Radiation induced bystander effect: mechanisms and potential clinical reflections

Abstract

A long held dogma in radiation biology has been that the effects of ionizing radiation arise only in the directly irradiated cells, and it was presumed that no effect would be expected in cells whose nuclei are spared from ionizing radiation. However, in the past twenty years, it has been suggested that irradiated cells are capable of production and secretion of signals to the neighboring unirradiated cells resulting in damage to these cells. This new challenging phenomenon is termed “the bystander effect”. Bystander effect can be reported in both cytoplasmic and nuclear irradiation in various cell types. Although the exact mechanisms of bystander effect production is not clearly defined yet, intercellular communication via gap junctions and lipid rafts, and secreted paracrine and endocrine soluble factors are potential suggested mechanisms. By this review article it has been aimed to summarize these mechanisms and the clinical reflections of bystander effect.

Keywords

• Bystander Effect,Cell Communication,Linear Energy Transfer,Radiation Effects

Radyoterapiye bağlı “bystander” etki: Oluşum mekanizmaları ve potansiyel klinik yansımalar

Öz

Günümüzde, genel radyobiyoloji anlayışına bir yenilik olarak, radyasyona maruz kalmamış komşu veya uzak hücre gruplarında da radyasyona maruz kalmış olanlara benzer biyolojik etkilerin görüldüğüne dair giderek artan miktarda kanıt oluşmaya başlamıştır. Bystander etki olarak adlandırılan bu etkiler deneysel olarak geniş bir hücre grubunda çekirdek ve sitoplazma radyasyon maruziyeti sonrasında görülebilmektedir. Bystander e tki sonucunda sağlam hücre gruplarında da bazı önemli genetik değişiklikler söz konusu olduğundan bu etkilerin karsinogenez açısından önemi de cevap bekleyen sorulardandır. Bystander etki oluşum mekanizmaları tam olarak bilinmese de hücre zarında bulunan gap junction'lar ve lipid boşlukların yanı sıra radyasyona maruz kalmış hücreler tarafından salınan parakrin ve endokrin faktörlerin rolü üzerinde durulmaktadır. Bu yazıda radyobiyolojinin yeni bir alanı olan bystander etkinin temel oluşum mekanizmalarından potansiyel klinik uygulamalarına kadar olan yeni literatür bilgilerinin özetlenmesi amaçlandı.

Anahtar Kelimeler

• Bystander etki/radyasyon etkisi, hücreler arası iletişim/radyasyon etkisi, lineer enerji transferi

References

1. 1. Nagasawa H, Little JB. Induction of sister chromatid exchanges by extremely low doses of alpha-particles. Cancer Res 1992;52(22):6394-6.
2. 2. Snyder AR. Review of radiation-induced bystander effects. Hum Exp Toxicol 2004;23(2):87-9.
3. 3. Deshpande A, Goodwin EH, Bailey SM, Marrone BL, Lehnert BE. Alpha-particle-induced sister chromatid exchange in normal human lung fibroblasts: evidence for an extranuclear target. Radiat Res 1996;145(3):260-7.
4. 4. Lorimore SA, Kadhim MA, Pocock DA, Papworth D, Stevens DL, Goodhead DT, et al. Chromosomal instability in the descendants of unirradiated surviving cells after alpha-particle irradiation. Proc Natl Acad Sci U S A 1998;95(10):5730-3.
5. 5. Mothersill C, Seymour C. Medium from irradiated human epithelial cells but not human fibroblasts reduces the clonogenic survival of unirradiated cells. Int J Radiat Biol 1997;71(4):421-7.
6. 6. Mothersill C, Seymour CB. Cell-cell contact during gamma irradiation is not required to induce a bystander effect in normal human keratinocytes: evidence for release during irradiation of a signal controlling survival into the medium. Radiat Res 1998;149(3):256-62.
7. 7. Seymour CB, Mothersill C. Delayed expression of lethal mutations and genomic instability in the progeny of human epithelial cells that survived in a bystander-killing environment. Radiat Oncol Investig 1997;5(3):106-10.
8. 8. Azzam EI, de Toledo SM, Gooding T, Little JB. Intercellular communication is involved in the bystander regulation of gene expression in human cells exposed to very low fluences of alpha particles. Radiat Res 1998;150(5):497-504.

9. 9. Mothersill C, Seymour C. Radiation-induced bystander effects: past history and future directions. Radiat Res 2001 Jun;155(6):759-67.
10. 10. Hamada N, Matsumoto H, Hara T, Kobayashi Y. Intercellular and intracellular signaling pathways mediating ionizing radiation-induced bystander effects. J Radiat Res (Tokyo) 2007;48(2):87-95.
11. 11. Shao C, Furusawa Y, Kobayashi Y, Funayama T, Wada S. Bystander effect induced by counted highLET particles in confluent human fibroblasts: a mechanistic study. FASEB J 2003;17(11):1422-7.
12. 12. Zhou H, Suzuki M, Gillispie J, Randers-Pehrson G, Hei TK. Cytoplasmic irradiation induced bystander mutagenesis. Radiat Res 2006;166:689.
13. 13. Zhou H, Suzuki M, Randers-Pehrson G, Vannais D, Chen G, Trosko JE, et al. Radiation risk to low fluences of alpha particles may be greater than we thought. Proc Natl Acad Sci U S A 2001;98(25):14410-5.
14. 14. Hu B, Wu L, Han W, Zhang L, Chen S, Xu A, et al. The time and spatial effects of bystander response in mammalian cells induced by low dose radiation. Carcinogenesis 2006;27(2):245-51.
15. 15.Burdak-Rothkamm S, Short SC, Folkard M, Rothkamm K, Prise KM. ATR-dependent radiationinduced gamma H2AX foci in bystander primary human astrocytes and glioma cells. Oncogene 2007;26(7):993-1002.
16. 16.Bishayee A, Hill HZ, Stein D, Rao DV, Howell RW. Free radical-initiated and gap junction-mediated bystander effect due to nonuniform distribution of incorporated radioactivity in a three-dimensional tissue culture model. Radiat Res 2001;155(2):335-44.
17. 17. Koyama S, Kodama S, Suzuki K, Matsumoto T, Miyazaki T, Watanabe M. Radiation-induced longlived radicals which cause mutation and transformation. Mutat Res 1998;421(1):45-54.
18. 18. Kumagai J, Masui K, Itagaki Y, Shiotani M, Kodama S, Watanabe M, et al. Long-lived mutagenic radicals induced in mammalian cells by ionizing radiation are mainly localized to proteins. Radiat Res 2003;160(1):95-102.
19. 19. Munro S. Lipid rafts: elusive or illusive? Cell 2003;115(4):377-88. 20. Nagasawa H, Cremesti A, Kolesnick R, Fuks Z, Little JB. Involvement of membrane signaling in the bystander effect in irradiated cells. Cancer Res 2002;62(9):2531-4.
20. 21. Shao C, Folkard M, Michael BD, Prise KM. Targeted cytoplasmic irradiation induces bystander responses. Proc Natl Acad Sci U S A 2004;101(37):13495-500.
21. 22. Hollowell JG Jr, Littlefield LG. Chromosome damage induced by plasma of x-rayed patients: an indirect e ffect of x-ray. Proc Soc Exp Biol Med 1968;129(1):240-4.
22. 23. Emerit I. Reactive oxygen species, chromosome mutation, and cancer: possible role of clastogenic factors in carcinogenesis. Free Radic Biol Med 1994;16(1):99-109.
23. 24. Narayanan PK, LaRue KE, Goodwin EH, Lehnert BE. Alpha particles induce the production of interleukin-8 by human cells. Radiat Res 1999;152(1):57-63.
24. 25.Barcellos-Hoff MH, Brooks AL. Extracellular signaling through the microenvironment: a hypothesis relating carcinogenesis, bystander effects, and genomic instability. Radiat Res 2001;156(5 Pt 2):618-27.
25. 26. Kroemer G.The proto-oncogene Bcl-2 and its role in regulating apoptosis. Nat Med 1997;3(6):614-20.
26. 27. Khan MA, Hill RP, Van Dyk J. Partial volume rat lung irradiation: an evaluation of early DNA damage. Int J Radiat Oncol Biol Phys 1998;40(2):467-76.
27. 28. Wu LJ, Randers-Pehrson G, Xu A, Waldren CA, Geard CR, Yu Z, et al. Targeted cytoplasmic irradiation with alpha particles induces mutations in mammalian cells. Proc Natl Acad Sci U S A 1999;96(9):4959-64.
28. 29. Zhou H, Randers-Pehrson G, Waldren CA, Vannais D, Hall EJ, Hei TK. Induction of a bystander mutagenic effect of alpha particles in mammalian cells. Proc Natl Acad Sci U S A 2000;97(5):2099-104.
29. 30. Nobler MP. The abscopal effect in malignant lymphoma and its relationship to lymphocyte circulation. Radiology 1969;93(2):410-2.
30. 31. Hahn EW, Feingold SM. Abscopal delay of embryonic development after prefertilization x-irradiation. Radiat Res 1973;53(2):267-72.
31. 32. Kaminski JM, Shinohara E, Summers JB, Niermann KJ, Morimoto A, Brousal J. The controversial abscopal effect. Cancer Treat Rev 2005;31(3):159-72.
32. 33. Park JY, Elshami AA, Amin K, Rizk N, Kaiser LR, Albelda SM. Retinoids augment the bystander effect in vitro and in vivo in herpes simplex virus thymidine kinase/ganciclovir-mediated gene therapy. Gene Ther 1997;4(9):909-17.
33. 34. Kunishige I, Samejima Y, Moriyama A, Saji F, Murata Y. cAMP stimulates the bystander effect in suicide gene therapy of human choriocarcinoma. Anticancer Res 1998;18(5A):3411-9.
34. 35.Robe PA, Princen F, Martin D, Malgrange B, Stevenaert A, Moonen G, et al. Pharmacological modulation of the bystander effect in the herpes simplex virus thymidine kinase/ganciclovir gene therapy system: effects of dibutyryl adenosine 3',5'-cyclic monophosphate, alpha-glycyrrhetinic acid, and cytosine arabinoside. Biochem Pharmacol 2000;60(2):241-9.
35. 36. Mesnil M, Piccoli C, Tiraby G, Willecke K, Yamasaki H. Bystander killing of cancer cells by herpes simplex virus thymidine kinase gene is mediated by connexins. Proc Natl Acad Sci U S A 1996;93(5):1831-5.
36. 37.Chen JK, Hu LJ, Wang D, Lamborn KR, Deen DF. Cytosine deaminase/5-fluorocytosine exposure induces bystander and radiosensitization effects in hypoxic glioblastoma cells in vitro. Int J Radiat Oncol Biol Phys 2007;67(5):1538-47.