Pathogenesis of skin carcinomas and a stem cell as focal origin

Abstract

Skin cancers had already been linked to excessive sun exposure in the nineteenth century, specifically skin carcinomas were found predominantly in people with outdoor jobs. Genotoxicity, mutagenesis, and carcinogenesis by UV radiation, as present in sunlight, were experimentally established in the early decades of the twentieth century. Before the 2nd World War spectral analyses showed that DNA was the target of UV radiation for cell death and mutations (1, 2): i.e., well before Watson and Crick published the correct model of the structure of DNA, explaining how genes made up of DNA carried the genetic code which could be straightforwardly copied for daughter cells. Miscopies would introduce mutations. Consequently, replication of damaged DNA, hampering correct copying, for cell division was identified as the most prominent cause of mutagenesis. Carcinogenesis is considered to evolve primarily as a "multi-hit" process in which mutations accumulate in cells until a combination of mutations (and possibly other genetic defects and epigenetic modulatory effects) emerges which drive a cell to malignancy. As such a cell destined for malignancy requires time and cell divisions to transform, the most likely candidates would appear to be adult stem cells that constitute the very basis of tissue renewal. This premise was evidenced by a correlation that Tomasetti and Vogelstein (3) found between rate of stem cell division in various tissues and the risk of cancer. This led them to the controversial statement that most cancers are "bad luck" arising from an inherent risk of mutation in cell division. UV irradiation is known to cause epidermal hyperproliferation and hyperplasia. This would increase the UV-related risk of carcinomas originating from the epidermis (4), in addition to the risk derived from the genotoxicity of UV radiation.