Angiogenesis, hypoxia and VEGF expression during tumour growth in a human xenograft tumour model
Angiogenesis, hypoxia and VEGF expression during tumour growth in a human xenograft tumour model
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DOI：
10.1016/j.mvr.2008.11.002
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发表时间：
2009-03-01
影响因子：
3.1
通讯作者：
Bussink, J.
中科院分区：
文献类型：
--
作者：
Hendriksen, E. M.;Span, P. N.;Bussink, J.
肿瘤细胞的生长和扩散需要血管生成。早期血管生成不是由细胞缺氧引起的，而可能是由促血管生成因子引起的。在生长过程中，肿瘤依赖于进一步诱导血管发育以获得足够的氧气和营养供应。如果供氧不足，由此产生的缺氧通过上调HIF-1 α和VEGF刺激血管生成。VEGF上调与治疗反应差和预后差有关。本研究的目的是分析小鼠生长过程中缺氧与血管生成的相互关系。因此，在肿瘤生长的后续阶段，研究了肿瘤血管结构和血管功能特性与缺氧和vegf表达的关系。将人胶质母细胞瘤多形性肿瘤系E106的肿瘤移植到胸腺小鼠体内。在移植后2天，当肿瘤的平均大小达到2,4,6,8和10mm时，收获肿瘤。VEGF在独立于HIF-1 α的血管生成早期出现。在小鼠生长过程中，ELISA测定VEGF从0.94 ng/mg升高到7.27 ng/mg。然而，肿瘤结构的肿瘤内异质性增加，即使在最大的肿瘤中，也检测到小的氧合良好的区域类似于最小肿瘤的相对组织良好的结构。观察到肿瘤血管在正常氧条件下的早期阶段和在缺氧条件下的后期阶段，在较大的肿瘤中存在这两种情况，表明抗血管生成治疗应针对HIF-1 α依赖和HIF-1 α独立的途径。(c) 2008爱思唯尔公司版权所有。
Tumour growth and spread of tumour cells requires angiogenesis. incipient angiogenesis is not induced by turnout cell hypoxia but probably by proangiogenic factors. During growth tumours depend on a further induction of vascular development for adequate oxygen and nutrient supply. If the oxygen supply is insufficient, the resulting hypoxia stimulates angiogenesis through upregulation of HIF-1 alpha and VEGF. VEGF upregulation is associated with a poor response to treatment and poor prognosis. The aim of the study was to analyze the interrelationship between hypoxia and angiogenesis during turnout growth. Therefore the tumour vasculature architecture and functional properties of the vessels were studied during subsequent phases of tumour growth in relation to hypoxia and VEGF-expression.Tumours from the human glioblastoma multiforme tumour line E106 were transplanted in athymic mice. Tumours were harvested at 2 days after transplantation and when tumours reached a mean size of 2, 4, 6, 8 and 10 mm. VEGF was present early in the onset of angiogenesis independent of HIF-1 alpha. During turnout growth VEGF increased from 0.94 to 7.27 ng/mg assessed by ELISA. However, there was increasing intratumoural heterogeneity in the architecture of the tumours, even in the largest tumours small well oxygenated areas were detected resembling the relatively well organized architecture of the smallest tumours. The observation that tumour vasculature develops in early phases under normoxic and at later phases under hypoxic conditions with the presence of both conditions in the larger tumours, suggested that anti-angiogenic therapy should be directed towards HIF-1 alpha dependent and HIF-1 alpha independent pathways. (c) 2008 Elsevier Inc. All rights reserved.