Oncogenes and angiogenesis: Signaling three-dimensional tumor growth
Oncogenes and angiogenesis: Signaling three-dimensional tumor growth
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DOI：
10.1046/j.1087-0024.2000.00012.x
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发表时间：
2000-12-01
影响因子：
--
通讯作者：
Kerbel, RS
中科院分区：
文献类型：
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作者：
Rak, J;Yu, JL;Kerbel, RS
三维肿瘤生长依赖于宿主血管向肿瘤部位的永久募集，（主要通过血管生成）被认为是由同一组基因改变触发的，至少部分是这样（激活的癌基因，失活/丢失的肿瘤抑制基因）作为恶性转化的其他方面负责有效的致癌基因能够解除癌细胞中血管生成刺激物和抑制物的表达。例如，突变型uas表达与血管内皮生长因子（VEGF）的产生增加和血小板反应蛋白-1（TSP-1）的下调相关。VEGF和血管生成的上调也可以通过其它致癌蛋白（例如，EGFR、Raf、MEK、PI 3 K）在Ras信号通路上以不同水平起作用。这种促血管生成影响的模式和程度可通过细胞类型（成纤维细胞或上皮来源）、表观遗传因素（缺氧、细胞变化、密度）和/或其他遗传病变（例如，p16或p53肿瘤抑制基因的预先丢失）的存在而显著改变。活化的癌基因（例如，uas、src、HER-2）诱导血管生成特性的共表达，同时伴有几种高度可选择的性状（有丝分裂发生增加、抗凋亡），这种情况可能加速细胞群体水平上血管生成表型的选择。另一方面，癌基因诱导的生长需求的降低也可以赋予肿瘤细胞对（紧密）接近血管的依赖性降低（尽管没有消除），即血管依赖性降低。因此，癌基因可以影响细胞生长、存活和血管生成的几个相互关联的方面。实验证据表明，原则上，通过有效使用特定的致癌基因拮抗剂和信号转导抑制剂，可以同时抑制这些特性（包括血管生成）中的许多特性（并诱导肿瘤停滞或消退）。
Three-dimensional tumor growth is dependent on the perpetual recruitment of host blood vessels to the tumor site, This recruitment process (mainly via angiogenesis) is thought to be triggered, at least in part, by the very same set of genetic alterations (activated oncogenes, inactivated/lost tumor suppressor genes) as those responsible for other aspects of malignant transformation (e,g,, aberrant mitogenesis, resistance to apoptosis), Potent oncogenes are able to deregulate expression of both angiogenesis stimulators and inhibitors in cancer cells. For example, mutant uas expression is associated with increased production of vascular endothelial growth factor (VEGF) and downregulation of thrombospondin-l (TSP-1). Upregulation of VEGF and angiogenesis can also be induced by constitutive activation of other oncogenic proteins (e,g., EGFR, Raf, MEK, PI3K) acting at various levels on the Ras signaling pathway. The mode and the magnitude of such proangiogenic influences can be significantly modified by cell type (fibroblastic or epithelial origin), epigenetic factors (hypoxia, changes in cell, density), and/or presence of additional genetic lesions (e,g,, pre-ceding loss of p16 or p53 tumor suppressor genes). Activated oncogenes (e,g,, uas, src, HER-2) induce co-expression of angiogenic properties concomitantly with several highly selectable traits (increased mitogenesis, resistance to apoptosis), a circumstance that may accelerate selection of the angiogenic phenotype at the cell population level. On the other hand oncogene-induced reduction in growth requirements may also endow tumor cells with a diminished (albeit not abrogated) dependence on (close) proximity to blood vessels, i,e,, with reduced vascular dependence, Thus, oncogenes can impact several interconnected aspects of cellular growth, survival, and angiogenesis. Experimental evidence suggests that, in principle, many of these properties (including angiogenesis) can be simultaneously suppressed (and tumor stasis or regression induced) by effective use of the specific oncogene antagonists and signal transduction inhibitors.