Environmental carcinogenesis is traditionally explained by the accumulation of genetic alterations induced by exogenous carcinogens. However, most exposed cells do not undergo malignant transformation because intrinsic tumor-suppressive mechanisms limit the expansion of damaged clones. Among these mechanisms, cellular senescence represents a major barrier that restricts proliferation following DNA damage, oncogenic stress, and other carcinogen-induced insults. In this review, we examine environmental carcinogenesis within a probabilistic evolutionary framework in which tumor initiation depends not only on mutation acquisition but also on the ability of rare cells to evade senescence-mediated growth arrest. Environmental carcinogens contribute to cancer development by increasing genomic instability, altering tissue microenvironments, and modifying selective pressures, whereas senescence acts as a critical constraint on clonal evolution. We further discuss how aging, immune surveillance, DNA-repair capacity, and tissue-specific factors influence the likelihood of senescence escape and malignant progression. This integrative perspective highlights carcinogenesis as a multistep stochastic process shaped by the interaction between mutational events, cellular fitness barriers, and microenvironmental selection. Understanding how these factors collectively regulate transformation may improve mechanistic models of cancer risk and identify new opportunities for prevention and early intervention.
Blanco et al. (Wed,) studied this question.