Promiscuous transcription of vascular endothelial growth factor and survival of tumors.
Promiscuous transcription of vascular endothelial growth factor and survival of tumors.
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血管内皮生长因子的混杂转录和肿瘤的存活。
DOI：
10.1093/jnci/92.13.1030
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Gallick,GE
中科院分区：
文献类型：
--
作者：
Ellis,LM;Gallick,GE
血管生成，即新血管形成的过程，是最活跃的研究领域之一，不仅在癌症领域，而且在发育生物学、心血管疾病、糖尿病和风湿病学领域都是如此。直到最近，通过基础科学研究获得的知识的扩展与临床应用之间一直存在着巨大的鸿沟。出于必要，包括经济力量和患者倡导在内的各种因素促使研究人员越来越意识到有必要根据潜在的临床应用来解释基础科学发现。在这一期的杂志上，Sheta等人(1)证明了人类前列腺癌细胞之间的细胞间通讯导致血管内皮生长因子（VEGF）的转录增加，这是迄今为止公认的最有效的血管生成因子。相比之下，正常的前列腺上皮生长到合流不表达更高水平的VEGF。细胞间接触显然是必需的，因为前列腺癌细胞分泌的可溶性因子或这些细胞与细胞外基质成分的结合不会增加VEGF转录。在一些精细的研究中，Sheta等人证明细胞-细胞接触诱导了由Src、局灶黏附激酶（FAK）和磷脂酰肌醇3-激酶（PI3K）介导的信号通路，导致丝裂原活化蛋白激酶（MAPK）以ras独立的方式激活。这些发现的意义是什么？它们对临床有潜在的重要意义吗？肿瘤细胞逃避密度依赖性生长抑制的能力是其体外特征之一。然而，很少有工作成功地阐明缺乏接触抑制的信号通路，或者这种特性是否对体内肿瘤生长真正重要。Sheta等人(1)证明肿瘤细胞接触直接导致VEGF转录增加，不仅为细胞-细胞接触的潜在相关性提供了强有力的证据，而且进一步加深了我们对肿瘤进展可能机制的理解。因此，这些研究为可能导致接触抑制部分恢复的药物开发的潜在目标提供了第一个见解。由于VEGF已被认为是肿瘤血管生成的主要调节因子，我们也认识到许多因素调节其表达。这些因素包括小肽（如胰岛素样生长因子、表皮生长因子、白细胞介素1和血小板源性生长因子）、酸度，以及最重要的缺氧（2-6）。此外，由激活的Ras、Raf或Src引起的细胞内异常信号传导可导致VEGF诱导（7-9）。此外，肿瘤抑制基因（如p53和VHL）的失活可以逆转VEGF表达的抑制（10-14）。Sheta等人(1)证明细胞密度通过FAK-PI3K-MEK（即MAPK/细胞外调节激酶）途径增加VEGF表达。虽然一些信号分子（如erk）与上述其他途径共享，但前列腺肿瘤细胞-细胞接触介导的VEGF表达的Ras独立性使该途径仅与
Angiogenesis, the process of formation of new blood vessels, is among the most active areas of research, not only in the field of cancer but also in the fields of developmental biology, cardiovascular disease, diabetes, and rheumatology. Until recently, there has been a great divide between the expansion of knowledge obtained by basic science investigations and clinical application. By necessity, various factors, including economic forces and patient advocacy, have provoked investigators to become increasingly aware of the need to interpret basic science findings in light of potential clinical applications. In this issue of the Journal, Sheta et al.(1) have demonstrated that cell–cell communication between human prostate cancer cells leads to increased transcription of vascular endothelial growth factor (VEGF), the most potent angiogenic factor recognized to date. In contrast, normal prostate epithelium grown to confluence does not express higher levels of VEGF. Cell–cell contact is clearly required, since soluble factors secreted from prostate cancer cells or the binding of these cells to extracellular matrix components does not increase VEGF transcription. In elegant studies, Sheta et al. demonstrate that cell–cell contact induces a signaling pathway mediated by Src, focal adhesion kinase (FAK), and phosphatidylinositol 3-kinase (PI3K), leading to the activation of mitogen-activated protein kinase (MAPK) in a Ras-independent manner.What are the implications of these findings, and are they potentially important in the clinic? The ability of tumor cells to escape density-dependent growth inhibition is one of their in vitro hallmarks. However, little work has succeeded in elucidating signaling pathways responsible for lack of contact inhibition or if this property is truly important to tumor growth in vivo. The demonstration by Sheta et al.(1) that contact of tumor cells leads directly to increased transcription of VEGF not only provides strong evidence for the potential relevance of cell–cell contact but also furthers our understanding of the possible mechanisms of tumor progression. Thus, these studies provide the first insights into potential targets for drug development that may lead to partial restoration of contact inhibition. As VEGF has become recognized as a dominant regulatory factor in tumor angiogenesis, we have also come to recognize that a multitude of factors regulate its expression. These factors include small peptides (such as insulin-like growth factor, epidermal growth factor, interleukin 1, and platelet-derived growth factor), acidity, and, most importantly, hypoxia (2–6). In addition, aberrant intracellular signaling resulting from activated Ras, Raf, or Src can lead to VEGF induction (7–9). Furthermore, inactivation of tumor suppressor genes, such as p53 and VHL, reverses repression of VEGF expression (10–14). Sheta et al.(1) demonstrate that cell density increases VEGF expression through an FAK–PI3K–MEK (ie, MAPK/extracellularregulated kinase) pathway. While some signaling molecules (eg, erk) are shared by other pathways indicated above, the Ras independence of prostate tumor cell–cell contact-mediated VEGF expression places this pathway in common only with