Sustained VEGF blockade results in microenvironmental sequestration of VEGF by tumors and persistent VEGF receptor-2 activation
Sustained VEGF blockade results in microenvironmental sequestration of VEGF by tumors and persistent VEGF receptor-2 activation
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DOI：
10.1158/1541-7786.mcr-07-0101
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发表时间：
2008-01-01
影响因子：
5.2
通讯作者：
Yamashiro, Darrell J.
中科院分区：
文献类型：
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作者：
Kadenhe-Chiweshe, Angela;Papa, Joey;Yamashiro, Darrell J.
血管内皮生长因子(VEGF)阻断已被临床验证为治疗人类癌症的一种方法，但几乎所有患者在治疗过程中最终都会发展为进展性疾病。为了剖析这一现象，我们在一个晚期儿童癌症模型中检测了持续阻断血管内皮生长因子的效果。晚期肝母细胞瘤异种移植的治疗导致血管系统的最初崩溃和显著的肿瘤消退。然而，在持续治疗期间，血管恢复了，同时肿瘤中硫酸肝素蛋白多糖Perlecan的表达显著增加。而血管内皮生长因子mRNA表达于存活的肿瘤细胞群的周边，分泌的血管内皮生长因子和Perlecan均聚集在中心血管周围。尽管循环中未结合的血管内皮生长因子陷阱，肝素酶的血管表达、血管内皮细胞生长因子受体-2配体结合和受体激活同时保持。内皮细胞存活信号通过Akt持续存在。这些发现为血管在持续阻断血管内皮生长因子的过程中存活提供了一种新的机制，并表明了细胞外基质分子在隔离和释放生物活性血管内皮生长因子方面的作用。
Vascular endothelial growth factor (VEGF) blockade has been validated clinically as a treatment for human cancers, yet virtually all patients eventually develop progressive disease during therapy. In order to dissect this phenomenon, we examined the effect of sustained VEGF blockade in a model of advanced pediatric cancer. Treatment of late-stage hepatoblastoma xenografts resulted in the initial collapse of the vasculature and significant tumor regression. However, during sustained treatment, vessels recovered, concurrent with a striking increase in tumor expression of perlecan, a heparan sulfate proteoglycan. Whereas VEGF mRNA was expressed at the periphery of surviving clusters of tumor cells, both secreted VEGF and perlecan accumulated circumferential to central vessels. Vascular expression of heparanase, VEGF receptor-2 ligand binding, and receptor activation were concurrently maintained despite circulating unbound VEGF Trap. Endothelial survival signaling via Akt persisted. These findings provide a novel mechanism for vascular survival during sustained VEGF blockade and indicate a role for extracellular matrix molecules that sequester and release biologically active VEGF.