Carcinogenesis In The Skin

The skin is the largest organ in humans. As it covers and protects our external surface, it is subject to mechanical damage and is exposed to a variety of potential carcinogens, chemicals, infectious agents, and radiation alike. Thus, a strong capacity for repair and regeneration is mandatory. This requirement is met by continuous turnover of the epidermis in a structural arrangement that minimizes the impact of carcinogenic agents and protects the body as a whole and the skin itself from cancer development (Figure 12.1).

The outmost layer of the epidermis ('stratum corneum') is composed of crosslinked dead keratinocytes filled with filamental proteins. This layer forms a barrier that rejects many infectious agents, reacts with chemicals and absorbs radiation. The underlying layers ('stratum granulosum' and 'stratum spinosum') are formed by living cells which are irreversibly committed to terminal differentiation (^■7.1). Therefore, genetic changes afflicted upon these cells become rarely permanent, because the cells are destined to becoming incapable of proliferation, losing their nuclei, and being eventually eliminated by shedding. Even the basal layer of epithelial cells in the skin, to which proliferation activity is largely confined, consists mostly of cells with a limited replicative potential. They form the transient amplification compartment. The actual stem cells of the skin are rare and are thought to proliferate normally very slowly, except during wound repair. Nevertheless, even then, the brunt of expansion is borne by the transient amplifying fraction.

Another factor in the protection against infection and carcinogenesis is the immune system of the skin. Langerhans cells are dendritic cells which present antigens for recognition by T-cells to elicit immune response against infectious agents and cancer cells.

Figure 12.1 The protective organization of the skin See text for further details.

Melanocytes help to protect specifically against light by producing melanin pigments which are deposited in the keratinocytes. As they differentiate, they carry the pigments to the upper layers of the skin. The extent of pigmentation is the most obvious factor modulating skin cancer risk.

In spite of its intricate protective system, the skin is the most frequent site of cancers in humans. The combined life-time risk for all skin cancers is estimated as 30-40% for lightly pigmented (Northwestern) Europeans, albeit lower for others according to pigmentation. Three different types of skin cancer are prevalent, in decreasing order basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma (Figure 12.2). Conversely, melanoma is by far the most lethal ofthese cancers, in «20% of all cases. SCC metastasizes only rarely, and BCC almost never.

The incidences of all three types of cancer have increased over the last decades, often steeply. This is particularly worrying in the case of the life-threatening

Figure 12.2 Histologies of skin cancers Histological aspects of A: squamous cell carcinoma, B: basal cell carcinoma, C: melanoma. In C, tumor cells within the epidermis are indicated by arrows.

melanoma. The presumed cause of the rise is an increased exposure to UV-rich sunlight. While the risk of skin cancers is modulated by a variety of genetic factors, short wavelength light is the most important exogenous carcinogen in the skin. Accordingly, most skin cancers, SCC and BCC, and to a lesser degree melanoma, develop in light-exposed areas of the skin.

UV light is categorized by wavelength into UVC (200-280 nm), UVB (280-320 nm), and UVA (320-400 nm). UVC cannot penetrate the upper layer of the skin, but «0.4% of UVB and a few percent of UVA reach the basal layer of the epidermis (Figure 12.3). Some UVA even penetrates into the dermis, as does most visible light. How much UVA and visible light reaches the deeper layers of the skin depends on the intensity of pigmentation.

Exposure to sunlight has a range of effects on the skin. At moderate doses, it is beneficial, while higher doses of UV-rich light are problematic. In DNA, UVC can induce single-strand and double-strand breaks and even ionization of bases by direct action. Like ionizing radiation, it also generates reactive oxygen species like hydroxyl radicals that damage DNA by reaction with bases and with the deoxyribose-phosphate backbone. The typical consequence of UVC exposure encountered by living cells is therefore death.

The effects of UVB are more subtle and therefore more dangerous. UVB can be absorbed by DNA, albeit weakly, and lead to photoproducts like thymine dimers and thymine-cytosine 6-4 adducts (Fig. 3.5). These are normally removed by nucleotide excision repair (^3.2). Hereditary defects in nucleotide excision repair cause xeroderma pigmentosum which is characterized by greatly enhanced photosensitivity and risk of skin cancers (^3.4).

Extensive DNA damage by UV radiation elicits activation of cellular checkpoints, and activates TP53 which can initiate apoptosis (^5.3). This happens at a large scale during 'sunburns'. In many skin cancers, inactivation of TP53

therefore appears to be a necessary initiating step, which has to take place before further mutations can be acquired. Indeed, TP53 mutations can be detected in morphologically altered, but non-cancerous regions of the skin.

UVA is only weakly mutagenic, but induces cellular reactions in different skin cell types such as modulation of immune responses, altered cytokine production, and activation of stress responses and proliferative signaling pathways. It is now thought that alterations of cellular interactions also contribute to the carcinogenic effect of UV radiation and are elicited by UVA as well as UVB. Diminuation of immune surveillance by inhibition of dendritic Langerhans cells and cytotoxic T-cells may be particularly important. In fact, even manifest carcinomas of the skin often still respond to treatment with stimulators of T-cell responses such as 'imiquimod'.

Figure 12.3 Action of different wavelength UV radiation in the skin See text for detailed explanation. Courtesy: Prof. V. Kolb-Bachofen

The complex mode of UV action illustrates that carcinogenesis requires more than mutations in DNA. Typically, it involves an altered tissue environment, in which tumor cells can more easily proliferate, escape from interactions with normal neighboring cells, and evade immune responses. Strong carcinogens, therefore, elicit such tissue reactions as well as a high rate of mutations. For instance, tobacco smoke inhalated in the lung also acts by several means including, of course, mutagenesis by polyaromates like benzopyrene, but also cell death with tissue repair, chronic inflammation induced by tar and particles, and a direct inhibitory effect of (non-mutagenic) nicotine on normal cells in the tissue.

The Smoker's Sanctuary

The Smoker's Sanctuary

Save Your Lungs And Never Have To Spend A Single Cent Of Ciggies Ever Again. According to a recent report from the U.S. government. Centers for Disease Control and Prevention, more than twenty percent of male and female adults in the U.S. smoke cigarettes, while more than eighty percent of them light up a cigarette daily.

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