Carcinogenesis Advance Access originally published online on July 30, 2009
Carcinogenesis 2009 30(11):1821-1831; doi:10.1093/carcin/bgp193
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Urinary bladder carcinogenesis induced by chronic exposure to persistent low-dose ionizing radiation after Chernobyl accident
Department of Pathology, Institute of Urology, Academy of Medical Sciences of Ukraine, 9a, Yu. Kotzubinsky Street, 04053 Kiev, Ukraine
1 Department of Pathology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan
2 Department of Urology, Institute of Urology, Academy of Medical Sciences of Ukraine, 9a, Yu. Kotzubinsky Street, 04053 Kiev, Ukraine
3 Present address: Japan Bioassay Research Center, 2445 Hirasawa, Hadano, Kanagawa 257-0015, Japan
* To whom correspondence should be addressed. Tel: +81 6 6645 3737; Fax: +81 6 6646 3093; Email: wani{at}med.osaka-cu.ac.jp
Urinary bladder urothelium as well as cells in the microenvironment of lamina propria (endothelial elements, fibroblasts and lymphocytes) demonstrate a number of responses to chronic persistent long-term, low-dose ionizing radiation (IR). Thus, oxidative stress occurs, accompanied by up-regulation of at least two signaling pathways (p38 mitogen-activated protein kinase and nuclear factor-
B cascades) and activation of growth factor receptors, in the bladder urothelium of people living in Cesium 137-contaminated areas of Ukraine, resulting in chronic inflammation and the development of proliferative atypical cystitis, so-called Chernobyl cystitis, which is considered a possible pre-neoplastic condition in humans. Furthermore, significant alterations in regulation of cell cycle transitions are associated with increased cell proliferation, along with up-regulated ubiquitination and sumoylation processes as well as inefficient DNA repair (base and nucleotide excision repair pathways) in the affected urothelium. The microenvironmental changes induced by chronic long-term, low-dose IR also appear to promote angiogenesis and remodeling of the extracellular matrix that could facilitate invasion as well as progression of pre-existing initiated cells to malignancy. Based on the available findings, new strategies have been developed for predicting and treatment of Chernobyl cystitis—a first step in urinary bladder carcinogenesis in humans.
Abbreviations: APE, apurinic/apyrimidinic endonuclease; BPH, benign prostate hypertrophy; CIS, carcinoma in situ; Cox2, cyclooxygenase 2; 137Cs, Cesium 137; EGFR, epidermal growth factor receptor; FGFR3, fibroblast growth factor receptor 3; iNOS, inducible NO synthase; IR, ionizing radiation; MAPK, mitogen-activated protein kinase; NF-B, nuclear factor-B; NO, nitric oxide; 8-OHdG, 8-hydroxydeoxyguanosine; PCNA, proliferating cell nuclear antigen; ROS, reactive oxygen species; SUMO, small Ub-related modifier; TGF, transforming growth factor; TGF-β1, TGF-beta1; Ub, ubiquitin; XPA, xeroderma pigmentosum A
Received March 26, 2009; revised July 28, 2009; accepted July 28, 2009.