Oncogenic bystander radiation effects in Patched heterozygous mouse cerebellum

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.cancer risk ͉ DNA damage ͉ in vivo ͉ medulloblastoma ͉ radiation

Role of connexin43 and ATP in long-range bystander radiation damage and oncogenesis in vivo

“…In this setting, the sum of attenuated and scattered radiation to the cerebellum is 0.036 Gy (1.2% of the total dose, see Monte Carlo simulation in Supplementary Methods), having undetectable genetic/oncogenic effects in directly irradiated cerebellum (Mancuso et al, 2008). This ensures that we were studying the indirect effects of exposure, rather than the direct effects of photons passing the shields and/or deflected in the cap through irradiated tissues.…”

“…We recently reported tumor induction in an in vivo mouse bystander model (Mancuso et al, 2008), stressing the potential significance of bystander responses for human health. Identifying the signaling mechanisms by which non-targeted radiation effects may cause tumor development is critical mechanistically, and for assessment of cancer risks associated with medical, occupational and environmental radiation exposures.…”

“…In our laboratory, by use of 12-O-tetradecanoylphorbol-13-acetate, we were able to inhibit expression of connexin43 (Cx43), the major gap junction intercellular communication (GJIC) constituent in central nervous system (CNS), and to reduce long-range radiation damage to the mouse brain (Mancuso et al, 2008). Although this strongly suggested a role of GJIC in bystander signaling, 12-O-tetradecanoylphorbol-13-acetate is not a specific GJIC inhibitor and exerts numerous effects on cellular functions.…”

CT exposure in adult and paediatric patients: a review of the mechanisms of damage, relative dose and consequent possible risks

“…Even repair is influenced by the structure; in fact the transcription zones are repaired faster than the silent zones, using enzymes and co-factors that recognise the damage. Their lack does not allow a timely repair influencing the survival and then the probability of inducing mutations and carcinogenesis processes [6].…”

Bystander Signalling: Exploring Clinical Relevance Through New Approaches and New Models

“…An important model which has been used to demonstrate the tumourigenic potential of abscopal effects is the Patched-1 (Ptch1 +/-) mouse (41,42). PTCH is a Sonic Hedgehog (SHH) receptor and negative regulator of the pathway causing predisposition to childhood medulloblastoma (43).…”