Skip to main content
SpringerLink
Log in

A role for genomic instability in cellular radioresistance?

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Summary

Inherent cellular radioresistance plays a critical role in the failure of radiotherapy. Although the consequences of radioresistance are well known, the molecular, biological, and cellular bases of radioresistance remain a mystery. We propose that genomic instability, the increased rate of acquisition of alterations in the mammalian genome, can directly modulate cells' sensitivity to radiation. In particular, destabilization of chromosomes occurring as a consequence of genomic instability may result in enhanced ‘plasticity of the genome’. This increased plasticity of the genome allows cells to better adapt to changes in local environment(s) during tumor progression, or improve cell survival following exposure to DNA damage encountered during radiotherapy protocols, thereby contributing to radioresistant cell populations found in tumors both before and after radiotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Weichselbaum RR, Dahlberg W, Little JB: Inherently radioresistant cells exist in some human tumors. Proc Natl Acad Sci USA 82: 4732–4735, 1985

    Google Scholar 

  2. Weichselbaum RR, Dahlberg W, Beckett M, Karrison T, Miller D, Clark J, Ervin TJ: Radiation-resistant and repairproficient human tumor cells may be associated with radiotherapy failure in head and neck-cancer patients. Proc Natl Acad Sci USA 83: 2684–2688, 1986

    Google Scholar 

  3. Weichselbaum RR, Beckett MA, Schwartz JL, Dritschilo A: Radioresistant tumor cells are present in head and neck carcinomas that recur after radiotherapy. Int J Radiat Oncol Biol Phys 15: 575–579, 1988

    Google Scholar 

  4. Cheng KC, Loeb LA: Genomic instability and tumor progression: mechanistic considerations. Adv Cancer Res 60: 121–156, 1993

    Google Scholar 

  5. Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 61: 759–767, 1990

    Google Scholar 

  6. Heim S, Mitelman F: Cancer cytogenetics. Alan R. Liss, Inc., New York 1987

    Google Scholar 

  7. Dracopoli NC, Houghton AN, Old LJ: Loss of polymorphic restriction fragments in malignant melanoma: Implications for tumor heterogeneity. Proc Natl Acad Sci USA 82: 1470–1474, 1985

    Google Scholar 

  8. Kaden DA, Bardwell L, Newmark P, Anisowicz A, Skopek TR, Sager R: High frequency of large spontaneous deletions of DNA in tumor-derived CHEF cells. Proc Natl Acad Sci USA 86: 2306–2310, 1989

    Google Scholar 

  9. Sager R, Gadi IK, Stephens L, Grabowy CT: Gene amplification: An example of accelerated evolution in tumorigenic cells. Proc Natl Acad Sci USA 82: 7015–7019, 1985

    Google Scholar 

  10. Tlsty TD, Margolin BH, Lum K: Differences in the rates of gene amplification in nontumorigenic and tumorigenic cell lines as measured by Luria-Delbruck fluctuation analysis. Proc Natl Acad Sci USA 86: 9441–9445, 1989

    Google Scholar 

  11. Aalltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen L, Mecklin J-P, Jarvinen H, Powell SM, Jien J, Hamilton SR, Petersen GM, Kinzler KW, Vogelstein B, de la Chapelle A: Clues to the pathogenesis of familial colorectal cancer. Science 260: 812–816, 1993

    Google Scholar 

  12. Thibodeau SN, Bren G, Schaid D: Microsatellite instability in cancer of the proximal colon. Science 260: 816–819, 1993

    Google Scholar 

  13. Reid BJ, Blount PL, Rubin CE, Levine DS, Haggitt RC, Rabinovitch PS: Flow-cytometric and histological progression to malignancy in Barrett's esophagus: prospective endoscopic surveillance of a cohort. Gastroenterology 102: 1212–1219, 1992

    Google Scholar 

  14. Alt FW, Dellems RE, Bertino JR, Schimke RT: Selective multiplication of dihydrofolate reductase genes in methotrexate-resistant variants of cultured murine cells. J Biol Chem 253: 1357–1370, 1978

    Google Scholar 

  15. Biedler JL, Meyers MB, Spengler BA: Homogeneously staining regions and double minute chromosomes, prevalent cytogenetic abnormalities of human neuroblastoma cells. Adv Cell Neurobiol 4: 267–307, 1983

    Google Scholar 

  16. Wahl GM: The importance of circular DNA in mammalian gene amplification. Cancer Res 49: 1333–1340, 1989

    Google Scholar 

  17. Hahn PJ: Molecular biology of double-minute chromosomes. BioEssays 15: 1–8, 1993

    Google Scholar 

  18. Ma C, Martin S, Trask B, Hamlin JL: Sister chromatid fusion initiates amplification of the dihydrofolate reductase gene in Chinese hamster cells. Genes Devel 7: 605–620, 1993

    Google Scholar 

  19. Smith KA, Gorman PA, Stark MB, Groves RP, Stark GR: Distinctive chromosomal structures are formed very early in the amplification of CAD genes in Syrian hamster cells. Cell 63: 1219–1227, 1990

    Google Scholar 

  20. Trask BJ, Hamlin JL: Early dihydrofolate reductase gene amplification events in CHO cells usually occur on the same chromosome arm as the original locus. Genes Devel 3: 1913–1925, 1989

    Google Scholar 

  21. Hahn P, Morgan WF, Painter RB: The role of acentric chromosome fragments in gene amplification. Somat Cell Mol Genet 13: 597–608, 1987

    Google Scholar 

  22. Ruiz J, Wahl GM: Chromosomal destabilization during gene amplification. Mol Cell Biol 10: 3056–3066, 1990

    Google Scholar 

  23. Hahn P, Nevaldine B, Morgan WF: X-ray induction of methotrexate resistance due to DHFR gene amplification. Somatic Cell Mol Genet 16: 413–423, 1990

    Google Scholar 

  24. Murnane JP, Kapp LN: A critical look at the association of human genetic syndromes with sensitivity to ionizing radiation. Sem Cancer Biol 4: 93–104, 1993

    Google Scholar 

  25. Gatti RA, Boder E, Vinters HV, Sparkes RS, Norman A, Lange K: Ataxia-telangiectasia: An interdisciplinary approach to pathogenesis. Medicine 70: 99–117, 1991

    Google Scholar 

  26. Bischoff FZ, Yim SO, Pathak S, Grant G, Siciliano MJ, Giovanella BC, Strong LC, Tainsky MA: Spontaneous abnormalities in normal fibroblasts from patients with Li-Fraumeni cancer syndrome: Aneuploidy and immortalization. Cancer Res 50: 7979–7984, 1990

    Google Scholar 

  27. Malkin D, Li FP, Strong LC, Fraumeni JF Jr, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA, Friend SH: Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas and other neoplasms. Science 250: 1233–1238, 1990

    Google Scholar 

  28. Srivastava S, Zou ZQ, Pirollo K, Blattner W, Chang EH: Germ-line transmission of a mutated p53 gene in a cancerprone family with Li-Fraumeni syndrome. Nature 348: 747–749, 1990

    Google Scholar 

  29. Livingstone LR, White A, Sprouse J, Livanos E, Jacks T, Tlsty TD: Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell 70: 923–935, 1992

    Google Scholar 

  30. Yin Y, Tainsky MA, Bischoff FZ, Strong LC, Wahl GM: Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cell 70: 937–948, 1992

    Google Scholar 

  31. Kuerbitz SJ, Plunkett BS, Walsh W, Kastan M: Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci USA 89: 7491–7495, 1992

    Google Scholar 

  32. Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW: Participation of p53 protein in the cellular response to DNA damage. Cancer Res 51: 6304–6311, 1991

    Google Scholar 

  33. Lane DP: p53, guardian of the genome. Nature 358: 15–16, 1992

    Google Scholar 

  34. Kastan MB, Zahn Q, el-Deiry WS, Carrier F, Jacks T, Walsh WV, Plunkett BS, Vogelstein B, Fornace AJ Jr: A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 71: 587–597, 1992

    Google Scholar 

  35. Lu X, Lane DP: Differential induction of transcriptionally active p53 following UV or ionizing radition: Defects in chromosome instability syndromes? Cell 75: 765–778, 1993

    Google Scholar 

  36. Painter RB: Cancer in ataxia-telangiectasia. Carcinogenesis 10: 355–361, 1985

    Google Scholar 

  37. Hartwell L: Defects in a cell cycle checkpoint may be responsible for the genomic instability of cancer cells. Cell 71: 543–546, 1992

    Google Scholar 

  38. Slichenmyer WJ, Nelson WG, Slebos RJ, Kastan MB: Loss of a p53-associated G1 checkpoint does not decrease cell survival following DNA damage. Cancer Res 4164-4168, 1993

  39. Brachman DG, Beckett M, Graves D, Haraf D, Vokes E, Weichselbaum RR: p53 mutation does not correlate with radiosensitivity in 24 head and neck cancer cell lines. Cancer Res 3667-3669, 1993

  40. Schwartz JL: The radiosensitivity of the chromosomes of the cells of human squamous cell carcinoma cell lines. Radiat Res 129: 96–101, 1992

    Google Scholar 

  41. Lane DP: A death in the life of p53. Nature 362: 786–787, 1993

    Google Scholar 

  42. Clarke AR, Purdie CA, Harrison DJ, Morris RG, Bird CC, Hooper ML, Wyllie AH: Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 362: 849–852, 1993

    Google Scholar 

  43. Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T: p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362: 847–849, 1993

    Google Scholar 

  44. Blackburn EH: Structure and function of telomeres. Nature 350: 569–573, 1991

    Google Scholar 

  45. Hastie ND, Allshire RC: Human telomeres: fusion and interstitial sites. Trends Genet 5: 326–331, 1989

    Google Scholar 

  46. Murnane JP, Sabatier L, Marder BA, Morgan WF: Telomere dynamics in an immortal human cell line. EMBO J 13: 4953–4962, 1994

    Google Scholar 

  47. Harley CB, Futcher AB, Greider CW: Telomeres shorten during ageing of human fibroblasts. Nature 345: 458–460, 1990

    Google Scholar 

  48. Hastie ND, Dempster M, Dunlop MG, Thompson AM, Green DK, Allshire RC: Telomere reduction in human colorectal carcinoma and with ageing. Nature 346: 866–868, 1990

    Google Scholar 

  49. Morin GB: The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats. Cell 59: 521–529, 1989

    Google Scholar 

  50. Counter CM, Avilion AA, LeFeuvre CE, Stewart NG, Greider CW, Harley CB, Bacchetti S: Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J 11: 1921–1929, 1992

    Google Scholar 

  51. Counter CM, Hirte HW, Bacchetti S, Harley CB: Telomerase activity in human ovarian carcinoma. Proc Natl Acad Sci USA 91: 2900–2904, 1994

    Google Scholar 

  52. Murnane JP, Yu L-C: Acquisition of telomere repeat sequences by transfected DNA integrated at the site of a chromosome break. Mol Cell Biol 13: 977–983, 1993

    Google Scholar 

  53. Day JP, Marder BA, Morgan WF: The telomere and its possible role in chromosome stabilization. Env Mol Mutagen 22: 245–249, 1993

    Google Scholar 

  54. Ward JF: DNA damage produced by ionizing radiation in mammalian cells: Identities, mechanisms of formation, and reparability. Prog Nucl Acids Mol Biol 35: 95–125, 1988

    Google Scholar 

  55. Phillips JW, Morgan WF: Restriction enzyme-induced DNA double-strand breaks as a model to study the mechanisms of chromosomal aberration formation.In: Dewey WC, Edington M, Fry RJM, Hall EJ, Whitmore GF (ed) Radiation research: a twentieth-century perspective. Academic Press, New York, 1992, pp 207–211

    Google Scholar 

  56. Jeggo PA: Studies on mammalian mutants defective in rejoining double-strand breaks in DNA. Mutat Res 239: 1–16, 1990

    Google Scholar 

  57. Phillips JW, Morgan WF: Illegitimate recombination induced by DNA double-strand breaks in a mammalian chromosome. Mol Cell Biol 14: 5794–5803, 1994

    Google Scholar 

  58. Carrano AV, Minkler J, Piluso D: On the fate of stable chromosomal aberrations. Mutat Res 30: 153–156, 1975

    Google Scholar 

  59. Hallahan DE, Virudachalam S, Sherman ML, Huberman E, Kufe DW, Weichselbaum RR: Tumor necrosis factor gene expression is mediated by protein kinase C following activation by ionizing radiation. Cancer Res 51: 4565–4569, 1991

    Google Scholar 

  60. Hallahan DE, Sukhatme VP, Sherman ML, Virudachalam S, Kufe D, Weichselbaum RR: Protein kinase C mediates x-ray inducibility of nuclear signal transducers EGR1 and JUN. Proc Natl Acad Sci USA 88: 2156–2160, 1991

    Google Scholar 

  61. Boothman DA, Bouvard I, Hughes EN: Identification and characterization of X-ray-induced proteins in human cells. Cancer Res 49: 2871–2878, 1989

    Google Scholar 

  62. Boothman DA, Meyers M, Fukunaga N, Lee SW: Isolation of x-ray-inducible transcripts from radioresistant human melanoma cells. Proc Natl Acad Sci USA 90: 7200–7204, 1993

    Google Scholar 

  63. Weichselbaum RR, Hallahan DE, Sukhatme V, Dritschilo A, Sherman ML, Kufe DW: Biological consequences of gene regulation after ionizing radiation exposure. J Nat Cancer Inst 83: 480–484, 1991

    Google Scholar 

  64. Chang WP, Little JB: Delayed reproductive death in X-irradiated Chinese hamster ovary cells. Int J Radiat Biol 60: 483–496, 1991

    Google Scholar 

  65. Chang WP, Little JB: Persistently elevated frequency of spontaneous mutations in progeny of CHO clones surviving x-irradiation: association with delayed reproductive death phenotype. Mutat Res 270: 191–199, 1992

    Google Scholar 

  66. Chang WP, Little JB: Delayed reproductive death as a dominant phenotype in cell clones surviving X-irradiation. Carcinogenesis 13: 923–928, 1992

    Google Scholar 

  67. Nias AHW, Gilbert CW, Lajtha LG, Lange CS: Clone-size analysis in the study of cell growth following single or during continuous irradiation. Int J Radiat Biol 9: 275–290, 1965

    Google Scholar 

  68. Seymour CB, Mothersill C, Alper T: High yields of lethal mutations in somatic mammalian cells that survive ionizing radiation. Int J Radiat Biol 50: 167–179, 1986

    Google Scholar 

  69. Sinclair WK: X-ray-induced heritable damage (small-colony formation) in cultured mammalian cells. Radiat Res 21: 584–611, 1964

    Google Scholar 

  70. Westra A, Barendsen GW: Proliferation characteristics of cultured mammalian cells after irradiation with sparsely and densely ionizing radiations. Int J Radiat Biol 11: 477–485, 1966

    Google Scholar 

  71. Mothersill C, Seymour C: The influence of lethal mutations on the quantification of radiation transformation frequencies. Int J Radiat Biol 51: 723–729, 1987

    Google Scholar 

  72. Brown DC, Trott KR: Clonal heterogeneity in the progeny of HeLa cells which survive X-irradiation. Int J Radiat Biol 66: 151–155, 1994

    Google Scholar 

  73. Mendonca MS, Antoniono RJ, Redpath JL: Delayed heritable damage and epigenetics in radiation-induced neoplastic transformation of human-hybrid cells. Radiat Res 134: 209–217, 1993

    Google Scholar 

  74. Holmberg K, Falt S, Johansson A, Lambert B: Clonal chromosome aberrations and genomic instability in X-irradiated human T-lymphocyte cultures. Mutat Res 286: 321–330, 1993

    Google Scholar 

  75. Kadhim MA, MacDonald DA, Goodhead DT, Lorimore SA, Marsden SJ, Wright EG: Transmission of chromosomal instability after plutonium alpha-particle irradiation. Nature (London) 355: 738–740, 1992

    Google Scholar 

  76. Marder BA, Morgan WF: Delayed chromosomal instability induced by DNA damage. Mol Cell Biol 13: 6667–6677, 1993

    Google Scholar 

  77. Martins MB, Sabatier L, Ricoul M, Pinton A, Dutrillaux B: Specific chromosome instability induced by heavy ions: a step towards transformation of human fibroblasts? Mutat Res 285: 229–237, 1993

    Google Scholar 

  78. Sabatier L, Dutrillaux B, Martin MB: Chromosome instability (Scientific Correspondence) Nature 357: 548, 1992

    Google Scholar 

  79. Schwartz JL, Rotmensch J, Giovanazzi S, Cohen MB, Weichselbaum RR: Faster repair of DNA double-strand breaks in radioresistant human tumor cells. Int J Radiat Oncol Biol Phys 15: 907–912, 1988

    Google Scholar 

  80. Schwartz JL, Vaughan ATM: Association among DNA/chromosome break rejoining rates, chromatin structure alterations, and radiation sensitivity in human tumor cell lines. Cancer Res 49: 5054–5057, 1989

    Google Scholar 

  81. Schwartz JL, Mustafi R, Beckett MA, Weichselbaum RR: Prediction of the radiation sensitivity of human squamous cell carcinoma cells using DNA filter elution. Radiat Res 123: 1–6, 1990

    Google Scholar 

  82. Schwartz JL, Mustafi R, Beckett MA, Czyzewski EA, Farhangi E, Grdina DJ, Rotmensch J, Weichselbaum RR: Radiation-induced DNA double-strand break frequencies in human squamous cell carcinoma cell lines of different radiation sensitivities. Int J Radiat Biol 59: 1341–1352, 1991

    Google Scholar 

  83. Schwartz JL: The radiosensitivity of the chromosomes of the cells of human squamous cell carcinoma cell lines. Radiat Res 129: 96–101, 1992

    Google Scholar 

  84. Pirollo KF, Garner R, Yuan SY, Li L, Blattner WA, Chang EH: raf involvement in the simultaneous genetic transfer of the radioresistant and transforming phenotypes. Int J Radiat Biol 55: 783–796, 1989

    Google Scholar 

  85. Alapetite C, Baroche C, Remvikos Y, Goubin G, Moustacchi E: Studies on the influence of the presence of an activated ras oncogene on thein vitro radiosensitivity of human mammary epithelial cells. Int J Radiat Biol 59: 385–396, 1991

    Google Scholar 

  86. Sklar MD: The ras oncogenes increase the intrinsic resistance of NIH 3T3 cells to ionizing radiation. Science 239: 646–647, 1988

    Google Scholar 

  87. Iliakis G, Metzger L, Muschel RJ, McKenna WG: Induction and repair of DNA double strand breaks in radiation-resistant cells obtained by transformation of primary rat embryo cells with the oncogenes H-ras andv-myc. Cancer Res 50: 6575–6579, 1990

    Google Scholar 

  88. Ling CC, Endlich B: Radioresistance induced by oncogenic transformation. Radiat Res 120: 267–279, 1989

    Google Scholar 

  89. McKenna WG, Weiss MC, Endlich B, Ling CC, Bakanauskas VJ, Kelsten ML, Muschel RJ: Synergistic effect of thev-myc oncogene with H-ras on radioresistance. Cancer Res 50: 97–102, 1990

    Google Scholar 

  90. Bishop JM: Molecular themes in oncogenesis. Cell 64: 235–248, 1991

    Google Scholar 

  91. Marshall CJ: Oncogenes and growth control. Cell 49: 723–725, 1987

    Google Scholar 

  92. Mitelman F: Catalogue of chromosomal aberrations in cancer. 4th Ed. Wiley-Liss, New York 1991

    Google Scholar 

  93. Solomon E, Borrow J, Goddard AD: Chromosome aberrations and cancer. Science 254: 1153–1160, 1991

    Google Scholar 

  94. Ray JH, German J: Sister chromatid exchange in the chromosome breakage syndromes.In: Sandberg AA (ed) Sister Chromatid Exchange. Alan R. Liss, Inc, New York, 1982, pp 533–577

    Google Scholar 

  95. Boothman DA, Wang M, Lee SW: Induction of tissue-type plasminogen activator by ionizing radiation in human malignant melanoma cells. Cancer Res 51: 5587–5595, 1991

    Google Scholar 

  96. Singh SP, Lavin MF: DNA-binding protein activated by gamma radiation in human cells. Mol Cell Biol 10: 5279–5285, 1990

    Google Scholar 

  97. Papathanasiou MA, Kerr NCK, Robbins JH, McBride OW, Alamo IJ, Barrett SF, Hickson ID, Fornace AJ Jr: Induction by ionizing radiation of the gadd45 gene in cultured human cells: Lack of mediation by protein kinase C. Mol Cell Biol 11: 1009–1016, 1991

    Google Scholar 

  98. Hallahan DE, Spriggs DR, Beckett MA, Kufe DW, Weichselbaum RR: Increased tumor necrosis factor α mRNA after cellular exposure to ionizing radiation. Proc Natl Acad Sci USA 86: 10104–10107, 1989

    Google Scholar 

  99. Sherman ML, Datta R, Hallahan DE, Weichselbaum RR, Kufe DW: Ionizing radiation regulates expression of the cjun protooncogene. Proc Natl Acad Sci USA 87: 5663–5666, 1990

    Google Scholar 

  100. Hall EJ: Radiobiology for the Radiologist. J.B. Lippincott Co., Philadelphia 1994

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Radiobiology and Environmental Health, University of California, Box 0750, 94143-0750, San Francisco, California, USA

    William F. Morgan & John P. Murnane

  2. Department of Radiation Oncology, University of California, Box 0750, 94143-0750, San Francisco, California, USA

    William F. Morgan

Authors
  1. William F. Morgan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John P. Murnane
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Morgan, W.F., Murnane, J.P. A role for genomic instability in cellular radioresistance?. Cancer Metast Rev 14, 49–58 (1995). https://doi.org/10.1007/BF00690211

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00690211

Key words

Search

Navigation