Oncogenic bystander radiation effects in Patched heterozygous mouse cerebellum

Mariateresa Mancuso, Emanuela Pasquali, Simona Leonardi, Mirella Tanori, Simonetta Rebessi, Vincenzo Di Majo, Simonetta Pazzaglia, Maria Pia Toni, Maria Pimpinella, Vincenzo Covelli, Anna Saran

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Abstract

The central dogma of radiation biology, that biological effects of ionizing radiation are a direct consequence of DNA damage occurring in irradiated cells, has been challenged by observations that genetic/epigenetic changes occur in unexposed "bystander cells" neighboring directly-hit cells, due to cell-to-cell communication or soluble factors released by irradiated cells. To date, the vast majority of these effects are described in cell-culture systems, while in vivo validation and assessment of biological consequences within an organism remain uncertain. Here, we describe the neonatal mouse cerebellum as an accurate in vivo model to detect, quantify, and mechanistically dissect radiation-bystander responses. DNA double-strand breaks and apoptotic cell death were induced in bystander cerebellum in vivo. Accompanying these genetic events, we report bystander-related tumor induction in cerebellum of radiosensitive Patched-1 (Ptch1) heterozygous mice after x-ray exposure of the remainder of the body. We further show that genetic damage is a critical component of in vivo oncogenic bystander responses, and provide evidence supporting the role of gap-junctional intercellular communication (GJIC) in transmission of bystander signals in the central nervous system (CNS). These results represent the first proof-of-principle that bystander effects are factual in vivo events with carcinogenic potential, and implicate the need for re-evaluation of approaches currently used to estimate radiation-associated health risks. © 2008 by The National Academy of Sciences of the USA.
Original languageEnglish
Pages (from-to)12445 - 12450
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number34
DOIs
Publication statusPublished - 26 Aug 2008
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Genetics
  • General

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