Abstract
Radiotherapy of tumours proximal to normal CNS structures is limited by the sensitivity of the normal tissue. Prior to the development of prophylactic strategies or treatment protocols a detailed understanding of the mechanisms of radiation induced CNS toxicity is mandatory. Histological analysis of irradiated CNS specimens defines possible target structures prior to a delineation of cellular and molecular mechanisms. Several lesions can be distinguished: Demyelination, proliferative and degenerative glial reactions, endothelial cell loss and capillary occlusion. All changes are likely to result from complex alterations within several functional CNS compartments. Thus, a single mechanism responsible cannot be separated. At least four factors contribute to the development of CNS toxicity: (1) damage to vessel structures; (2) deletion of oligodendrocyte-2 astrocyte progenitors (O-2A) and mature oligodendrocytes; (3) deletion of neural stem cell populations in the hippocampus, cerebellum and cortex; (4) generalized alterations of cytokine expression. Several underlying cellular and molecular mechanisms involved in radiation induced CNS toxicity have been identified. The article reviews the currently available data on the cellular and molecular basis of radiation induced CNS side effects. http://www.bjcancer.com © 2001 Cancer Research Campaign
Keywords: radiotherapy, CNS toxicity, molecular and cellular mechanisms
Full Text
The Full Text of this article is available as a PDF (74.0 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Adamson I. Y., Bowden D. H., Wyatt J. P. A pathway to pulmonary fibrosis: an ultrastructural study of mouse and rat following radiation to the whole body and hemithorax. Am J Pathol. 1970 Mar;58(3):481–498. [PMC free article] [PubMed] [Google Scholar]
- Belka C., Rudner J., Wesselborg S., Stepczynska A., Marini P., Lepple-Wienhues A., Faltin H., Bamberg M., Budach W., Schulze-Osthoff K. Differential role of caspase-8 and BID activation during radiation- and CD95-induced apoptosis. Oncogene. 2000 Feb 24;19(9):1181–1190. doi: 10.1038/sj.onc.1203401. [DOI] [PubMed] [Google Scholar]
- Bellinzona M., Gobbel G. T., Shinohara C., Fike J. R. Apoptosis is induced in the subependyma of young adult rats by ionizing irradiation. Neurosci Lett. 1996 Apr 26;208(3):163–166. doi: 10.1016/0304-3940(96)12572-6. [DOI] [PubMed] [Google Scholar]
- Brüstle O., Jones K. N., Learish R. D., Karram K., Choudhary K., Wiestler O. D., Duncan I. D., McKay R. D. Embryonic stem cell-derived glial precursors: a source of myelinating transplants. Science. 1999 Jul 30;285(5428):754–756. doi: 10.1126/science.285.5428.754. [DOI] [PubMed] [Google Scholar]
- Cammer W. Effects of TNFalpha on immature and mature oligodendrocytes and their progenitors in vitro. Brain Res. 2000 May 12;864(2):213–219. doi: 10.1016/s0006-8993(00)02178-8. [DOI] [PubMed] [Google Scholar]
- Chiang C. S., Mason K. A., Withers H. R., McBride W. H. Alteration in myelin-associated proteins following spinal cord irradiation in guinea pigs. Int J Radiat Oncol Biol Phys. 1992;24(5):929–937. doi: 10.1016/0360-3016(92)90477-y. [DOI] [PubMed] [Google Scholar]
- Chong M. J., Murray M. R., Gosink E. C., Russell H. R., Srinivasan A., Kapsetaki M., Korsmeyer S. J., McKinnon P. J. Atm and Bax cooperate in ionizing radiation-induced apoptosis in the central nervous system. Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):889–894. doi: 10.1073/pnas.97.2.889. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chow B. M., Li Y. Q., Wong C. S. Radiation-induced apoptosis in the adult central nervous system is p53-dependent. Cell Death Differ. 2000 Aug;7(8):712–720. doi: 10.1038/sj.cdd.4400704. [DOI] [PubMed] [Google Scholar]
- Doetsch F., García-Verdugo J. M., Alvarez-Buylla A. Regeneration of a germinal layer in the adult mammalian brain. Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11619–11624. doi: 10.1073/pnas.96.20.11619. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dowling P., Shang G., Raval S., Menonna J., Cook S., Husar W. Involvement of the CD95 (APO-1/Fas) receptor/ligand system in multiple sclerosis brain. J Exp Med. 1996 Oct 1;184(4):1513–1518. doi: 10.1084/jem.184.4.1513. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Eissner G., Kohlhuber F., Grell M., Ueffing M., Scheurich P., Hieke A., Multhoff G., Bornkamm G. W., Holler E. Critical involvement of transmembrane tumor necrosis factor-alpha in endothelial programmed cell death mediated by ionizing radiation and bacterial endotoxin. Blood. 1995 Dec 1;86(11):4184–4193. [PubMed] [Google Scholar]
- Ffrench-Constant C., Raff M. C. The oligodendrocyte-type-2 astrocyte cell lineage is specialized for myelination. 1986 Sep 25-Oct 1Nature. 323(6086):335–338. doi: 10.1038/323335a0. [DOI] [PubMed] [Google Scholar]
- Finco T. S., Baldwin A. S. Mechanistic aspects of NF-kappa B regulation: the emerging role of phosphorylation and proteolysis. Immunity. 1995 Sep;3(3):263–272. doi: 10.1016/1074-7613(95)90112-4. [DOI] [PubMed] [Google Scholar]
- Gobbel G. T., Bellinzona M., Vogt A. R., Gupta N., Fike J. R., Chan P. H. Response of postmitotic neurons to X-irradiation: implications for the role of DNA damage in neuronal apoptosis. J Neurosci. 1998 Jan 1;18(1):147–155. doi: 10.1523/JNEUROSCI.18-01-00147.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Groves A. K., Barnett S. C., Franklin R. J., Crang A. J., Mayer M., Blakemore W. F., Noble M. Repair of demyelinated lesions by transplantation of purified O-2A progenitor cells. Nature. 1993 Apr 1;362(6419):453–455. doi: 10.1038/362453a0. [DOI] [PubMed] [Google Scholar]
- Hallahan D. E., Spriggs D. R., Beckett M. A., Kufe D. W., Weichselbaum R. R. Increased tumor necrosis factor alpha mRNA after cellular exposure to ionizing radiation. Proc Natl Acad Sci U S A. 1989 Dec;86(24):10104–10107. doi: 10.1073/pnas.86.24.10104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hallahan D. E., Virudachalam S. Intercellular adhesion molecule 1 knockout abrogates radiation induced pulmonary inflammation. Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6432–6437. doi: 10.1073/pnas.94.12.6432. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Herzog K. H., Chong M. J., Kapsetaki M., Morgan J. I., McKinnon P. J. Requirement for Atm in ionizing radiation-induced cell death in the developing central nervous system. Science. 1998 May 15;280(5366):1089–1091. doi: 10.1126/science.280.5366.1089. [DOI] [PubMed] [Google Scholar]
- Hopewell J. W., Cavanagh J. B. Effects of X irradiation on the mitotic activity of the subependymal plate of rats. Br J Radiol. 1972 Jun;45(534):461–465. doi: 10.1259/0007-1285-45-534-461. [DOI] [PubMed] [Google Scholar]
- Hsu H., Shu H. B., Pan M. G., Goeddel D. V. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell. 1996 Jan 26;84(2):299–308. doi: 10.1016/s0092-8674(00)80984-8. [DOI] [PubMed] [Google Scholar]
- Ijichi A., Noel F., Sakuma S., Weil M. M., Tofilon P. J. Ex vivo gene delivery of platelet-derived growth factor increases 0-2A progenitors in adult rat spinal cord. Gene Ther. 1996 May;3(5):389–395. [PubMed] [Google Scholar]
- Lee F. S., Hagler J., Chen Z. J., Maniatis T. Activation of the IkappaB alpha kinase complex by MEKK1, a kinase of the JNK pathway. Cell. 1997 Jan 24;88(2):213–222. doi: 10.1016/s0092-8674(00)81842-5. [DOI] [PubMed] [Google Scholar]
- Li P., Nijhawan D., Budihardjo I., Srinivasula S. M., Ahmad M., Alnemri E. S., Wang X. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997 Nov 14;91(4):479–489. doi: 10.1016/s0092-8674(00)80434-1. [DOI] [PubMed] [Google Scholar]
- Li Y. Q., Jay V., Wong C. S. Oligodendrocytes in the adult rat spinal cord undergo radiation-induced apoptosis. Cancer Res. 1996 Dec 1;56(23):5417–5422. [PubMed] [Google Scholar]
- Mabie P. C., Mehler M. F., Marmur R., Papavasiliou A., Song Q., Kessler J. A. Bone morphogenetic proteins induce astroglial differentiation of oligodendroglial-astroglial progenitor cells. J Neurosci. 1997 Jun 1;17(11):4112–4120. doi: 10.1523/JNEUROSCI.17-11-04112.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Miyashita T., Reed J. C. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell. 1995 Jan 27;80(2):293–299. doi: 10.1016/0092-8674(95)90412-3. [DOI] [PubMed] [Google Scholar]
- Narita M., Shimizu S., Ito T., Chittenden T., Lutz R. J., Matsuda H., Tsujimoto Y. Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria. Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14681–14686. doi: 10.1073/pnas.95.25.14681. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Noble M., Murray K., Stroobant P., Waterfield M. D., Riddle P. Platelet-derived growth factor promotes division and motility and inhibits premature differentiation of the oligodendrocyte/type-2 astrocyte progenitor cell. Nature. 1988 Jun 9;333(6173):560–562. doi: 10.1038/333560a0. [DOI] [PubMed] [Google Scholar]
- Peissner W., Kocher M., Treuer H., Gillardon F. Ionizing radiation-induced apoptosis of proliferating stem cells in the dentate gyrus of the adult rat hippocampus. Brain Res Mol Brain Res. 1999 Jul 23;71(1):61–68. doi: 10.1016/s0169-328x(99)00170-9. [DOI] [PubMed] [Google Scholar]
- Peña L. A., Fuks Z., Kolesnick R. N. Radiation-induced apoptosis of endothelial cells in the murine central nervous system: protection by fibroblast growth factor and sphingomyelinase deficiency. Cancer Res. 2000 Jan 15;60(2):321–327. [PubMed] [Google Scholar]
- Phillips T. L. An ultrastructural study of the development of radiation injury in the lung. Radiology. 1966 Jul;87(1):49–54. doi: 10.1148/87.1.49. [DOI] [PubMed] [Google Scholar]
- Quarmby S., Kumar P., Kumar S. Radiation-induced normal tissue injury: role of adhesion molecules in leukocyte-endothelial cell interactions. Int J Cancer. 1999 Jul 30;82(3):385–395. doi: 10.1002/(sici)1097-0215(19990730)82:3<385::aid-ijc12>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
- Raff M. C., Lillien L. E., Richardson W. D., Burne J. F., Noble M. D. Platelet-derived growth factor from astrocytes drives the clock that times oligodendrocyte development in culture. Nature. 1988 Jun 9;333(6173):562–565. doi: 10.1038/333562a0. [DOI] [PubMed] [Google Scholar]
- Raff M. C., Miller R. H., Noble M. A glial progenitor cell that develops in vitro into an astrocyte or an oligodendrocyte depending on culture medium. Nature. 1983 Jun 2;303(5916):390–396. doi: 10.1038/303390a0. [DOI] [PubMed] [Google Scholar]
- Raju U., Gumin G. J., Tofilon P. J. Radiation-induced transcription factor activation in the rat cerebral cortex. Int J Radiat Biol. 2000 Aug;76(8):1045–1053. doi: 10.1080/09553000050111514. [DOI] [PubMed] [Google Scholar]
- Schultheiss T. E., Kun L. E., Ang K. K., Stephens L. C. Radiation response of the central nervous system. Int J Radiat Oncol Biol Phys. 1995 Mar 30;31(5):1093–1112. doi: 10.1016/0360-3016(94)00655-5. [DOI] [PubMed] [Google Scholar]
- Susin S. A., Lorenzo H. K., Zamzami N., Marzo I., Snow B. E., Brothers G. M., Mangion J., Jacotot E., Costantini P., Loeffler M. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature. 1999 Feb 4;397(6718):441–446. doi: 10.1038/17135. [DOI] [PubMed] [Google Scholar]
- Sánchez I., Hughes R. T., Mayer B. J., Yee K., Woodgett J. R., Avruch J., Kyriakis J. M., Zon L. I. Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun. Nature. 1994 Dec 22;372(6508):794–798. doi: 10.1038/372794a0. [DOI] [PubMed] [Google Scholar]
- Tada E., Yang C., Gobbel G. T., Lamborn K. R., Fike J. R. Long-term impairment of subependymal repopulation following damage by ionizing irradiation. Exp Neurol. 1999 Nov;160(1):66–77. doi: 10.1006/exnr.1999.7172. [DOI] [PubMed] [Google Scholar]
- Verheij M., Bose R., Lin X. H., Yao B., Jarvis W. D., Grant S., Birrer M. J., Szabo E., Zon L. I., Kyriakis J. M. Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature. 1996 Mar 7;380(6569):75–79. doi: 10.1038/380075a0. [DOI] [PubMed] [Google Scholar]
- Verheij M., Dewit L. G., Boomgaard M. N., Brinkman H. J., van Mourik J. A. Ionizing radiation enhances platelet adhesion to the extracellular matrix of human endothelial cells by an increase in the release of von Willebrand factor. Radiat Res. 1994 Feb;137(2):202–207. [PubMed] [Google Scholar]
- Vrdoljak E., Bill C. A., Stephens L. C., van der Kogel A. J., Ang K. K., Tofilon P. J. Radiation-induced apoptosis of oligodendrocytes in vitro. Int J Radiat Biol. 1992 Oct;62(4):475–480. doi: 10.1080/09553009214552361. [DOI] [PubMed] [Google Scholar]
- Zollinger H. U. Die Strahlenvasculopathie. Pathol Eur. 1970;5(2):145–163. [PubMed] [Google Scholar]
- van der Maazen R. W., Kleiboer B. J., Verhagen I., van der Kogel A. J. Irradiation in vitro discriminates between different O-2A progenitor cell subpopulations in the perinatal central nervous system of rats. Radiat Res. 1991 Oct;128(1):64–72. [PubMed] [Google Scholar]
- van der Maazen R. W., Verhagen I., Kleiboer B. J., van der Kogel A. J. Radiosensitivity of glial progenitor cells of the perinatal and adult rat optic nerve studied by an in vitro clonogenic assay. Radiother Oncol. 1991 Apr;20(4):258–264. doi: 10.1016/0167-8140(91)90125-z. [DOI] [PubMed] [Google Scholar]