Chambers A F, Tuck A B
London Regional Cancer Centre, Ontario, Canada.
Crit Rev Oncog. 1993;4(2):95-114.
Transfected ras oncogenes have been shown to induce metastatic properties in some cells. Clarification of the mechanisms by which ras is able to increase the metastatic ability in model systems will improve our understanding of tumor progression to metastasis, even in those cells in which ras activation has not been implicated. Many of the consequences of ras expression also have been detected in cells that have become metastatic in the apparent absence of an altered ras gene, suggesting that there is a set of common changes that can lead to metastasis with multiple signals capable of eliciting these changes. These changes, which have been documented for some ras-transformed cells, include increased expression or activity of various degradative enzymes, including metalloproteinases (type IV collagenases) and cysteine proteinases (cathepsins L and B), as well as decreased expression or activity of their inhibitors (TIMPs and cystatins, respectively). In addition, some metastatic ras-transformed cells have an increased expression of calcyclin, a cytoplasmic calcium-binding protein, and osteopontin, a secreted calcium-binding protein with possible adhesive function. Not all cells, however, respond in the same fashion to a ras oncogene signal. Some cells are resistant to ras-mediated tumor progression to metastasis. Understanding the mechanism by which these cells fail to respond to a specific oncogene signal may provide clues with broader applicability and potential therapeutic relevance. In this review, we summarize some of the studies in which ras has been used as a tool to learn about the molecular requirements for metastasis. We discuss ras-mediated changes in gene expression and how these may contribute to metastatic ability, as well as some possible mechanisms by which ras expression may result in altered expression of other genes. We also consider some cell lines which appear to be resistant to an oncogenic ras signal and possible mechanisms for this nonresponsiveness. These studies are providing insights into the molecular mechanisms of tumor metastasis and the responses of cells to oncogenic signals.
已证明转染的ras癌基因可在某些细胞中诱导转移特性。阐明ras在模型系统中增加转移能力的机制，将增进我们对肿瘤进展至转移的理解，即使在那些尚未涉及ras激活的细胞中也是如此。在明显没有ras基因改变的情况下已发生转移的细胞中，也检测到了ras表达的许多后果，这表明存在一组共同的变化，多种信号能够引发这些变化，进而导致转移。这些变化在一些ras转化细胞中已有记录，包括各种降解酶（包括金属蛋白酶（IV型胶原酶）和半胱氨酸蛋白酶（组织蛋白酶L和B））的表达或活性增加，以及它们的抑制剂（分别为金属蛋白酶组织抑制因子和胱抑素）的表达或活性降低。此外，一些转移性ras转化细胞中，细胞质钙结合蛋白钙周期蛋白和具有可能黏附功能的分泌性钙结合蛋白骨桥蛋白的表达增加。然而，并非所有细胞对ras癌基因信号的反应方式都相同。一些细胞对ras介导的肿瘤进展至转移具有抗性。了解这些细胞无法对特定癌基因信号作出反应的机制，可能会提供具有更广泛适用性和潜在治疗相关性的线索。在本综述中，我们总结了一些将ras用作工具来了解转移分子需求的研究。我们讨论了ras介导的基因表达变化以及这些变化如何可能有助于转移能力，以及ras表达可能导致其他基因表达改变的一些可能机制。我们还考虑了一些似乎对致癌性ras信号具有抗性的细胞系以及这种无反应性的可能机制。这些研究正在深入了解肿瘤转移的分子机制以及细胞对致癌信号的反应。
