The Oncologist-2004-Perlis-182-7

For example 70 weeks of exposure to uv irradiation

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Unformatted text preview: ample, 70 weeks of exposure to UV irradiation alone caused 5 of 13 Monodelphis domestica opossums to develop melanocytic tumors [16]. Administration of a topical carcinogen, 7,12-dimethylbenz(a)anthracene (DMBA), and UV irradiation induced melanomas in hairless and newborn mice [17]. A single exposure of UV-B or UVA light was sufficient to induce melanomas in a cross between platyfish and swordtail fish [18]. One new animal model reinforces epidemiological findings that childhood sunburn is a significant risk factor for developing melanoma. Noonan and colleagues found that a single high dose of UV radiation was sufficient to produce melanoma-like tumors in neonatal, but not adult, mice if the skin cells expressed a growth factor that stimulates melanocytes [19, 20]. Chin and colleagues established a second elegant genetic model of murine melanoma in which the INK4a gene deletion cooperates with Ras overexpression [21]. In a more recent development of the model driven by H-Ras activation and loss of p19ARF function, UV light exposure resulted in a marked acceleration in melanoma genesis [22]. UV-radiation-induced melanomas showed a strict reciprocal relationship between cyclin-dependent kinase (Cdk)6 amplification and p16INK4a loss, which is consistent with the actions of UV light along the Rb pathway. Although these animal models provide important insights into the role of UV light in melanoma causation, they differ from human skin in critical and obvious ways. Correlating animal models with human disease is difficult because of the unique architecture of murine skin. In mice, melanocytes are in the dermis and hair follicle and rarely in the epidermis, whereas in human skin, melanocytes are confined to the basal layer of the epidermis. Until 1998, a direct causal relationship between UV-B light and melanoma in humans had not been established. RAG-1 immune-deficient mice with grafted newborn human foreskin have proven such a relationship [23]. Seventythree percent of UV-B radiation-treated xenografts manifested melanocytic hyperplasia, while one graft treated with both DMBA and UV-B light developed a human malignant melanoma. This was the first experimental system to provide evidence that UV-B radiation and an exogenous carcinogen could produce human malignant melanoma de novo. A similar model induced human melanoma using a combination of UV-B light and overexpression of an endogenous growth factor, basic fibroblast growth factor (bFGF) (Fig. 1) [15]. Numerous local stressors may stimulate increases in cytokine production. Such stressors include trauma, infection, and other causes of inflammation. Sunburn clinically reflects an overdose of UV light leading to inflammation with an increase in cytokine production. While the mechanisms for this model of melanoma Perlis, Herlyn genesis remain to be further elucidated, the study reveals a direct role for UV-B light and at least one endogenous growth factor in melanoma genesis. B-RAF IN MELANOMA A fortuitous discovery in 2002 has electrified the melanoma field because it opens new avenues for melanoma diagnosis and therapy [24, 25]. Davies...
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