EUROPEAN RADIATION RESEARCH 2012

Influence of the embryonic developmental stage on brain cancer-induction by ionizing radiation in Ptc1+/- mice

18 Oct 2012, 16:20

1m

Poster Hall (Vietri sul Mare)

poster preferred Radiation Carcinogenesis Poster Session 3

Speaker

Dr Mirella Tanori (Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA) CR-Casaccia)

Description

Cancer risk deriving from in utero exposure to ionizing radiation is an important and unresolved issue of radiation protection, as clear-cut conclusion on the estimated excess relative risk of childhood cancer has not been reached. Experimental studies conducted on sensitive models of radiation-induced pediatric tumors may be useful helping to improve mechanistic understanding and quantification of risk. The Patched1 heterozygous knockout mice (Ptc1+/-) provide a powerful model of medulloblastoma (MB), a frequent pediatric tumor that closely mimics a subset of the human disease. Irradiation of newborn Ptc1+/- mice dramatically increases the frequency and shortens the latency of MB. Origins of MB are related to development of the normal cerebellum. In mammalian embryos the cerebellum comprises two distinct germinal zones: (i) the ventricular zone, harboring multipotent stem cells that give rise to most of the neurons and glia, and (ii) the external granule layer (EGL), a secondary germinal zone of line-restricted granule cell precursors (GCPs). In the mouse, starting at embryonic day (E) 13-14, GCPs leave the rhombic lip and migrate over the cerebellar anlage to start forming an EGL (E15), where GCPs remain mitotically active until the second postnatal week. Proliferation in the EGL is regulated by Purkinje neurons via Sonic Hedgehog signaling. Although the cell of origin for human tumors has been often inferred based on expression of markers associated with particular cell types, changes in marker-expression during transformation and tumor heterogeneity with respect to expression of lineage makers may represent confounding factors. Here, we took advantage of a peculiarity of cerebellar neurogenesis, i.e., that distinct populations are born during temporal windows of specification. We therefore applied an oncogenic insult (X-rays) to embryos at E13.5, when the multipotent stem cells are specified but the EGL has not yet formed, or at E16.5, during the phase of expansion of the GCPs to form the EGL. The tumorigenic potential of irradiation in distinct pools of multipotent or fate-restricted progenitors is being evaluated. The results of these experiments will be discussed in light of their potential to shed light on MB origin, a matter of paramount importance having implication for development of targeted cellular therapies.