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Vol. 18, No. 5-6, 1998
Issue release date: September–December (March 2000)

c-K-ras Overexpression Is Characteristic for Metastases Derived from a Methylcholanthrene-Induced Fibrosarcoma

Algarra I. · Perez M. · Serrano M.J. · Garrido F. · Gaforio J.J.
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We investigated the relationship between the activation of the c-myc and c-K-ras proto-oncogenes and the acquisition of metastatic potential in a methylcholanthrene-induced BALB/c fibrosarcoma. The murine fibrosarcoma GR9 was originally induced in BALB/c mice following exposure to the carcinogenic chemical 3-methylcholanthrene. To induce spontaneous metastasis, we used two tumor cell clones (B9 and G2) known to differ in their metastatic potential, local tumor growth, H-2 class I expression and sensitivity to natural killer (NK) cells. The metastatic nodes were obtained from the lung, liver and kidney. The results showed: (1) amplification of the c-myc proto-oncogene in original tumor clones as well as in all metastatic nodes; (2) mRNA overexpression without amplification of the K-ras proto-oncogene in the metastatic cells, regardless of their anatomical location; (3) no c-K-ras point mutations at codons 12 and 61, and (4) in general, a statistically significantly reduced in vitro sensitivity of metastatic tumor cells to NK cells as compared with the tumor clones used to induce them (p < 0.05). These results therefore suggest that overexpressed c-K-ras mRNA is important during tumor progression, perhaps rendering metastatic tumor cells more resistant to lysis by NK cells.

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  1. Weinberg RA: Oncogenes, antioncogenes, and the molecular bases of multistep carcinogenesis. Cancer Res 1989;49:3713–3721.
  2. Lenardo M, Rustgi AK, Schievella AR, Bernards R: Suppression of MHC class I gene expression by N-myc through enhancer inactivation. EMBO J 1989;8:3351–3358.
  3. Versteeg R, Noordermeer IA, Kruse-Walters M, Ruiter D, Schrier PJ: c-myc down-regulates class I HLA expression in human melanomas. EMBO J 1988;7:1023–1029.
  4. Ruiz-Cabello F, Klein E, Garrido F: MHC antigens on human tumors. Immunol Lett 1991;29:181–190.
  5. Barbacid M: ras genes. Annu Rev Biochem 1987;56:779–827.
  6. Sukumar S: ras oncogenes in chemical carcinogenesis. Curr Top Microbiol Immunol 1989;148:83–114.
  7. Bourne HR, Sanders DA, McCormick F: The GTPase superfamily: A conserved switch for diverse cell functions. Nature 1990;348:125–132.
  8. Lu YY, Blair DG, Segal S, Shih TY, Clanton DJ: Tumorigenicity, metastasis and suppression of MHC class I expression in murine cells transformed by mutant v-ras deficient in GTP binding. Int J Cancer Suppl 1991;6:45–48.

    External Resources

  9. Land H, Parada LF, Weinberg RA: Tumorigenic conversion of primary embryo fibroblast requires at least two coooperating oncogenes. Nature 1983;304:596–602.
  10. Fearon ER: Genetic alterations underlying colorectal tumorigenesis. Cancer Surv 1991;12:119–136.
  11. Pérez M, Garrido A, Algarra I, Garrido F: Different H-2 in clones derived from a new BALB/c solid tumor. Its relevance for tumor growth. Immunología 1985;4:60–69.
  12. Garrido A, Pérez M, Delgado C, Garrido ML, Rojano J, Algarra I, Garrido F: Influence of class I H-2 gene expression on local tumor growth. Description of a model obtained from clones derived from a solid BALB/c tumor. Exp Clin Immunogenet 1986;13:98–110.
  13. Pérez M, Algarra I, Ljunggren HG, Caballero A, Mialdea MJ, Gaforio JJ, Klein G, Karre K, Garrido F: A weakly tumorigenic phenotype with high MHC class I expression is associated with high metastatic potential after surgical removal of the primary murine fibrosarcoma. Int J Cancer 1990;46:258–261.

    External Resources

  14. Chirgwin JM, Przybyla AE, MacDonald RJ, Rutter WJ: Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry 1979;18:5294–5299.

    External Resources

  15. Blin N, Stafford DW: A general method for isolation of high molecular weight DNA from eukarotes. Nucleic Acids Res 1976;3:2303–2308.
  16. Dalla-Favera R, Gelmann EP, Martinotti S, Franchini G, Papas TS, Gallo RC, Wong-Staal F: Cloning and characterization of different human sequences related to the onc gene (v-myc) of avian myelocytomatosis virus (MC29). Proc Nat Acad Sci USA 1982;79:6497–6501.
  17. Ellis RW, Defeo D, Shih TY, Gonda MA, Young HA, Tsuchida N, Lowy DR, Scolnick EM: The p21 src genes of Harvey and Kirsten sarcoma viruses originate from divergent members of a family of normal vertebrate genes. Nature 1981;292:506–511.

    External Resources

  18. Nudel U, Zakut R, Shani M, Neuman S, Levy A, Yaffe D: The nucleotide sequence of the rat cytoplasmic β-actin gene. Nucleic Acids Res 1981;11:1759–1771.
  19. Janssen JWG, Lyons L, Steenvoorden AC, Seliger H, Bartra CR: Concurrent mutations in two different ras genes in acute myelocytic leukemias. Nucleic Acids Res 1987;15:5669–5680.
  20. Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA: Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 1988;239:487–491.
  21. Oliva MR, Cabrera T, Esquivias J, Perez-Ayala M, Redondo M, Ruiz-Cabello F, Garrido F: K-ras mutations (codon 12) are not involved in down-regulation of MHC class-I genes in colon carcinomas. Int J Cancer 1990;146:426–431.
  22. Aznavoorian S, Murphy AN, Stetler-Stevenson WG, Liotta LA: Molecular aspects of tumor cell invasion and metastasis. Cancer 1993;71:1368–1383.
  23. Liu E, Hjelle B, Morgan R, Hecht F, Bishop JM: Mutations of the Kirsten-ras proto-oncogene in human preleukaemia. Nature 1987;300:186–188.
  24. Brodeur GM, Seeger RC, Schwab M, Varmus HE, Bishop JM: Amplification of N-myc in untreated human neuroblastoma correlated with advanced disease stage. Science 1984;244:1121–1124.
  25. Niwa O, Kamiya K, Furihata C, Nitta Y, Wang Z, Fan YJ, Ninomiya Y, Kotomura N, Numoto M, Kominami R: Association of minisatellite instability with c-myc amplification and K-ras mutation in methylcholanthrene-induced mouse sarcomas. Cancer Res 1995;55:5670–5676.

    External Resources

  26. Kozma L, Kiss I, Nagv A, Szakáll S, Ember I: Investigation of c-myc and K-ras amplification in renal clear cell adenocarcinoma. Cancer Lett 1997;111:127–131.

    External Resources

  27. Sekine I, Takami S, Guang SG, Yokose T, Kodama T, Nishiwaki Y, Kinoshita M, Matsumoto H, Ogura T, Nagai K: Role of epidermal growth factor receptor overexpression, K-ras point mutation and c-myc amplification in the carcinogenesis of non-small cell lung cancer. Oncol Rep 1998;5:351–354.

    External Resources

  28. Kretzner L, Blackwood EM, Eisenman RN: Myc and Max proteins possess distinct transcriptional activities. Nature 1992;359:426–429.
  29. Gaforio JJ, Pérez M, Algarra I, Mialdea MJ, Ljunggren HG, Garrido F: Differential mRNA levels of c-myc, c-fos and MHC class I in several clones of a murine fibrosarcoma. Int J Cancer 1991;49:906–910.
  30. Algarra I, Öhlén C, Pérez M, Ljunggren HG, Klein G, Garrrido F, Karre K: NK sensitivity and lung clearance of MHC-class-I-deficient cells within a heterogeneous fibrosarcoma. Int J Cancer 1989;44:675–680.
  31. Peltenburg LT, Steegenga WT, Krüse KM, Schrier PI. C-myc-induced natural killer cell sensitivity of human melanoma cells is reversed by HLA-B27 transfection. Eur J Immunol 1992;22:2737–2740.

    External Resources

  32. Algarra I, Pérez M, Gaforio JJ, Gasca F, Garrido F: In vivo activation of NK cells induces inhibition of lung colonization of H-2 positive and H-2 negative fibrosarcoma tumor clones. Clin Exp Metastasis 1994;13:31–36.
  33. Algarra I, Gonzalez A, Pérez M, Gaforio JJ, Garrido F: Effect of in vivo activation of natural killer (NK) cells by a tilorone analogue on the survival of mice injected intravenously with different experimental murine tumours. Clin Exp Immunol 1996;103:499–505.

    External Resources

  34. Algarra I, Gaforio JJ, Garrido A, Mialdea MJ, Pérez M, Garrido F: Heterogeneity of MHC-class-I antigens in clones of methylcholanthrene-induced tumors. Implications for local growth and metastasis. Int J Cancer Suppl 1991;6:73–81.

    External Resources

  35. Hanna N: Inhibition of experimental tumor metastasis by selective activation of natural killer cells. Cancer Res 1982;42:1337–1342.
  36. Roth C, Rochlitz C, Kourilsky P: Immune response against tumors. Adv Immunol 1994;57:281–351.
  37. Höglund P, Sundback J, Olsson-Alheim MY, Johansson M, Salcedo M, Öhlen C, Ljunggren HG, Sentman CL, Kärre K: Host MHC class I gene control of NK-cell specificity in the mouse. Immunol Rev 1997;155:11–28.

    External Resources

  38. Pedrinaci S, Algarra I, Garcia Lora A, Gaforio JJ, Pérez M, Garrido F: Selective upregulation of MHC class I expression in metastatic colonies derived from tumor clones of a murine fibrosarcoma. Int J Clin Lab Res, in press.
  39. Garrido F, Ruiz-Cabello F, Cabrera T, Pérez-Villar JJ, López-Botet M, Duggan-Keen M, Stern PL: Implications for immunosurveillance of altered HLA class I phenotypes in human tumours. Immunol Today 1997;18:89–95.

    External Resources

  40. Thorgeirsson UP, Turpeenniemi-Hujanaen T, Williams JE, Westin EH, Heilman CA, Talmadge JE, Liotta LA: NIH/3T3 cells transfected with human tumor DNA containing activated ras oncogenes express the metastatic phenotype in nude mice. Mol Cell Biol 1985;5:259–262.
  41. Greig RG, Koestler TP, Trainer DL, Corwin SP, Miles L, Kline T, Sweet R, Yokoyama S, Poste G: Tumorigenic and metastatic properties of ‘normal’ and ras-transfected NIH/3T3 cells. Proc Natl Acad Sci USA 1985;82:3698–3701.

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