Dose and spatial effects in long-distance radiation signaling in vivo: Implications for abscopal tumorigenesis

TitleDose and spatial effects in long-distance radiation signaling in vivo: Implications for abscopal tumorigenesis
Publication TypeArticolo su Rivista peer-reviewed
Year of Publication2013
AuthorsMancuso, Mariateresa, Giardullo Paola, Leonardi Simona, Pasquali Emanuela, Casciati Arianna, De Stefano Ilaria, Tanori Mirella, Pazzaglia Simonetta, and Saran Anna
JournalInternational Journal of Radiation Oncology Biology Physics
Keywordsanimal cell, animal experiment, animal model, animal tissue, Animals, Apoptosis, Apoptotic cell death, article, Brain, Bystander Effect, carcinogenesis, cell death, Cell Surface, Central nervous systems, Cerebellar Neoplasms, cerebellum, cerebellum injury, cerebellum tumor, controlled study, Dose-dependent, Dose-Response Relationship, Fully protected, gene mutation, Germ-Line Mutation, Harmful effects, in vivo study, In-vivo, Ionizing radiation, irradiation, Mammals, Mice, mouse, Mouse models, Neoplasms, Non-targeted, nonhuman, priority journal, protein Patched 1, Radiation, Radiation damage, radiation dose, radiation protection, radiation response, Radiation Tolerance, Radiation-Induced, radiosensitivity, Receptors, Shielding, Spatial dependence, Spatial effect, Time Factors, Tissue, Tumor development, Tumorigenesis, Whole-Body Irradiation, X rays

Purpose: To investigate the dose and spatial dependence of abscopal radiation effects occurring in vivo in the mouse, along with their tumorigenic potential in the central nervous system (CNS) of a radiosensitive mouse model. Methods and Materials: Patched1 (Ptch1)+/- mice, carrying a germ-line heterozygous inactivating mutation in the Ptch1 gene and uniquely susceptible to radiation damage in neonatal cerebellum, were exposed directly to ionizing radiation (1, 2, or 3 Gy of x-rays) or treated in a variety of partial-body irradiation protocols, in which the animals' head was fully protected by suitable lead cylinders while the rest of the body was exposed to x-rays in full or in part. Apoptotic cell death was measured in directly irradiated and shielded cerebellum shortly after irradiation, and tumor development was monitored in lifetime groups. The same endpoints were measured using different shielding geometries in mice irradiated with 3 or 10 Gy of x-rays. Results: Although dose-dependent cell death was observed in off-target cerebellum for all doses and shielding conditions tested, a conspicuous lack of abscopal response for CNS tumorigenesis was evident at the lowest dose of 1 Gy. By changing the amount of exposed body volume, the shielding geometry could also significantly modulate tumorigenesis depending on dose. Conclusions: We conclude that interplay between radiation dose and exposed tissue volume plays a critical role in nontargeted effects occurring in mouse CNS under conditions relevant to humans. These findings may help understanding the mechanisms of long-range radiation signaling in harmful effects, including carcinogenesis, occurring in off-target tissues. © 2013 Elsevier Inc. All rights reserved.


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