Heterogeneity of the tumor vasculature: the need for new tumor blood vessel type-specific targets.
Heterogeneity of the tumor vasculature: the need for new tumor blood vessel type-specific targets.
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DOI：
10.1007/s10585-012-9500-6
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发表时间：
2012-10
影响因子：
4
通讯作者：
Dvorak HF
中科院分区：
文献类型：
--
作者：
Nagy JA;Dvorak HF
针对VEGF-A及其受体的疗法在治疗许多小鼠肿瘤方面是有效的，但在治疗人类癌症患者方面效果较差。为了阐明可能导致这种反应差异的原因，我们研究了人类和小鼠癌症中出现的血管的性质，以及免疫缺陷小鼠对表达VEGF-A164的腺病毒的反应中产生的肿瘤“替代”血管。肿瘤和肿瘤替代血管都是异质的，并且通过两个不同的过程形成，即血管生成和动静脉生成。形成的第一个新的血管生成血管是母血管（MV）; MV来自预先存在的小静脉和毛细血管，并随着时间的推移演变成肾小球样微血管增生（GMP），随后演变成毛细血管和血管畸形（VM）。动脉-静脉发生是由先前存在的动脉和静脉的重塑和扩大引起的，导致供给和排出血管生成血管的供血动脉（FA）和引流静脉（DV）的形成。在这些不同的血管类型中，只有最先形成的两种，MV和GMP，对抗VEGF治疗高度反应，而“晚期”形成的毛细血管，VM，FA和DV相对无反应。这一发现可能至少部分解释了人类癌症对抗VEGF/VEGFR治疗的反应相对较差，因为在发现之前存在数月或数年的人类癌症预计含有大部分晚期形成的血管。抗血管癌治疗的未来可能取决于在“晚期”血管上找到新的靶点，除了与VEGF/VEGFR轴相关的靶点。
Therapies directed against VEGF-A and its receptors are effective in treating many mouse tumors but have been less so in treating human cancer patients. To elucidate the reasons that might be responsible for this difference in response, we investigated the nature of the blood vessels that appear in human and mouse cancers and the tumor “surrogate” blood vessels that develop in immunodeficient mice in response to an adenovirus expressing VEGF-A164. Both tumor and tumor surrogate blood vessels are heterogeneous and form by two distinct processes, angiogenesis and arterio-venogenesis. The first new angiogenic blood vessels to form are mother vessels (MV); MV arise from preexisting venules and capillaries and evolve over time into glomeruloid microvascular proliferations (GMP) and subsequently into capillaries and vascular malformations (VM). Arterio-venogenesis results from the remodeling and enlargement of preexisting arteries and veins, leading to the formation of feeder arteries (FA) and draining veins (DV) that supply and drain angiogenic vessels. Of these different blood vessel types, only the two that form first, MV and GMP, were highly responsive to anti-VEGF therapy, whereas “late”-formed capillaries, VM, FA and DV were relatively unresponsive. This finding may explain, at least in part, the relatively poor response of human cancers to anti-VEGF/VEGFR therapies, because human cancers, present for months or years prior to discovery, are expected to contain a large proportion of late-formed blood vessels. The future of anti-vascular cancer therapy may depend on finding new targets on “late” vessels, apart from those associated with the VEGF/VEGFR axis.
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影响因子：
5.7
作者：
Nagy JA;Chang SH;Shih SC;Dvorak AM;Dvorak HF
通讯作者：
Dvorak HF
DOI：
10.1038/nrc2442
发表时间：
2008-08
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
11.2
作者：
Sitohy B;Nagy JA;Jaminet SC;Dvorak HF
通讯作者：
Dvorak HF
影响因子：
11.2
作者：
Sitohy B;Nagy JA;Dvorak HF
通讯作者：
Dvorak HF
影响因子：
64.8
作者：
KIM, KJ;LI, B;FERRARA, N
通讯作者：
FERRARA, N