Disruptive chemicals, senescence and immortality

Abstract

Carcinogenesis is thought to be a multistep process, with clonal evolution playing a central role in the process. Clonal evolution involves the repeated 'selection and succession' of rare variant cells that acquire a growth advantage over the remaining cell population through the acquisition of 'driver mutations' enabling a selective advantage in a particular micro-environment. Clonal selection is the driving force behind tumorigenesis and possesses three basic requirements: (i) effective competitive proliferation of the variant clone when compared with its neighboring cells, (ii) acquisition of an indefinite capacity for self-renewal, and (iii) establishment of sufficiently high levels of genetic and epigenetic variability to permit the emergence of rare variants. However, several questions regarding the process of clonal evolution remain. Which cellular processes initiate carcinogenesis in the first place? To what extent are environmental carcinogens responsible for the initiation of clonal evolution? What are the roles of genotoxic and non-genotoxic carcinogens in carcinogenesis? What are the underlying mechanisms responsible for chemical carcinogen-induced cellular immortality? Here, we explore the possible mechanisms of cellular immortalization, the contribution of immortalization to tumorigenesis and the mechanisms by which chemical carcinogens may contribute to these processes.

Figure 1.

Simplified scheme of the effector pathways contributing to cellular senescence.

Figure 2.

Proposed carcinogenic roles for different chemical compounds underlining the relevance of ‘immortalization’ compounds. (I) Compound acting on somatic cells at different levels (DNA-damage for example) Compound A may induce senescence. (II) The same compound A acting on a stem cell that does not have replicative constraints will induce tumorigenesis. (III) If the same compound A acts after an ‘immortalization’ compound (compound B) that overrides the senescence barrier, the compound will be carcinogenic in these somatic cells. (IV) Similar to III, but in this case, both compounds act in a mixture.