Honda Kazuhisa, Sakaguchi Takehisa, Sakai Keiko, Schmedt Christian, Ramirez Angel, Jorcano Jose Luis, Tarakhovsky Alexander, Kamisoyama Hiroshi, Sakai Takao
Department of Biomedical Engineering and Orthopaedic Research Center/ND20, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Carcinogenesis. 2007 Oct;28(10):2074-81. doi: 10.1093/carcin/bgm112. Epub 2007 May 10.
The Src family kinases (SFKs) are believed to play critical roles in malignant transformation, as well as in growth, invasion and dissemination of neoplastic tissue. Inhibition of SFK-mediated signal transduction and activation of downstream targets inhibits tumor progression. To determine whether constitutive activity of SFK per se is sufficient to induce tumorigenesis in vivo, we have generated a mouse model with a keratinocyte-restricted deletion of the SFK-negative regulator csk (Csk-K5 mice). Even though expression levels of SFKs were lower in C-terminal Src kinase (Csk)-null keratinocytes, activity levels were higher than in control keratinocytes. At the age of 3 months, all Csk-K5 mice displayed signs of chronic inflammation in dermis and epidermal hyperplasia. About 19% of Csk-K5 mice (7 out of 36) developed papillomatous lesions. However, these lesions did not show any signs of neoplastic transformation over the next 8 months. Epidermal hyperplasia and hyperkeratosis in Csk-K5 mice were associated with an increased number of stem cells in the interfollicular epidermis, an increased proliferation of basal keratinocytes and a delayed terminal differentiation of the suprabasal keratinocytes. Our results clearly demonstrate that even though SFK-mediated signaling promotes tumor progression, elevated activity of SFKs in vivo alone is not sufficient to induce neoplastic transformation.
Src家族激酶（SFKs）被认为在恶性转化以及肿瘤组织的生长、侵袭和扩散中发挥关键作用。抑制SFK介导的信号转导和下游靶点的激活可抑制肿瘤进展。为了确定SFK本身的组成性活性是否足以在体内诱导肿瘤发生，我们构建了一种小鼠模型，该模型在角质形成细胞中特异性缺失SFK负调节因子csk（Csk-K5小鼠）。尽管在C端Src激酶（Csk）缺失的角质形成细胞中SFKs的表达水平较低，但其活性水平高于对照角质形成细胞。3个月大时，所有Csk-K5小鼠均表现出真皮慢性炎症和表皮增生的迹象。约19%的Csk-K5小鼠（36只中的7只）出现乳头状病变。然而，在接下来的8个月里，这些病变未显示出任何肿瘤转化的迹象。Csk-K5小鼠的表皮增生和角化过度与毛囊间表皮干细胞数量增加、基底角质形成细胞增殖增加以及基底上层角质形成细胞终末分化延迟有关。我们的结果清楚地表明，尽管SFK介导的信号传导促进肿瘤进展，但仅体内SFKs活性升高不足以诱导肿瘤转化。
