Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor
Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor
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DOI：
10.1634/theoncologist.2014-0465
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发表时间：
2015-06-01
期刊：
影响因子：
5.8
通讯作者：
Adjei, Alex A.
中科院分区：
文献类型：
--
作者：
Zhao, Yujie;Adjei, Alex A.
血管生成，或新毛细血管的形成，主要发生在人类发育和繁殖过程中；然而，血管生成的异常调节也是在包括癌症在内的一些病理条件下发现的一个基本过程。肿瘤血管生成是肿瘤侵袭和转移所必需的过程，是肿瘤进展的重要控制点。尽管尚未完全了解，但肿瘤血管生成的复杂过程涉及多种信号通路的高度调控。促血管生成信号分子血管内皮生长因子（VEGF）及其同源受体（VEGF受体2 [VEGFR-2]）在血管生成中起着核心作用，通常在人类癌症中高度表达，最初的临床研究主要集中在抑制VEGF/VEGFR信号传导上。然而，这种方法往往导致短暂的反应和进一步的疾病进展，因为血管生成是由多种途径调节的，当单一途径被抑制时，这些途径能够相互补偿。例如，血小板衍生生长因子（PDGF）和PDGF受体（PDGFR）以及成纤维细胞生长因子（FGF）和FGF受体（FGFR）途径提供了抗vegf /VEGFR治疗的潜在逃逸机制，可以促进肿瘤生长的恢复。因此，最近的治疗集中于同时抑制多种信号通路。这篇综合综述讨论了单独抑制VEGF信号作为抗血管生成策略的局限性，其他血管生成途径包括PDGF/PDGFR和FGF/FGFR的重要性，以及针对多种血管生成途径治疗晚期实体瘤的新型和新兴药物。
Angiogenesis, or the formation of new capillary blood vessels, occurs primarily during human development and reproduction; however, aberrant regulation of angiogenesis is also a fundamental process found in several pathologic conditions, including cancer. As a process required for invasion and metastasis, tumor angiogenesis constitutes an important point of control of cancer progression. Although not yet completely understood, the complex process of tumor angiogenesis involves highly regulated orchestration of multiple signaling pathways. The proangiogenic signaling molecule vascular endothelial growth factor (VEGF) and its cognate receptor (VEGF receptor 2 [VEGFR-2]) play a central role in angiogenesis and often are highly expressed in human cancers, and initial clinical efforts to develop antiangiogenic treatments focused largely on inhibiting VEGF/VEGFR signaling. Such approaches, however, often lead to transient responses and further disease progression because angiogenesis is regulated by multiple pathways that are able to compensate for each other when single pathways are inhibited. The platelet-derived growth factor (PDGF) and PDGF receptor (PDGFR) and fibroblast growth factor (FGF) and FGF receptor (FGFR) pathways, for example, provide potential escape mechanisms from anti-VEGF/VEGFR therapy that could facilitate resumption of tumor growth. Accordingly, more recent treatments have focused on inhibiting multiple signaling pathways simultaneously. This comprehensive review discusses the limitations of inhibiting VEGF signaling alone as an antiangiogenic strategy, the importance of other angiogenic pathways including PDGF/PDGFR and FGF/FGFR, and the novel current and emerging agents that target multiple angiogenic pathways for the treatment of advanced solid tumors.