MECHANISMS OF INDUCTION OF SKIN CANCER BY UV RADIATION

Holly Soehnge, Allal Ouhtit and Honnavara N. Ananthaswamy

Department of Immunology, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Blvd., Box 178, Houston, TX 77030

Received 10/20/97 Accepted 10/24/97

5. A MODEL FOR UV-INDUCTION OF SKIN CANCER

The epidermal keratinocytes of the skin are the most susceptible to damage from UV exposure, due to their localization relative to the skin surface; therefore, most skin cancers in humans arise from the epidermis. The cellular and molecular events that contribute to the development of UV-induced skin cancer is a complex process involving at least two distinct pathways that interact or converge to cause skin cancer (Figure 5). One pathway involves the action of UV on target cells (keratinocytes) for neoplastic transformation, and the other involves the effects of UV on the host's immune system. There is evidence to indicate that UV-induced DNA damage plays an important role in both pathways. In the normal human epidermis, cells are constantly turning over, about once a month. During this period, stem cells in the basal layer undergo cell division, and the keratinocytes differentiate into squamous cells producing keratin and other proteins, and finally desquamate (106, 107). Chronic exposure to sunlight causes damage to the skin including erythema, edema, hyperplasia, formation of sunburn cells, photoaging, suppression of the immune system and skin cancer. Some of the molecular events that occur in cells following UV exposure are, DNA damage, induction of p53 and p53-regulated proteins, cell cycle arrest, errors in DNA repair and/or replication, mutations in p53 and other genes (Figure 5). In addition, UV-induced DNA damage causes the production of immunosuppressive cytokines and some types of immunosuppression that may contribute to the emergence of skin cancer.

Figure 5. A model for induction of skin cancer by UV

The p53 tumor suppressor gene appears to be one of the key UV-responsive genes, and mutations in this gene is thought to initiate the process of skin carcinogenesis. Jonason et al, (59) used a scanning confocal microscope to reconstruct a three-dimensional immunofluorescent cone of mutant p53-positive keratinocytes from an epidermal whole mount of sun-exposed skin. They found the apex of the cone at the dermal-epidermal junction, indicating the location of initiating stem cells and suggesting p53 mutation as a marker for the progeny of a single stem cell. It seems likely that UV radiation targets particularly those original cells at the basal layer and damages the p53 gene by inducing cyclobutane pyrimidine dimers and (6-4) photoproducts at sites of adjacent pyrimidines. Photodamage to DNA induces the expression of p53 protein and cause cell cycle arrest, thereby permitting the repair of the damage. If the DNA damage is too much and left unrepaired, the cell undergoes apoptosis. In addition, UV-induced pyrimidine dimers may inhibit transcription factor binding thereby interfering with other important DNA-dependent processess (12). Thus, UV radiation may inhibit p53 binding and transcriptional activities leading to the deregulation of its function, such as DNA repair and apoptosis (108-111). The deregulation of p53 functions and slow repair of UV-induced photoproducts at particular codons (112) may lead to the induction and accumulation of p53 mutations, particularly C-->T or tandem CC--> TT transitions thereby initiating the molecular process of carcinogenesis. The location of these mutations in the p53 gene in human NMSC is not random; there are 9 known hotspot mutations in the p53 gene that result in amino acid sequence changes (53, 54) inactivating the critical functions of the p53 protein. This is taken as evidence that these mutations do indeed offer some selective growth advantage to the initiated cells. Therefore, chronic exposure to sunlight can cause massive suicide of normal cells containing wild-type p53 protein by apoptosis (cellular proof reading) leaving more space for the p53-mutant cell to clonally expand and replace the dying sunburned cells (promotion) thus leading to abnormal precancerous cells. Sunlight is, therefore, acting as an initiator and a promoter; this phenomenon has been termed "double punch of sunlight" (76). However, even though 4% of the normal sun-exposed skin cells have p53 mutations, very few develop into actinic keratoses (AK) or cancer. In addition, AK, which is a premalignant lesion have a high frequency of UV-specific p53 mutations and allelic loss of many genes, including p53, rarely (1:1000) progress to SCC (106).

It appears that this is only a part of the story. Based on the hypothetical model of the multistep process of carcinogenesis, it has been suggested that alterations in two different gatekeeper genes may lead to cancer development (113). The development of NMSC may then involve p53 as the first gatekeeper gene (114), and the predisposed clones described above may acquire an alteration of another gatekeeper gene. The tumor suppressor gene ptc is suspected to play such a role in UV-induction of BCC (94, 95), and the ESS1 gene localized on chromosome 9q31 in the induction of SCC (115).

UV radiation plays a dual role in the development of skin cancer. On one hand, UV radiation induces genetic alterations in keratinocytes, leading to their neoplastic transformation. On the other hand, UV radiation depresses the immune responses in the skin, which can permit the growth of emerging tumors produced by the effects of UV-induced DNA damage (reviewed in ref. 5). Studies by Kripke and coworkers (5) have shown that a majority of UV-induced mouse skin tumors are highly antigenic in that they are rejected when transplanted into normal syngeneic hosts, but they grow progressively in mice exposed to subcarcinogenic doses of UV. The systemic suppression results from the induction of suppressor T cells, either by damaged Langerhans cells or inflammatory macrophages that enter the skin following UV exposure (5). Another mechanism may be the release of soluble factors at the site of UV irradiation that act to suppress the immune system (reviewed in 116). These factors include cytokines such as IL-10, TNF-alpha, and IL-1alpha that can suppress the immune system and prevent T-cell mediated responses; these are known to be secreted by keratinocytes after UV damage (116). In addition, UV irradiation can also convert normal skin chromophores into agents that are immunosuppressive, such as the conversion of trans-urocanic acid to cis-urocanic acid (117). Analogous to the model, immunosuppressed patients have a higher risk for development of NMSC, as in renal transplant patients who develop an increased number of SCCs, BCCs, virus-associated skin tumors, and keratoacanthomas, mostly on sun-exposed areas (118, 119).

Recent studies have shown that UV-induced DNA damage plays an important role in the suppression of specific immune responses. In studies to investigate the effects of enhanced repair of UV-induced pyrimidine dimers on UV-induced immunosuppression, it was found that topical application of liposomes containing T4N5 endonuclease or DNA photolyase to mouse skin following UV irradiation abrogated UV-induced suppression of contact hypersensitivity (reviewed in 120). Thus, carcinogenesis by UV radiation appears to operate by the distinct mechanisms of genetic mutation and immunosuppression.