Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1989 Mar 1;169(3):953–972. doi: 10.1084/jem.169.3.953

Transformation of human kidney proximal tubule cells by ras-containing retroviruses. Implications for tumor progression

PMCID: PMC2189254  PMID: 2494294

Abstract

Normal human kidney proximal tubule cells into which a ras oncogene was inserted undergo a series of transformation-related alterations that are characteristic of renal carcinomas. These include changes in morphology, growth potential, anchorage dependence, antigen expression, growth factor production, and chromosomal stability. Further, there are spontaneous progressive alterations in vitro in the karyotype and antigenic profile of the transformed cells. Cytogenetic analyses suggest that alterations of chromosome 21 may play an early and pivotal role in the development of transformed proximal tubule cells.

Full Text

The Full Text of this article is available as a PDF (1.4 MB).

Selected References

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

  1. Albino A. P., Houghton A. N., Eisinger M., Lee J. S., Kantor R. R., Oliff A. I., Old L. J. Class II histocompatibility antigen expression in human melanocytes transformed by Harvey murine sarcoma virus (Ha-MSV) and Kirsten MSV retroviruses. J Exp Med. 1986 Nov 1;164(5):1710–1722. doi: 10.1084/jem.164.5.1710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Anzano M. A., Roberts A. B., Meyers C. A., Komoriya A., Lamb L. C., Smith J. M., Sporn M. B. Synergistic interaction of two classes of transforming growth factors from murine sarcoma cells. Cancer Res. 1982 Nov;42(11):4776–4778. [PubMed] [Google Scholar]
  3. Balmain A. Transforming ras oncogenes and multistage carcinogenesis. Br J Cancer. 1985 Jan;51(1):1–7. doi: 10.1038/bjc.1985.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bander N. H., Cordon-Cardo C., Finstad C. L., Whitmore W. F., Jr, Vaughan E. D., Jr, Oettgen H. F., Melamed M., Old L. J. Immunohistologic dissection of the human kidney using monoclonal antibodies. J Urol. 1985 Mar;133(3):502–505. doi: 10.1016/s0022-5347(17)49041-0. [DOI] [PubMed] [Google Scholar]
  5. Bander N. H. Monoclonal antibodies: state of the art. J Urol. 1987 Apr;137(4):603–612. doi: 10.1016/s0022-5347(17)44154-1. [DOI] [PubMed] [Google Scholar]
  6. Bander N. H. Study of the normal human kidney and kidney cancer with monoclonal antibodies. Uremia Invest. 1984;8(3-4):263–273. doi: 10.3109/08860228409115852. [DOI] [PubMed] [Google Scholar]
  7. Bishop J. M. The molecular genetics of cancer. Science. 1987 Jan 16;235(4786):305–311. doi: 10.1126/science.3541204. [DOI] [PubMed] [Google Scholar]
  8. Carroll P. R., Murty V. V., Reuter V., Jhanwar S., Fair W. R., Whitmore W. F., Chaganti R. S. Abnormalities at chromosome region 3p12-14 characterize clear cell renal carcinoma. Cancer Genet Cytogenet. 1987 Jun;26(2):253–259. doi: 10.1016/0165-4608(87)90059-8. [DOI] [PubMed] [Google Scholar]
  9. Carubia J. M., Yu R. K., Macala L. J., Kirkwood J. M., Varga J. M. Gangliosides of normal and neoplastic human melanocytes. Biochem Biophys Res Commun. 1984 Apr 30;120(2):500–504. doi: 10.1016/0006-291x(84)91282-8. [DOI] [PubMed] [Google Scholar]
  10. Cavenee W. K., Hansen M. F., Nordenskjold M., Kock E., Maumenee I., Squire J. A., Phillips R. A., Gallie B. L. Genetic origin of mutations predisposing to retinoblastoma. Science. 1985 Apr 26;228(4698):501–503. doi: 10.1126/science.3983638. [DOI] [PubMed] [Google Scholar]
  11. Chattopadhyay S. K., Oliff A. I., Linemeyer D. L., Lander M. R., Lowy D. R. Genomes of murine leukemia viruses isolated from wild mice. J Virol. 1981 Sep;39(3):777–791. doi: 10.1128/jvi.39.3.777-791.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cheresh D. A., Harper J. R., Schulz G., Reisfeld R. A. Localization of the gangliosides GD2 and GD3 in adhesion plaques and on the surface of human melanoma cells. Proc Natl Acad Sci U S A. 1984 Sep;81(18):5767–5771. doi: 10.1073/pnas.81.18.5767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cheung N. K., Saarinen U. M., Neely J. E., Landmeier B., Donovan D., Coccia P. F. Monoclonal antibodies to a glycolipid antigen on human neuroblastoma cells. Cancer Res. 1985 Jun;45(6):2642–2649. [PubMed] [Google Scholar]
  14. Cordon-Cardo C., Finstad C. L., Bander N. H., Melamed M. R. Immunoanatomic distribution of cytostructural and tissue-associated antigens in the human urinary tract. Am J Pathol. 1987 Feb;126(2):269–284. [PMC free article] [PubMed] [Google Scholar]
  15. Cordon-Cardo C., Lloyd K. O., Finstad C. L., McGroarty M. E., Reuter V. E., Bander N. H., Old L. J., Melamed M. R. Immunoanatomic distribution of blood group antigens in the human urinary tract. Influence of secretor status. Lab Invest. 1986 Oct;55(4):444–454. [PubMed] [Google Scholar]
  16. Cordon-Cardo C., Reuter V. E., Finstad C. L., Sheinfeld J., Lloyd K. O., Fair W. R., Melamed M. R. Blood group-related antigens in human kidney: modulation of Lewis determinants in renal cell carcinoma. Cancer Res. 1989 Jan 1;49(1):212–218. [PubMed] [Google Scholar]
  17. Creasy M. R., Crolla J. A., Alberman E. D. A cytogenetic study of human spontaneous abortions using banding techniques. Hum Genet. 1976 Feb 29;31(2):177–196. doi: 10.1007/BF00296145. [DOI] [PubMed] [Google Scholar]
  18. Detrisac C. J., Sens M. A., Garvin A. J., Spicer S. S., Sens D. A. Tissue culture of human kidney epithelial cells of proximal tubule origin. Kidney Int. 1984 Feb;25(2):383–390. doi: 10.1038/ki.1984.28. [DOI] [PubMed] [Google Scholar]
  19. Doniger J., Di Paolo J. A., Popescu N. C. Transformation of Bloom's syndrome fibroblasts by DNA transfection. Science. 1983 Dec 9;222(4628):1144–1146. doi: 10.1126/science.6648529. [DOI] [PubMed] [Google Scholar]
  20. Dudouet B., Robine S., Huet C., Sahuquillo-Merino C., Blair L., Coudrier E., Louvard D. Changes in villin synthesis and subcellular distribution during intestinal differentiation of HT29-18 clones. J Cell Biol. 1987 Jul;105(1):359–369. doi: 10.1083/jcb.105.1.359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Duesberg P. H. Activated proto-onc genes: sufficient or necessary for cancer? Science. 1985 May 10;228(4700):669–677. doi: 10.1126/science.3992240. [DOI] [PubMed] [Google Scholar]
  22. Finstad C. L., Cordon-Cardo C., Bander N. H., Whitmore W. F., Melamed M. R., Old L. J. Specificity analysis of mouse monoclonal antibodies defining cell surface antigens of human renal cancer. Proc Natl Acad Sci U S A. 1985 May;82(9):2955–2959. doi: 10.1073/pnas.82.9.2955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Fishman P. H., Brady R. O. Biosynthesis and function of gangliosides. Science. 1976 Nov 26;194(4268):906–915. doi: 10.1126/science.185697. [DOI] [PubMed] [Google Scholar]
  24. Fradet Y., Cordon-Cardo C., Thomson T., Daly M. E., Whitmore W. F., Jr, Lloyd K. O., Melamed M. R., Old L. J. Cell surface antigens of human bladder cancer defined by mouse monoclonal antibodies. Proc Natl Acad Sci U S A. 1984 Jan;81(1):224–228. doi: 10.1073/pnas.81.1.224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Fukushi Y., Orikasa S., Shepard T., Hakomori S. Changes of Lex and dimeric Lex haptens and their sialylated antigens during development of human kidney and kidney tumors. J Urol. 1986 May;135(5):1048–1056. doi: 10.1016/s0022-5347(17)45973-8. [DOI] [PubMed] [Google Scholar]
  26. Furth M. E., Davis L. J., Fleurdelys B., Scolnick E. M. Monoclonal antibodies to the p21 products of the transforming gene of Harvey murine sarcoma virus and of the cellular ras gene family. J Virol. 1982 Jul;43(1):294–304. doi: 10.1128/jvi.43.1.294-304.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Furukawa K., Clausen H., Hakomori S., Sakamoto J., Look K., Lundblad A., Mattes M. J., Lloyd K. O. Analysis of the specificity of five murine anti-blood group A monoclonal antibodies, including one that identifies type 3 and type 4 A determinants. Biochemistry. 1985 Dec 17;24(26):7820–7826. doi: 10.1021/bi00347a047. [DOI] [PubMed] [Google Scholar]
  28. Gröne H. J., Weber K., Helmchen U., Osborn M. Villin--a marker of brush border differentiation and cellular origin in human renal cell carcinoma. Am J Pathol. 1986 Aug;124(2):294–302. [PMC free article] [PubMed] [Google Scholar]
  29. Houghton A. N., Albino A. P., Cordon-Cardo C., Davis L. J., Eisinger M. Cell surface antigens of human melanocytes and melanoma. Expression of adenosine deaminase binding protein is extinguished with melanocyte transformation. J Exp Med. 1988 Jan 1;167(1):197–212. doi: 10.1084/jem.167.1.197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Hsu S. M., Soban E. Color modification of diaminobenzidine (DAB) precipitation by metallic ions and its application for double immunohistochemistry. J Histochem Cytochem. 1982 Oct;30(10):1079–1082. doi: 10.1177/30.10.6182185. [DOI] [PubMed] [Google Scholar]
  31. Karthaus H. F., Bussemakers M. J., Schalken J. A., Kurth K. H., Feitz W. F., Debruyne F. M., Bloemers H. P., Van de Ven W. J. Expression of proto-oncogenes in xenografts of human renal cell carcinomas. Urol Res. 1987;15(6):349–353. doi: 10.1007/BF00265665. [DOI] [PubMed] [Google Scholar]
  32. Karthaus H. F., Schalken J. A., Feitz W. F., Debruyne F. M., de Haan P. T., Bloemers H. P., Van de Ven W. J. Expression of the human fes cellular oncogene in renal cell tumors. Urol Res. 1986;14(3):123–127. doi: 10.1007/BF00255829. [DOI] [PubMed] [Google Scholar]
  33. Klein G. The approaching era of the tumor suppressor genes. Science. 1987 Dec 11;238(4833):1539–1545. doi: 10.1126/science.3317834. [DOI] [PubMed] [Google Scholar]
  34. Knudson A. G., Jr Hereditary cancer, oncogenes, and antioncogenes. Cancer Res. 1985 Apr;45(4):1437–1443. [PubMed] [Google Scholar]
  35. Lloyd K. O. Philip Levine award lecture. Blood group antigens as markers for normal differentiation and malignant change in human tissues. Am J Clin Pathol. 1987 Jan;87(1):129–139. doi: 10.1093/ajcp/87.1.129. [DOI] [PubMed] [Google Scholar]
  36. Nakakuma H., Sanai Y., Shiroki K., Nagai Y. Gene-regulated expression of glycolipids: appearance of GD3 ganglioside in rat cells on transfection with transforming gene E1 of human adenovirus type 12 DNA and its transcriptional subunits. J Biochem. 1984 Nov;96(5):1471–1480. doi: 10.1093/oxfordjournals.jbchem.a134976. [DOI] [PubMed] [Google Scholar]
  37. O'Donnell P. V., Stockert E., Obata Y., Old L. J. Leukemogenic properties of AKR dualtropic (MCF) viruses: amplification of murine leukemia virus-related antigens on thymocytes and acceleration of leukemia development in AKR mice. Virology. 1981 Jul 30;112(2):548–563. doi: 10.1016/0042-6822(81)90301-9. [DOI] [PubMed] [Google Scholar]
  38. Pfeffer L. M., Kopelovich L. Differential genetic susceptibility of cultured human skin fibroblasts to transformation by Kirsten murine sarcoma virus. Cell. 1977 Feb;10(2):313–320. doi: 10.1016/0092-8674(77)90225-2. [DOI] [PubMed] [Google Scholar]
  39. Pfeffer L. M., Stebbing N., Donner D. B. Cytoskeletal association of human alpha-interferon-receptor complexes in interferon-sensitive and -resistant lymphoblastoid cells. Proc Natl Acad Sci U S A. 1987 May;84(10):3249–3253. doi: 10.1073/pnas.84.10.3249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Pincus T., Hartley J. W., Rowe W. P. A major genetic locus affecting resistance to infection with murine leukemia viruses. IV. Dose-response relationships in Fv-1-sensitive and resistant cell cultures. Virology. 1975 Jun;65(2):333–342. doi: 10.1016/0042-6822(75)90039-2. [DOI] [PubMed] [Google Scholar]
  41. Pircher R., Lawrence D. A., Jullien P. Latent beta-transforming growth factor in nontransformed and Kirsten sarcoma virus-transformed normal rat kidney cells, clone 49F. Cancer Res. 1984 Dec;44(12 Pt 1):5538–5543. [PubMed] [Google Scholar]
  42. Pukel C. S., Lloyd K. O., Travassos L. R., Dippold W. G., Oettgen H. F., Old L. J. GD3, a prominent ganglioside of human melanoma. Detection and characterisation by mouse monoclonal antibody. J Exp Med. 1982 Apr 1;155(4):1133–1147. doi: 10.1084/jem.155.4.1133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Rao V. N., Papas T. S., Reddy E. S. erg, a human ets-related gene on chromosome 21: alternative splicing, polyadenylation, and translation. Science. 1987 Aug 7;237(4815):635–639. doi: 10.1126/science.3299708. [DOI] [PubMed] [Google Scholar]
  44. Real F. X., Rettig W. J., Chesa P. G., Melamed M. R., Old L. J., Mendelsohn J. Expression of epidermal growth factor receptor in human cultured cells and tissues: relationship to cell lineage and stage of differentiation. Cancer Res. 1986 Sep;46(9):4726–4731. [PubMed] [Google Scholar]
  45. Rettig W. J., Cordon-Cardo C., Ng J. S., Oettgen H. F., Old L. J., Lloyd K. O. High-molecular-weight glycoproteins of human teratocarcinoma defined by monoclonal antibodies to carbohydrate determinants. Cancer Res. 1985 Feb;45(2):815–821. [PubMed] [Google Scholar]
  46. Ritz J., Sallan S. E., Bast R. C., Jr, Lipton J. M., Clavell L. A., Feeney M., Hercend T., Nathan D. G., Schlossman S. F. Autologous bone-marrow transplantation in CALLA-positive acute lymphoblastic leukemia after in-vitro treatment with J5 monoclonal antibody and complement. Lancet. 1982 Jul 10;2(8289):60–63. doi: 10.1016/s0140-6736(82)91686-5. [DOI] [PubMed] [Google Scholar]
  47. Robine S., Huet C., Moll R., Sahuquillo-Merino C., Coudrier E., Zweibaum A., Louvard D. Can villin be used to identify malignant and undifferentiated normal digestive epithelial cells? Proc Natl Acad Sci U S A. 1985 Dec;82(24):8488–8492. doi: 10.1073/pnas.82.24.8488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Rowley J. D. Human oncogene locations and chromosome aberrations. Nature. 1983 Jan 27;301(5898):290–291. doi: 10.1038/301290a0. [DOI] [PubMed] [Google Scholar]
  49. Sager R., Tanaka K., Lau C. C., Ebina Y., Anisowicz A. Resistance of human cells to tumorigenesis induced by cloned transforming genes. Proc Natl Acad Sci U S A. 1983 Dec;80(24):7601–7605. doi: 10.1073/pnas.80.24.7601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Seyfried T. N., Yu R. K. Ganglioside GD3: structure, cellular distribution, and possible function. Mol Cell Biochem. 1985 Sep;68(1):3–10. doi: 10.1007/BF00219383. [DOI] [PubMed] [Google Scholar]
  51. Shin S. I., Freedman V. H., Risser R., Pollack R. Tumorigenicity of virus-transformed cells in nude mice is correlated specifically with anchorage independent growth in vitro. Proc Natl Acad Sci U S A. 1975 Nov;72(11):4435–4439. doi: 10.1073/pnas.72.11.4435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Slamon D. J., deKernion J. B., Verma I. M., Cline M. J. Expression of cellular oncogenes in human malignancies. Science. 1984 Apr 20;224(4646):256–262. doi: 10.1126/science.6538699. [DOI] [PubMed] [Google Scholar]
  53. Trifillis A. L., Regec A. L., Trump B. F. Isolation, culture and characterization of human renal tubular cells. J Urol. 1985 Feb;133(2):324–329. doi: 10.1016/s0022-5347(17)48932-4. [DOI] [PubMed] [Google Scholar]
  54. Ueda R., Ogata S., Morrissey D. M., Finstad C. L., Szkudlarek J., Whitmore W. F., Oettgen H. F., Lloyd K. O., Old L. J. Cell surface antigens of human renal cancer defined by mouse monoclonal antibodies: identification of tissue-specific kidney glycoproteins. Proc Natl Acad Sci U S A. 1981 Aug;78(8):5122–5126. doi: 10.1073/pnas.78.8.5122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Ueda R., Shiku H., Pfreundschuh M., Takahashi T., Li L. T., Whitmore W. F., Oettgen H. F., Old L. J. Cell surface antigens of human renal cancer defined by autologous typing. J Exp Med. 1979 Sep 19;150(3):564–579. doi: 10.1084/jem.150.3.564. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Varmus H. Retroviruses. Science. 1988 Jun 10;240(4858):1427–1435. doi: 10.1126/science.3287617. [DOI] [PubMed] [Google Scholar]
  57. Vessella R. L., Moon T. D., Chiou R. K., Nowak J. A., Arfman E. W., Palme D. F., Peterson G. A., Lange P. H. Monoclonal antibodies to human renal cell carcinoma: recognition of shared and restricted tissue antigens. Cancer Res. 1985 Dec;45(12 Pt 1):6131–6139. [PubMed] [Google Scholar]
  58. Watkins P. C., Tanzi R. E., Cheng S. V., Gusella J. F. Molecular genetics of human chromosome 21. J Med Genet. 1987 May;24(5):257–270. doi: 10.1136/jmg.24.5.257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Weaver D. J., Michalski K., Miles J. Cytogenetic analysis in renal cell carcinoma: correlation with tumor aggressiveness. Cancer Res. 1988 May 15;48(10):2887–2889. [PubMed] [Google Scholar]
  60. Wolman S. R., Camuto P. M., Golimbu M., Schinella R. Cytogenetic, flow cytometric, and ultrastructural studies of twenty-nine nonfamilial human renal carcinomas. Cancer Res. 1988 May 15;48(10):2890–2897. [PubMed] [Google Scholar]
  61. Yoakum G. H., Lechner J. F., Gabrielson E. W., Korba B. E., Malan-Shibley L., Willey J. C., Valerio M. G., Shamsuddin A. M., Trump B. F., Harris C. C. Transformation of human bronchial epithelial cells transfected by Harvey ras oncogene. Science. 1985 Mar 8;227(4691):1174–1179. doi: 10.1126/science.3975607. [DOI] [PubMed] [Google Scholar]
  62. Yoshida M. A., Ohyashiki K., Ochi H., Gibas Z., Pontes J. E., Prout G. R., Jr, Huben R., Sandberg A. A. Cytogenetic studies of tumor tissue from patients with nonfamilial renal cell carcinoma. Cancer Res. 1986 Apr;46(4 Pt 2):2139–2147. [PubMed] [Google Scholar]
  63. Zbar B., Brauch H., Talmadge C., Linehan M. Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma. 1987 Jun 25-Jul 1Nature. 327(6124):721–724. doi: 10.1038/327721a0. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES