Ionizing radiation-induced cancer: perplexities of the bystander effect

Ionizing radiation (IR) is a carcinogen. This has been established beyond doubt from many years of studies such as those conducted among the survivors of the atomic bomb attacks on Hiroshima and Nagasaki and later from the Chernobyl accident. Despite immense progress in the field of carcinogenesis, complete understanding of the underlying mechanisms behind IR-induced cancer remains elusive. In particular, the long gestation period between exposure to IR and the onset of cancer, frequently unpredictable, and sometimes lasting for many years, remains poorly understood. The centrality of DNA damage and misrepair in carcinogenesis research has not entirely benefited IR-induced cancer research and the past decade has seen a shift in understanding radiation-driven cellular mechanisms beyond simplistic models of targeted DNA damage. This paper presents a viewpoint on the gaps in our knowledge of IR-induced cancer with a focus on the nontargeted bystander effect, the mechanisms underlying which may be key to radiotherapeutic advances.