Abounader R, Ranganathan S, Lal B, Fielding K, Book A, Dietz H, Burger P, Laterra J
Department of Neuroscience and Kennedy Krieger Research Institute, Baltimore, MD 21205, USA.
J Natl Cancer Inst. 1999 Sep 15;91(18):1548-56. doi: 10.1093/jnci/91.18.1548.
BACKGROUND: Expression of scatter factor (SF), also known as hepatocyte growth factor (HGF), and its receptor, c-met, is often associated with malignant progression of human tumors, including gliomas. Overexpression of SF/HGF in experimental gliomas enhances tumorigenicity and tumor-associated angiogenesis (i.e., growth of new blood vessels). However, the role of endogenous SF/HGF or c-met expression in the malignant progression of gliomas has not been examined directly. In this study, we tested the hypothesis that human glioblastomas can be SF/HGF-c-met dependent and that a reduction in endogenous SF/HGF or c-met expression can lead to inhibition of tumor growth and tumorigenicity. METHODS: Expression of the SF/HGF and c-met genes was inhibited by transfecting glioblastoma cells with chimeric transgenes consisting of U1 small nuclear RNA, a hammerhead ribozyme, and antisense sequences. The effects of reduced SF/HGF and c-met expression on 1) SF/HGF-dependent induction of immediate early genes (c-fos and c-jun), indicative of signal transduction; 2) anchorage-independent colony formation (clonogenicity), an in vitro correlate of solid tumor malignancy; and 3) intracranial tumor formation in immunodeficient mice were quantified. Statistical tests were two-sided. RESULTS: Introduction of the transgenes into glioblastoma cells reduced expression of the SF/HGF and c-met genes to as little as 2% of control cell levels. Reduction in c-met expression specifically inhibited SF/HGF-dependent signal transduction (P<.01). Inhibition of SF/HGF or c-met expression in glioblastoma cells possessing an SF/HGF-c-met autocrine loop reduced tumor cell clonogenicity (P =.005 for SF/HGF and P=.009 for c-met) and substantially inhibited tumorigenicity (P<.0001) and tumor growth in vivo (P<.0001). CONCLUSIONS: To our knowledge, this is the first successful inhibition of SF/HGF and c-met expression in a tumor model directly demonstrating a role for endogenous SF/HGF and c-met in human glioblastoma. Our results suggest that targeting the SF/HGF-c-met signaling pathway may be an important approach in controlling tumor progression.
背景：散射因子（SF），也被称为肝细胞生长因子（HGF），及其受体c-met的表达常常与人类肿瘤包括胶质瘤的恶性进展相关。在实验性胶质瘤中SF/HGF的过表达增强了致瘤性和肿瘤相关的血管生成（即新血管的生长）。然而，内源性SF/HGF或c-met表达在胶质瘤恶性进展中的作用尚未得到直接研究。在本研究中，我们检验了以下假设：人类胶质母细胞瘤可能依赖SF/HGF-c-met，并且内源性SF/HGF或c-met表达的降低可导致肿瘤生长和致瘤性的抑制。 方法：通过用由U1小核RNA、锤头状核酶和反义序列组成的嵌合转基因转染胶质母细胞瘤细胞来抑制SF/HGF和c-met基因的表达。降低SF/HGF和c-met表达对以下方面的影响进行了量化：1）SF/HGF依赖的即刻早期基因（c-fos和c-jun）的诱导，这表明信号转导；2）不依赖贴壁的集落形成（克隆形成能力），这是实体瘤恶性程度的体外相关指标；3）免疫缺陷小鼠颅内肿瘤的形成。统计检验采用双侧检验。 结果：将转基因导入胶质母细胞瘤细胞后，SF/HGF和c-met基因的表达降低至对照细胞水平的2%。c-met表达的降低特异性地抑制了SF/HGF依赖的信号转导（P<0.01）。在具有SF/HGF-c-met自分泌环的胶质母细胞瘤细胞中，抑制SF/HGF或c-met表达降低了肿瘤细胞的克隆形成能力（SF/HGF为P = 0.005，c-met为P = 0.009），并显著抑制了体内致瘤性（P<0.0001）和肿瘤生长（P<0.0001）。 结论：据我们所知，这是首次在肿瘤模型中成功抑制SF/HGF和c-met表达，直接证明内源性SF/HGF和c-met在人类胶质母细胞瘤中的作用。我们的结果表明，靶向SF/HGF-c-met信号通路可能是控制肿瘤进展的重要方法。
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