Journal Mobile Options
Table of Contents
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.
To view the fulltext, log in and/or choose pay-per-view option

Individual Users: Register with Karger Login Information

Please create your User ID & Password





Contact Information











I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in

Abstract

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.

Copyright © 2000 S. Karger AG, Basel



Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  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.


Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50