Induction of human squamous cell-type carcinomas by arsenic

Abstract

Arsenic is a potent human carcinogen. Around one hundred million people worldwide have potentially been exposed to this metalloid at concentrations considered unsafe. Exposure occurs generally through drinking water from natural geological sources, making it difficult to control this contamination. Arsenic biotransformation is suspected to have a role in arsenic-related health effects ranging from acute toxicities to development of malignancies associated with chronic exposure. It has been demonstrated that arsenic exhibits preference for induction of squamous cell carcinomas in the human, especially skin and lung cancer. Interestingly, keratins emerge as a relevant factor in this arsenic-related squamous cell-type preference. Additionally, both genomic and epigenomic alterations have been associated with arsenic-driven neoplastic process. Some of these aberrations, as well as changes in other factors such as keratins, could explain the association between arsenic and squamous cell carcinomas in humans.

Figure 1

Carcinogenic mechanisms of arsenic transformation. Ingested arsenic undergoes a biotransformation process. (1) Biotransformation could lead to arsenic excretion, when conjugated with glutathione. (2) Biotransformation generates reactive oxygen species (ROS), namely, superoxide anions (O₂ ⁻), hydrogen peroxide (H₂O₂), hydroxyl radicals (OH), that induce single-strand (ssDNA) and double-strand (dsDNA) breaks by inducing oxidative damage. The process can also inhibit DNA break repair mechanisms for ssDNA breaks (base excision repair (BER)) and for dsDNA breaks (homologous recombination (HR) and/or nonhomologous end joining (NHEJ)). Additionally, ROS derived from arsenic biotransformation can act as cocarcinogens, for example, increasing damage potential of ultraviolet (UV) light. Furthermore, the requirement of S-adenosyl methionine (SAM) for arsenic biotransformation can lead to depletion of SAM, which is the substrate for DNA methylation.

Figure 2

DNA copy-number alteration at chromosome 9q in arsenic-exposed lung SqCC. CNA frequencies are overlaid in this karyogram. Profiles of 52 lung SqCC biopsies were generated using a submegabase resolution tiling-set rearray (SMRTr) platform. Twenty-two arsenic-exposed samples (shown in red) were obtained from lung cancer patients from northern Chile. Thirty samples from patients without known arsenic exposure (green) were obtained from North American individuals. Regions in yellow denote a sector of overlapping alteration status in both groups. The magnitude of red, green, and yellow bars represents percentage of samples (0–100%, with blue vertical lines representing 50% frequency) exhibiting DNA gains (to the right) and DNA losses (to the left). Dotted line represents 9q12 cytoband.