Noonan F P, Otsuka T, Bang S, Anver M R, Merlino G
Department of Dermatology, The George Washington University Medical Center, Washington, DC 20037, USA.
Cancer Res. 2000 Jul 15;60(14):3738-43.
The dramatic rise in incidence of malignant melanoma experienced by populations both within the United States and throughout the world over the last several decades has been attributed to enhanced exposure to the UV spectrum of sunlight radiation. This hypothesis can now be tested using genetically engineered mouse models predisposed to malignant melanoma. Here we use melanoma-prone transgenic mice inappropriately expressing hepatocyte growth factor/scatter factor (HGF/SF) in the skin as an experimental model system to ascertain the consequences of a chronic regimen of suberythemal UV radiation on melanoma genesis. HGF/SF is a multifunctional regulator capable of stimulating growth, motility, invasiveness, and morphogenetic transformation in cells, including melanocytes, expressing its receptor tyrosine kinase Met. HGF/SF transgenic mice demonstrate ectopic interfollicular localization and accumulation of melanocytes within the truncal dermis, epidermis, and junction and if untreated develop primary cutaneous melanoma with a mean onset age of approximately 21 months. Transgenic mice and their wild-type littermates subjected to UV radiation three times weekly using FS40 sunlamps (60% UVB and 40% UVA), with daily UV doses graded from 2.25 to 6.0 kJ/m2, developed skin tumors with a mean onset age of 26 and 37 weeks, respectively (P < 0.001, Kaplan-Meier log rank test). However, the repeated doses of suberythemal UV radiation used in this study failed to accelerate melanoma genesis, instead inducing the development of nonmelanoma tumors that included squamous cell carcinomas, squamous papillomas, and sarcomas. The conspicuous absence of melanocytic tumors occurred despite the immunohistochemical detection of a significant stimulation (P < 0.001) in melanocyte-specific bromodeoxyuridine incorporation in response to only 2 weeks of UV irradiation (total UV dose of 13.5 kJ/m2), resulting in 2.6- and 4.6-fold increases in the number of melanocytes in the dermis and epidermis, respectively. These data indicate that chronic suberythemal UV radiation preferentially favors the development of nonmelanocytic over melanocytic neoplasms in this transgenic animal, consistent with the pathogenesis proposed for sun exposure-associated skin cancer based on retrospective studies in the human population. Our findings suggest that the HGF/SF transgenic mouse will be useful as an experimental model for determining the consequences of exposure to various regimens of UV radiation and for elucidating the mechanisms by which such consequences are realized.
在过去几十年中，美国和全球人群中恶性黑色素瘤的发病率急剧上升，这归因于日光紫外线辐射暴露的增加。现在可以使用易患恶性黑色素瘤的基因工程小鼠模型来检验这一假设。在此，我们将皮肤中不适当表达肝细胞生长因子/扩散因子（HGF/SF）的易患黑色素瘤的转基因小鼠作为实验模型系统，以确定亚红斑紫外线辐射的慢性方案对黑色素瘤发生的影响。HGF/SF是一种多功能调节剂，能够刺激包括黑素细胞在内的表达其受体酪氨酸激酶Met的细胞的生长、运动、侵袭和形态发生转化。HGF/SF转基因小鼠在躯干真皮、表皮和交界处表现出黑素细胞的异位毛囊间定位和积累，若不治疗，会发展为原发性皮肤黑色素瘤，平均发病年龄约为21个月。使用FS40太阳灯（60%UVB和40%UVA）每周对转基因小鼠及其野生型同窝小鼠进行三次紫外线辐射，每日紫外线剂量从2.25至6.0 kJ/m²不等，它们分别在26周和37周时出现皮肤肿瘤（P < 0.001，Kaplan-Meier对数秩检验）。然而，本研究中使用的重复亚红斑紫外线辐射剂量未能加速黑色素瘤的发生，反而诱导了非黑色素瘤肿瘤的发展，包括鳞状细胞癌、鳞状乳头状瘤和肉瘤。尽管免疫组化检测显示，仅2周的紫外线照射（总紫外线剂量为13.5 kJ/m²）就能显著刺激（P < 0.001）黑素细胞特异性溴脱氧尿苷掺入，导致真皮和表皮中黑素细胞数量分别增加2.6倍和4.6倍，但明显没有黑素细胞肿瘤出现。这些数据表明，在这种转基因动物中，慢性亚红斑紫外线辐射优先促进非黑素细胞肿瘤而非黑素细胞肿瘤的发展，这与基于对人群的回顾性研究提出的阳光暴露相关皮肤癌的发病机制一致。我们的研究结果表明，HGF/SF转基因小鼠将作为一种实验模型，用于确定暴露于各种紫外线辐射方案的后果以及阐明实现这些后果的机制。
