Conditional expression of K-ras in an epithelial compartment that includes the stem cells is sufficient to promote squamous cell carcinogenesis
Conditional expression of K-ras in an epithelial compartment that includes the stem cells is sufficient to promote squamous cell carcinogenesis
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DOI：
10.1158/0008-5472.can-04-2623
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发表时间：
2004-12-15
期刊：
影响因子：
11.2
通讯作者：
Gutkind, JS
中科院分区：
文献类型：
--
作者：
Vitale-Cross, L;Amornphimoltham, P;Gutkind, JS
Ras基因是人类癌症中最常发生突变的致癌基因。然而，ras在肿瘤起始中的作用尚不清楚，因为ras在原代细胞中的表达可导致细胞周期阻滞甚至细胞凋亡死亡。此外，当在小鼠表皮中表达时，突变ras促进良性乳头瘤的形成，其中只有少数会发展为癌。然而，在这些情况下，ras-转基因的表达通常局限于基底上或滤泡上皮细胞，这些细胞可能缺乏自我更新能力。因此，仍然可以想象，活性ras在其他上皮细胞室中的表达可能发挥促进恶性进展的独特能力。为了解决这一可能性，我们对携带四环素诱导系统（tet-on受体）的转基因小鼠进行了工程改造，并在tet调节应答元件的控制下，将其与表达K-ras（G12D）致癌基因的小鼠杂交。服用强力霉素后，仅10至20天内，皮肤、口腔黏膜、唾液腺、舌头、食道、前胃和子宫颈的鳞状上皮发生增生、乳头状瘤、发育不良和转移癌等增生性病变。最明显的病变是皮肤和口腔粘膜的浸润性鳞状癌。这些发现提示癌基因在包括干细胞在内的上皮腔室中的表达可能足以促进鳞状癌的发生。他们还提供了一个分子定义的条件动物模型系统，其中负责癌症起始，维持和转移性扩散的机制可以很容易地研究。
Ras genes are the most frequently mutated oncogenes in human cancer. However, the contribution of ras to tumor initiation still is unclear because ras expression in primary cells can cause cell cycle arrest and even cell death by apoptosis. Furthermore, when expressed in the epidermis of mice, mutant ras promotes the formation of benign papillomas, only few of which will progress into carcinomas. However, in these cases, ras-transgene expression often is restricted to suprabasal or follicular epithelial cells that may lack self-renewal capacity. Thus, it still is conceivable that expression of active ras in other epithelial compartments may exert a distinct ability to promote malignant progression. To address this possibility, transgenic mice carrying the tetracycline-inducible system (tet-on receptor) targeted to the basal layer of stratified epithelium, which includes the epithelial stem cells, were engineered and crossed with mice expressing the K-ras(G12D) oncogene under the control of tet-regulated responsive elements. On doxycycline administration, proliferative lesions ranging from hyperplasias, papillomas, and dysplasias to metastatic carcinomas developed in squamous epithelia of the skin, oral mucosa, salivary glands, tongue, esophagus, forestomach, and uterine cervix within just 10 to 20 days. The most noticeable lesions were invasive squamous carcinomas of the skin and oral mucosa. These findings suggest that the expression of oncogenes in an epithelial compartment that includes the stem cells may be sufficient to promote squamous carcinogenesis. They also provide a molecularly defined conditional animal model system in which the mechanisms responsible for cancer initiation, maintenance, and metastatic spread can be readily investigated.