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Elife ; 112022 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-35302491

RESUMO

A rare but severe complication of curative-intent radiation therapy is the induction of second primary cancers. These cancers preferentially develop not inside the planning target volume (PTV) but around, over several centimeters, after a latency period of 1-40 years. We show here that normal human or mouse dermal fibroblasts submitted to the out-of-field dose scattering at the margin of a PTV receiving a mimicked patient's treatment do not die but enter in a long-lived senescent state resulting from the accumulation of unrepaired DNA single-strand breaks, in the almost absence of double-strand breaks. Importantly, a few of these senescent cells systematically and spontaneously escape from the cell cycle arrest after a while to generate daughter cells harboring mutations and invasive capacities. These findings highlight single-strand break-induced senescence as the mechanism of second primary cancer initiation, with clinically relevant spatiotemporal specificities. Senescence being pharmacologically targetable, they open the avenue for second primary cancer prevention.


Assuntos
Reparo do DNA , Segunda Neoplasia Primária , Animais , Carcinogênese , Transformação Celular Neoplásica , Senescência Celular , Quebras de DNA de Cadeia Simples , Dano ao DNA , Camundongos
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