Neuroendocrine neoplasms of the lung. Pathol Annu 18:287–330PubMedGoogle Scholar
  13. Hand PH, Thor A, Wunderlich D, Muraro R, Caruso A, Schlom J (1984) Monoclonal antibodies of predifined specificity detect activated ras gene expression in human mammary and colonic carcinomas. Proc Natl Acad Sci (USA) 81:5227–5231CrossRefGoogle Scholar
  14. Hsu SM, Raine L, Fanger H (1981) The use of avidin-biotin peroxidase complex (ABC) in immunoperoxidase techniques: A comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 29:577–581PubMedGoogle Scholar
  15. Kurzrock R, Gallick GE, Gutterman JU (1986) Differential expression of p21ras gene products among histological subtypes of fresh primary human lung tumors. Cancer Res 46: 1530–1534PubMedGoogle Scholar
  16. Lacal JC, Srivastava SK, Anderson PS, Aaronson SA (1986) Ras p21 proteins with high or low GTPase activity can efficiently transform NIH/3T3 cells. Cell 44:609–617PubMedCrossRefGoogle Scholar
  17. Land H, Parada LF, Weingerg RA (1983) Cellular oncogenes and multistep carcinogenesis. Science 22:771–778CrossRefGoogle Scholar
  18. Lee I, Radosevich JA, Ma Y, Combs SG, Rosen ST, Gould VE (1985) Immunohistochemical analysis of pulmonary carcinomas using monoclonal antibody 44-3A6. Cancer Res 45: 5808–5812PubMedGoogle Scholar
  19. Lee I, Radosevich JA, Chejfec G, May Y, Warren WH, Gould VE (1986) Mesotheliomas: Improved differential diagnosis from metastatic lung carcinomas using monoclonal antibodies 44-3A6 and 624A12. Am J Pathol 123:497–507PubMedGoogle Scholar
  20. Lee I, Radosevich JA, Ma Y, Warren WH, Rosen ST, Gould VE (1987) Immunohistochemical demonstration of lacto-N-fucopentose III in lung carcinomas with monoclonal antibody 624A12. Pathol Res Pract 182:40–47PubMedGoogle Scholar
  21. Lee I, Gould KA, Radosevich JA, Schlom J, Banner BF, Gould VE (1987) Differential expression of ras oncogene products in liver diseases. Lab Invest 56:42(A)Google Scholar
  22. McCoy MS, Toole JJ, Cunningham JM, Chang EH, Lowy DR, Weinberg RA (1983) Characterization of a human colon/lung carcinoma oncogene. Nature (Lond) 302:79–81CrossRefGoogle Scholar
  23. Piehl MR, Lee I, Ma Y, Warren WH, Radosevich JA, Rosen ST, Gould VE (1987) Subsets of pulmonary large cell undifferentiated carcinomas defined immunohistochemically. Lab Invest 56:60 (A)Google Scholar
  24. Pulciani S, Santos E, Lauver AV, Long LK, Aaronson SA, Barbacid (1982) Oncogenes in solid human tumors. Nature (Lond) 300:539–542CrossRefGoogle Scholar
  25. Reddy EP, Reynolds RK, Santos E, Barbacid M (1982) A point mutation is responsible for the acquisition of transforming proterties by T24 human bladder carcinoma oncogene. Nature (Lond) 300:149–152CrossRefGoogle Scholar
  26. Rosen ST, Mulshine JL, Cuttitta F, Fedorke J, Carnewy DN, Gazdar AF, Minna JD (1984) Analysis of human small cell lung cancer differentiation antigens using a panel of rat monoclonal antibodies. Cancer Res 44:2052–2061PubMedGoogle Scholar
  27. Santos E, Martin-Zanca D, Reddy EP, Pierotti MA, Porta GD, Barbacid M (1984) Malignant activation of a K-ras oncogene in lung carcinoma but not in normal tissue of the same patient. Science 223:661–664PubMedCrossRefGoogle Scholar
  28. Slamon DJ, DeKernion JB, Verma IM, Cline MJ (1984) Expression of cellular oncogenes in human malignancies. Science 24:256–262CrossRefGoogle Scholar
  29. Smith MR, DeGudicibus SJ, Stacey DW (1986) Requirement of c-ras proteins during viral oncogene transformation. Nature (Lond) 320:540–543CrossRefGoogle Scholar
  30. Spandidos DA, Wilkie NM (1984) Malignant transformation of early passage rodent cells by a single mutated human oncogene. Nature (Lond) 310:469–475CrossRefGoogle Scholar
  31. Taparowsky E, Suard Y, Fasano O, Shimizu K, Goldfarb M, Wigler M (1982) Activation of the T24 bladder carcinoma transforming gene is linked to a single amino acid change. Nature (Lond) 300:762–764CrossRefGoogle Scholar
  32. Thor A, Hand W, Wunderlich D, Caruso A, Muraro R, Schlom J (1984) Monoclonal antibodies define differential ras gene expression in malignant and benign colonie diseases. Nature (Lond) 311:562–565CrossRefGoogle Scholar
  33. Thor A, Ohuchi N, Hand PH, Callahan R, Weeks MO, Theillet C, Lidereau R, Escot C, Page DL, Vilasi V, Schlom J (1986) Ras oncogene alterations and enhanced levels of ras p21 expression in a spectrum of benign and malignant human mammary tissue. Lab Invest 55:603–615PubMedGoogle Scholar
  34. Viola MV, Fromowitz, Oravez S, Deb S, Finkel G, Lundy J, Hand P, Thor A, Schlom J (1986) Expression of ras oncogene p21 in prostate cancer. N Engl J Med 314:133–137PubMedGoogle Scholar
  35. Warren WH, Memoli VA, Kittle CF, Jensik RJ, Faber LP, Gould VE (1984) The biological implications of bronchial tumors. J Thorac Cardiov Surg 87:274–282PubMedGoogle Scholar
  36. World Health Organization Histological typing of Lung Tumors (1982) Second Edition. Am J Clin Pathol 77:123–136Google Scholar

Copyright information

© Springer-Verlag 1987

Authors and Affiliations

  • Inchul Lee
    • 1
  • Victor E. Gould
    • 1
  • James A. Radosevich
    • 2
  • Ann Thor
    • 3
  • Yixing Ma
    • 2
  • Jeffrey Schlom
    • 3
  • Steven T. Rosen
    • 2
  1. 1.Department of PathologyRush-Presbyterian-St. Luke’s Medical CenterChicago
  2. 2.Department of Medicine, Section of OncologyNorthwestern University /VA Lakeside Medical CenterChicago
  3. 3.Tumor Immunology and Biology BranchNational Cancer InstituteBethesdaUSA

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