title: Dose and spatial effects in long-distance radiation signaling in vivo: implications for abscopal tumorigenesis.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA) Centro Ricerche (CR) Casaccia, Rome, Italy. mariateresa.mancuso@enea.it
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Mancuso
authors.forename: Paola
authors.initials: P
authors.lastname: Giardullo
authors.forename: Simona
authors.initials: S
authors.lastname: Leonardi
authors.forename: Emanuela
authors.initials: E
authors.lastname: Pasquali
authors.forename: Arianna
authors.initials: A
authors.lastname: Casciati
authors.forename: Ilaria
authors.initials: I
authors.lastname: De Stefano
authors.forename: Mirella
authors.initials: M
authors.lastname: Tanori
authors.forename: Simonetta
authors.initials: S
authors.lastname: Pazzaglia
authors.forename: Anna
authors.initials: A
authors.lastname: Saran
mesh_terms: D000818:Animals; D024201:Bystander Effect / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D002528:Cerebellar Neoplasms / Q000209:etiology*; D002531:Cerebellum / Q000528:radiation effects*; D004307:Dose-Response Relationship, Radiation; D018095:Germ-Line Mutation / Q000235:genetics; D051379:Mice; D009381:Neoplasms, Radiation-Induced / Q000209:etiology*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011835:Radiation Protection / Q000379:methods*; D011836:Radiation Tolerance / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D013997:Time Factors; D014916:Whole-Body Irradiation / Q000379:methods
chemical_list: C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface