Chemical Carcinogenesis at a Glance
- In 1775, Sir Percivall Pott's report of scrotal cancer in chimney sweeps established a link between environmental exposure and cutaneous malignancy.
- Over 200 chemicals have been linked to human cancer development, according to the National Toxicology Program's 11th Report on Carcinogens (2005).
- Chemicals implicated in human skin cancer development include polycyclic aromatic hydrocarbons and arsenic.
- Studies in mouse skin have defined operational stages of epithelial carcinogenesis: initiation, promotion, and malignant progression. Chemicals linked to human cancer are classified as tumor initiators, promoters, or “complete” carcinogens.
- Tumor initiation, associated with gene mutations that permanently alter the cell's biological responsiveness, is irreversible; tumor promotion a nonmutagenic process that provides a selective growth advantage to initiated cells, is reversible at early stages; agents that facilitate malignant progression are generally genotoxic.
- Most carcinogens must undergo metabolic activation, which involves enzymes involved in xenobiotic metabolism, including cytochrome p450 enzymes and glutathione S-transferase.
- An individual's likelihood of developing chemically induced skin cancer is a function of exposure history; presence of additional risk factors (e.g., UV exposure); and genetic background, including gene polymorphisms that influence susceptibility.
According to the American Cancer Society, it is estimated that over 2,000,000 cases of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), 46,770 cases of melanoma in situ, and 68,130 cases of invasive melanoma will be diagnosed that in the year 2010.1 The precise number of nonmelanoma skin cancers is unknown since they are not routinely reported to registries, but recent data suggest that previous approximations are likely to have been underestimates.2 Although only a small fraction of patients with nonmelanoma skin cancer will die as a result of their cancer, which is SCC in nearly all cases, the frequency of these cancers nonetheless results in an estimated 1,000 and 2,000 deaths per year. In contrast, although much less common than nonmelanoma skin cancer, melanoma has a continually rising death rate now estimated at 8,700 per year, and it is currently predicted that the lifetime risk in Caucasians of developing melanoma is a staggering 1 in 37 for males and 1 in 56 for females.1 Because they are so common, cutaneous cancers have a major impact on health care costs: in addition to the mortality burden, treatment is associated with considerable morbidity and cosmetic defects. For these reasons, understanding the etiology and pathogenesis of these malignancies is a significant public health goal, and development of rational nondeforming therapies to reduce morbidity and mortality is urgently needed. The high prevalence of skin cancer, the external location of the tumors, and well-defined preneoplastic lesions all provide an excellent opportunity for studying the factors regulating cutaneous cancer induction in humans. Those qualities that facilitate the study of cutaneous neoplasms in human populations have also been useful in establishing relevant animal models. Advances in molecular genetics, keratinocyte cell culture, and development of genetically altered mice and reconstructed human skin models have greatly facilitated the analysis of ...