Yano S, Shinohara H, Herbst R S, Kuniyasu H, Bucana C D, Ellis L M, Davis D W, McConkey D J, Fidler I J
Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Cancer Res. 2000 Sep 1;60(17):4959-67.
We investigated the molecular mechanisms of angiogenesis in experimental brain metastasis. Cells from six different human cancer cell lines (proven to produce visceral metastasis) were injected into the internal carotid artery of nude mice. Colon carcinoma (KM12SM) and lung adenocarcinoma (PC14PE6 and PC14Br) cells produced large, fast-growing parenchymal brain metastases, whereas lung squamous cell carcinoma (H226), renal cell carcinoma (SN12PM6), and melanoma (TXM13) cells produced only a few slow-growing brain metastases. Rapidly progressing brain metastases contained many enlarged blood vessels. The expression of VEGF mRNA and protein by the tumor cells directly correlated with angiogenesis and growth of brain metastasis. Causal evidence for the essential role of VEGF in this process was provided by transfecting PC14PE6 and KM12SM cells with antisense-VEGF165 gene, which significantly decreased the incidence of brain metastasis. In contrast, transfection of H226 human lung squamous carcinoma cells with sense-VEGF121 or sense-VEGF165 neither enhanced nor inhibited formation of brain metastases. Collectively, the results indicate that VEGF expression is necessary but not sufficient for the production of brain metastasis and that the inhibition of VEGF represents an important therapeutic target.
我们研究了实验性脑转移中血管生成的分子机制。将来自六种不同人类癌细胞系（已证实可产生内脏转移）的细胞注入裸鼠的颈内动脉。结肠癌细胞（KM12SM）和肺腺癌细胞（PC14PE6和PC14Br）产生大量快速生长的实质性脑转移瘤，而肺鳞状细胞癌细胞（H226）、肾癌细胞（SN12PM6）和黑色素瘤细胞（TXM13）仅产生少数生长缓慢的脑转移瘤。快速进展的脑转移瘤含有许多扩张的血管。肿瘤细胞中VEGF mRNA和蛋白的表达与脑转移瘤的血管生成和生长直接相关。通过用反义VEGF165基因转染PC14PE6和KM12SM细胞，为VEGF在此过程中的关键作用提供了因果证据，这显著降低了脑转移的发生率。相反，用正义VEGF121或正义VEGF165转染H226人肺鳞状细胞癌细胞既不增强也不抑制脑转移瘤的形成。总体而言，结果表明VEGF表达对于脑转移的产生是必要的但不是充分的，并且抑制VEGF代表一个重要的治疗靶点。
