Spontaneous squamous cell carcinoma induced by the somatic inactivation of retinoblastoma and Trp53 tumor suppressors
Spontaneous squamous cell carcinoma induced by the somatic inactivation of retinoblastoma and Trp53 tumor suppressors
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DOI：
10.1158/0008-5472.can-07-3049
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发表时间：
2008-02-01
期刊：
影响因子：
11.2
通讯作者：
Paramio, Jesus M.
中科院分区：
文献类型：
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作者：
Martínez-Cruz, Belen Ana;Santos, Mirentxu;Paramio, Jesus M.
鳞状细胞癌（SCC）是最具侵袭性的非黑色素瘤皮肤癌。虽然对SCC的病因改变知之甚少，但在器官移植患者中，靶向p53和pRb依赖性途径的人乳头瘤病毒的E7和E6癌基因已被广泛参与。在这里，我们报告的功能后果的同时消除Trp 53和视网膜母细胞瘤（Rb）基因在表皮中使用Cre-loxP系统。p53的缺失，而不是pRb，产生自发的肿瘤发展，表明p53是主要的肿瘤抑制剂作用于小鼠表皮。虽然pRb和p53的同时失活不会加重Rb缺陷表皮中观察到的增殖和/或分化的表型，但在双缺陷小鼠中，自发性SCC发展严重加速。肿瘤是侵袭性的，未分化的，显示毛囊起源。详细的分析表明，这种加速是由表皮生长因子受体/Akt通路的过早激活介导的，导致正常和发育不良毛囊的增殖增加和肿瘤血管生成增加。该模型的分子特征为了解表皮肿瘤形成提供了有价值的工具，并可能最终有助于开发治疗侵袭性鳞状细胞癌的疗法。
Squamous cell carcinomas (SCC) represent the most aggressive type of nonmelanoma skin cancer. Although little is known about the causal alterations of SCCs, in organ-transplanted patients the E7 and E6 oncogenes of human papillomavirus, targeting the p53- and pRb-dependent pathways, have been widely involved. Here, we report the functional consequences of the simultaneous elimination of Trp53 and retinoblastoma (Rb) genes in epidermis using Cre-loxP system. Loss of p53, but not pRb, produces spontaneous tumor development, indicating that p53 is the predominant tumor suppressor acting in mouse epidermis. Although the simultaneous inactivation of pRb and p53 does not aggravate the phenotype observed in Rb-deficient epidermis in terms of proliferation and/or differentiation, spontaneous SCC development is severely accelerated in doubly deficient mice. The tumors are aggressive and undifferentiated and display a hair follicle origin. Detailed analysis indicates that the acceleration is mediated by premature activation of the epidermal growth factor receptor/Akt pathway, resulting in increased proliferation in normal and dysplastic hair follicles and augmented tumor angiogenesis. The molecular characteristics of this model provide valuable tools to understand epidermal tumor formation and may ultimately contribute to the development of therapies for the treatment of aggressive squamous cancer.