The critical roles of somatic mutations and environmental tumor-promoting agents in cancer risk

Abstract

Cancer is driven by genomic mutations in 'cancer driver' genes, which have essential roles in tumor development. These mutations may be caused by exposure to mutagens in the environment or by endogenous DNA-replication errors in tissue stem cells. Recent observations of abundant mutations, including cancer driver mutations, in histologically normal human tissues suggest that mutations alone are not sufficient for tumor development, thus prompting the question of how single mutant cells give rise to neoplasia. In a concept supported by decades-old data from mouse tumor models, non-mutagenic tumor-promoting agents have been posited to activate the proliferation of dormant mutated cells, thus generating actively growing lesions, with the promotion stage as the rate-limiting step in tumor formation. Non-mutagenic promoting agents, either endogenous or environmental, may therefore have a more important role in human cancer etiology than previously thought.

Fig. 1 ∣. The permanence of the initiated state.

a, Standard initiation-promotion model. Mice are treated once with a carcinogen (usually DMBA) at 8 weeks of age and 1 week later with twice-weekly treatment with a promoting agent (usually TPA). Treatment with either DMBA alone (top row) or TPA alone (second row) does not give rise to tumor development during a follow-up period of 1 year. However, DMBA followed by TPA induces benign tumors (papillomas) in 1–2 months, some of which progress to carcinomas after 5–12 months. b, Delayed-promotion model. Treatment with the carcinogen is followed a delay of 6–18 months before the start of promoter treatment. Benign tumors appear 1–2 months after starting TPA, and carcinomas develop after 5–12 months. The overall tumor yield decreases slightly after longer delay periods^-.

Fig. 2 ∣. Publications per year from 1974–2018.

These publications were identified through a search for ‘TPA tumor promotion’ (left) or ‘oncogene’ (right), showing the shift in emphasis.