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Low-dose ionizing radiation: induction of differential intracellular signalling possibly affecting intercellular communication

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Abstract

Given the complexity of the carcinogenic process and the lack of any mechanistic understanding of how ionizing radiation at low-level exposures affects the multistage, multimechanism processes of carcinogenesis, it is imperative that concepts and paradigms be reexamined when extrapolating from high dose to low dose. Any health effect directly linked to low-dose radiation exposure must have molecular/biochemical and biological bases. On the other hand, demonstrating some molecular/biochemical or cellular effect, using surrogate systems for the human being, does not necessarily imply a corresponding health effect. Given the general acceptance of an extrapolated LNT model, our current understanding of carcinogenesis cries out for a resolution of a real problem. How can a low-level acute, or even a chronic, exposure of ionizing radiation bring about all the different mechanisms (mutagenic, cytotoxic, and epigenetic) and genotypic/phenotypic changes needed to convert normal cells to an invasive, malignant cell, given all the protective, repair, and suppressive systems known to exist in the human body? Until recently, the prevailing paradigm that ionizing radiation brings about cancer primarily by DNA damage and its conversion to gene and chromosomal mutations, drove our interpretation of radiation carcinogenesis. Today, our knowledge includes the facts both that epigenetic events play a major role in carcinogenesis and that low-dose radiation can also induce epigenetic events in and between cells in tissues. This challenges any simple extrapolation of the LNT model. Although a recent delineation of “hallmarks” of the cancer process has helped to focus on how ionizing radiation might contribute to the induction of cancers, several other hallmarks, previously ignored—namely, the stem cells in tissues as targets for carcinogenesis and the role of cell–cell communication processes in modulating the radiation effects on the target cell—must be considered, particularly for the adaptive response, bystander effects, and genomic instability phenomena.

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References

  1. Tumars (2003) It’s not just mutations anymore: stroma tumor cells spur growth. BioMedNet News Weekly

  2. Potter VR (1978) Phenotypic diversity in experimental hepatomas: the concept of partially blocked ontogeny. Br J Cancer 38:1–23

    Google Scholar 

  3. Bonner WM (2003) Low-dose radiation: thresholds, bystander effects, and adaptive responses. Proc Natl Acad Sci U S A 100:4973–4975

    Google Scholar 

  4. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  CAS  PubMed  Google Scholar 

  5. Trosko JE (2001) Commentary: is the concept of “tumor promotion” a useful paradigm? Mol Carcinog 30:131–137

    Google Scholar 

  6. Trosko JE, Chang CC (1988) Nongenotoxic mechanisms in carcinogenesis: role of inhibited intercellular communication. In: Hart RW, Hoerger FD (eds) Banbury Report 31: Carcinogen risk assessment: new directions in the quantitative and qualitative assessment aspects. Cold Spring Harbor Laboratory, Cold Spring Harbor, pp 139–170

    Google Scholar 

  7. Pitot HC, Dragan YP (1991) Facts and theories concerning the mechanisms of carcinogenesis. FASEB J 5:2280–2286

    Google Scholar 

  8. Weinstein IB, Gattoni CS, Kirschmeier P, Lambert M, Hsiao W, Backer J, Jeffrey A (1984) Multistage carcinogenesis involves multiple genes and multiple mechanisms. J Cell Physiol Suppl 3:127–137

    Google Scholar 

  9. Fialkow PJ (1979) Clonal origin of human tumors. Annu Rev Med 30:135–143

    Google Scholar 

  10. Markert CL (1968) Neoplasia: a disease of cell differentiation. Cancer Res 28:1908–1914

    Google Scholar 

  11. Till JE (1982) Stem cells in differentiation and neoplasia. J Cell Physiol Suppl 1:3–11

    Google Scholar 

  12. Sell S (1993) Cellular origin of cancer: dedifferentiation or stem cell maturation arrest? Environ Health Perspect 101[Suppl 5]:15–26

    Google Scholar 

  13. Chang CC, Trosko JE, El-Fouly MH, Gibson DR, D’Ambrosio SM (1987) Contact insensitivity of a subpopulation of normal human fetal kidney epithelial cells and of human carcinoma cell lines. Cancer Res 47:1634–1645

    Google Scholar 

  14. Kao CY, Nomata K, Oakley CS, Welsch CW, Chang CC (1995) Two types of normal human breast epithelial cells derived from reduction mammoplasty: phenotypic characterization and response to SV40 transfection. Carcinogenesis 16:531–538

    Google Scholar 

  15. Sun W, Kang KS, Morita I, Trosko JE, Chang CC (1999) High susceptibility of a human breast epithelial cell type with stem cell characteristics to telomerase activation and immortalization. Cancer Res 59:6118–6123

    Google Scholar 

  16. Kang KS, Morita I, Cruz A, Jeon YJ, Trosko JE, Chang CC (1997) Expression of estrogen receptors in a normal human breast epithelial cell type with luminal and stem cell characteristics and its neoplastically transformed cell lines. Carcinogenesis 18:251–257

    Google Scholar 

  17. Kao CY, Oakley CS, Welsch CW, Chang CC (1997) Growth requirements and neoplastic transformation of two types of normal human breast epithelial cells derived from reduction mammoplasty. In Vitro Cell Dev Biol Anim 33:282–288

    Google Scholar 

  18. Tai MH, Madhukar BV, Olson LK, Linning KD, VanCamp L, Tsao MS, Trosko JE (2003) Characterization of gap junctional intercellular communication in immortalized human ductal epithelial cells with stem cell characteristics. Pancreas 26:e18–e26

    Google Scholar 

  19. Matic M, Evans WH, Brink PR, Simon M (2002) Epidermal stem cells do not communicate through gap junctions. J Invest Dermatol 118:110–116

    Google Scholar 

  20. Matic M, Petrov IN, Chen S, Wang C, Dimitrijevich SD, Wolosin JM (1997) Stem cells of the corneal epithelium lack connexins and metabolite transfer capacity. Differentiation 61:251–260

    Google Scholar 

  21. Prockop DJ (1998) Marrow stromal cells as stem cells for continual renewal of nonhematopoietic tissues and as potential vectors for gene therapy. J Cell Biochem 30:284–285

    Google Scholar 

  22. Land H, Parada LF, Weinberg RA (1983) Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature 304:596–602

    Google Scholar 

  23. Chang CC, Sun W, Cruz A, Saitoh M, Tai MH, Trosko JE (2001) A human breast epithelial cell type with stem cell characteristics as target cells for carcinogenesis. Radiat Res 155:201–207

    Google Scholar 

  24. Al Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100:3983–3988

    Google Scholar 

  25. Dick JE (2003) Breast cancer stem cells revealed. Proc Natl Acad Sci U S A 100:3547–3549

    Google Scholar 

  26. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828

    Google Scholar 

  27. Loewenstein WR (1979) Junctional intercellular communication and the control of growth. Biochim Biophys Acta 560:1–65

    Google Scholar 

  28. Yotti LP, Chang CC, Trosko JE (1979) Elimination of metabolic cooperation in Chinese hamster cells by a tumor promoter. Science 206:1089–1091

    Google Scholar 

  29. Trosko JE, Ruch RJ (1998) Cell-cell communication in carcinogenesis. Front Biosci 3:208–236

    Google Scholar 

  30. King TJ, Lampe PD (2004) Mice deficient for the gap junction protein Connexin32 exhibit increased radiation-induced tumorigenesis associated with elevated mitogen-activated protein kinase (p44/Erk1, p42/Erk2) activation. Carcinogenesis 25:669–680

    Google Scholar 

  31. Trosko JE (2004) Role of stem cells and cell-cell communication in radiation carcinogenesis: ignored concepts. In: Fliedner T, Dainiac N (eds) Radiation-induced multi-organ involvement and failure: a challenge for pathological, diagnostic and therapeutic approaches and research (in press)

  32. Edwards GO, Botchway SW, Hirst G, Wharton CW, Chipman JK, Meldrum RA (2004) Gap junction communication dynamics and bystander effects from ultrasoft X-rays. Br J Cancer 90:1450–1456

    Google Scholar 

  33. Shao C, Furusawa Y, Aoki M, Ando K (2003) Role of gap junctional intercellular communication in radiation-induced bystander effects in human fibroblasts. Radiat Res 160:318–323

    Google Scholar 

  34. Shao C, Furusawa Y, Kobayashi Y, Funayama T, Wada S (2003) Bystander effect induced by counted high-LET particles in confluent human fibroblasts: a mechanistic study. FASEB J 17:1422–1427

    Google Scholar 

  35. Azzam EI, de Toledo SM, Little JB (2003) Expression of CONNEXIN43 is highly sensitive to ionizing radiation and other environmental stresses. Cancer Res 63:7128–7135

    Google Scholar 

  36. Snyder AR (2004) Review of radiation-induced bystander effects. Hum Exp Toxicol 23:87–89

    Google Scholar 

  37. Wright EG (2004) Commentary on radiation-induced bystander effects. Hum Exp Toxicol 23:91–94

    Google Scholar 

  38. Wang B, Ohyama H, Shang Y, Fujita K, Tanaka K, Nakajima T, Aizawa S, Yukawa O, Hayata I (2004) Adaptive response in embryogenesis, IV: protective and detrimental bystander effects induced by X radiation in cultured limb bud cells of fetal mice. Radiat Res 161: 9–16

    Google Scholar 

  39. Mitchell SA, Randers-Pehrson G, Brenner DJ, Hall EJ (2004) The bystander response in C3H 10T1/2 cells: the influence of cell-to-cell contact. Radiat Res 161:397–401

    Google Scholar 

  40. Trosko JE (1995) Epigenetics biomarkers: potentials and limitations. In: Mendelsohn ML, Peeters JP, Normandy MJ (eds) Biomarkers and occupational health. Joseph Henry, Washington, DC, pp 264–274

    Google Scholar 

  41. Jones L (2001) Stem cells: so what’s in a niche? Curr Biol 11:R484–R486

    Google Scholar 

  42. Barcellos-Hoff MH, Brooks AL (2001) Extracellular signaling through the microenvironment: a hypothesis relating carcinogenesis, bystander effects, and genomic instability. Radiat Res 156:618–627

    Google Scholar 

  43. Trosko JE (1995) Biomarkers for low-level exposure causing epigenetic responses in stem cells. Stem Cells 13[Suppl 1]:231–239

    Google Scholar 

  44. Feinendegen LE, Loken MK, Booz J, Muhlensiepen H, Sondhaus CA, Bond VP (1995) Cellular mechanisms of protection and repair induced by radiation exposure and their consequences for cell system responses. Stem Cells 13:7–20

    Google Scholar 

  45. Trosko JE (1994) Radiation-induced carcinogenesis: paradigm consideration. In: Calabrese EJ (ed) Biological effects of low level exposures. CRC, Boca Raton, pp 205–241

    Google Scholar 

  46. Stuhlmann D, Ale-Agha N, Reinehr R, Steinbrenner H, Ramos MC, Sies H, Brenneisen P (2003) Modulation of homologous gap junctional intercellular communication of human dermal fibroblasts via a paracrine factor(s) generated by squamous tumor cells. Carcinogenesis 24:1737–1748

    Google Scholar 

  47. Trosko JE (1998) Radiation, signal transduction, and modulation of intercellular communication. In: Peterson LE, Abrahamson S (eds) Effects of ionizing radiation. Joseph Henry, Washington, DC, pp 177–192

    Google Scholar 

  48. Upham BL, Wagner JG (2001) Toxicant-induced oxidative stress in cancer. Toxicol Sci 64:1–3

    Google Scholar 

  49. Potten CS, Merritt A, Hickman J, Hall P, Faranda A (1994) Characterization of radiation-induced apoptosis in the small intestine and its biological implications. Int J Radiat Biol 65:71–78

    Google Scholar 

  50. UNSCEAR (2000) Effects at low radiation doses. United Nations Scientific Committee on the Effects of Atomic Radiation. United Nations, New York

  51. Trosko JE, Chang CC (2003) Hallmarks of radiation carcinogenesis: ignored concepts. In: Shibata Y, Yamashita S, Watanabe M, Tomonaga M (eds) Radiation and humankind. International Congress Series, No. 1258. Elsevier, Amsterdam, pp 31–36

  52. Trosko JE, Chang CC (2001) Role of stem cells and gap junctional intercellular communication in human carcinogenesis. Radiat Res 155:175–180

    Google Scholar 

  53. Trosko JE (2003) The role of stem cells and gap junctional intercellular communication in carcinogenesis. J Biochem Mol Biol 36:43–48

    Google Scholar 

  54. Martindale JL, Holbrook NJ (2002) Cellular response to oxidative stress: signaling for suicide and survival. J Cell Physiol 192:1–15

    Google Scholar 

  55. Benhar M, Engelberg D, Levitzki A (2002) ROS, stress-activated kinases and stress signaling in cancer. Embo Rep 3:420–425

    Google Scholar 

  56. Trosko JE, Chang CC, Madhukar BV (1990) Modulation of intercellular communication during radiation and chemical carcinogenesis. Radiat Res 123:241–251

    Google Scholar 

  57. Trosko JE (1991) Possible role of intercellular communication in the modulation of the biological response to radiation. Yokohama Med Bull 42:151–165

    Google Scholar 

  58. Morgan WF, Day JP, Kaplan MI, McGhee EM, Limoli CL (1996) Genomic instability induced by ionizing radiation. Radiat Res 146:247–258

    Google Scholar 

  59. Ullrich RL, Ponnaiya B (1998) Radiation-induced instability and its relation to radiation carcinogenesis. Int J Radiat Biol 74:747–754

    Google Scholar 

  60. Brenner DJ, Doll R, Goodhead DT, Hall EJ, Land CE, Little JB, Lubin JH, Preston DL, Preston RJ, Puskin JS, Ron E, Sachs RK, Samet JM, Setlow RB, Zaider M (2003) Cancer risks attributable to low doses of ionizing radiation: assessing what we really know. Proc Natl Acad Sci U S A 100:13761–13766

    Google Scholar 

  61. Thilly WG (2003) Have environmental mutagens caused oncomutations in people? Nat Genet 34:255–259

    Google Scholar 

  62. Trosko JE et al (1998) Gap junctions. In: Hertzberg EL, Johnson RG (eds) Gap junctions: modern cell biology, vol 7. Liss, New York, pp 435–448

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Authors and Affiliations

  1. Department of Pediatrics and Human Development, Michigan State University, 246 National Food Safety and Toxicology Center, East Lansing, MI, 48824, USA

    James E. Trosko, Chia-Cheng Chang, Brad L. Upham & Mei-Hui Tai

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  1. James E. Trosko
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  2. Chia-Cheng Chang
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  3. Brad L. Upham
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  4. Mei-Hui Tai
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Correspondence to James E. Trosko.

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Trosko, J.E., Chang, CC., Upham, B.L. et al. Low-dose ionizing radiation: induction of differential intracellular signalling possibly affecting intercellular communication. Radiat Environ Biophys 44, 3–9 (2005). https://doi.org/10.1007/s00411-005-0269-8

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