Highly invasive transitional cell carcinoma of the bladder in a simian virus 40 T-antigen transgenic mouse model
Highly invasive transitional cell carcinoma of the bladder in a simian virus 40 T-antigen transgenic mouse model
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DOI：
10.1016/s0002-9440(10)64594-4
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发表时间：
2000-09-01
影响因子：
6
通讯作者：
Sandgren, EP
中科院分区：
文献类型：
--
作者：
Grippo, PJ;Sandgren, EP
移行细胞癌 (TCC) 是一种膀胱尿路上皮细胞肿瘤，通常出现在两种类型中：乳头状非侵入性或侵入性 TCC，尽管也可能出现中间形式。每一种都有独特的形态和临床病程。 p53 和 pRb 基因表达的改变与更严重的侵袭性 TCC 相关，表明这些肿瘤抑制蛋白活性的丧失可能与这种疾病有关。为了直接检验这一假设，我们开发了转基因小鼠，在细胞角蛋白 19 基因 (CK19) 调控元件的控制下，在尿路上皮细胞中表达猿病毒 40 大 T 抗原 (TAg)。在一种 CK19-TAg 谱系中，所有转基因小鼠均出现高度侵袭性膀胱肿瘤，类似于侵袭性人类膀胱 TCC。疾病进展阶段包括原位癌基质浸润、肌肉浸润、快速生长，并且在 20% 的受影响小鼠中，出现血管内肺转移，但从未观察到乳头状病变。蛋白质印迹分析表明，TAg 与 p53 和 pRb 均结合，这已被证明会导致这些蛋白质失活。我们的研究结果支持以下建议：(i) p53 和/或 pRb 失活构成侵袭性 TCC 病因学中的一个因果步骤，(ii) 乳头状和侵袭性 TCC 可能具有不同的分子原因，(iii) 原位癌可能代表侵袭性 TCC 进展的早期阶段。
Transitional cell carcinoma (TCC), a neoplasm of urinary bladder urothelial cells, generally appears in either of two farms, papillary non-invasive or invasive TCC, although intermediate forms can occur. Each has a distinctive morphology and clinical course. Altered expression of the p53 and pRb genes has been associated with the more serious invasive TCC, suggesting that the loss of activity of these tumor suppressor proteins may have a causal role in this disease. To test this hypothesis directly, transgenic mice were developed that expressed the simian virus 40 large T antigen (TAg) in urothelial cells under the control of the cytokeratin 19 gene (CK19) regulatory elements. in one CK19-TAg Lineage, all transgenic mice developed highly invasive bladder neoplasms that resembled invasive human bladder TCCs. Stages of disease progression included development of carcinoma in situ stromal invasion, muscle invasion, rapid growth, and, in 20% of affected mice, intravascular lung metastasis, Papillary lesions never were observed. Western blot analysis indicated that TAg was bound to both p53 and pRb, which has been shown to cause inactivation of these proteins. Our findings support suggestions that (i) inactivation of p53 and/or pRb constitutes a causal step in the etiology of invasive TCC, (ii) papillary and invasive TCC may have different molecular causes, and (iii) carcinoma in situ can represent an early stage in the progression to invasive TCC.