Hendriksen E M, Span P N, Schuuring J, Peters J P W, Sweep F C G J, van der Kogel A J, Bussink J
Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Microvasc Res. 2009 Mar;77(2):96-103. doi: 10.1016/j.mvr.2008.11.002. Epub 2008 Dec 7.
Tumour growth and spread of tumour cells requires angiogenesis. Incipient angiogenesis is not induced by tumour 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 tumour 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 tumour 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.
肿瘤生长和肿瘤细胞扩散需要血管生成。初期血管生成并非由肿瘤细胞缺氧诱导，而是可能由促血管生成因子诱导。在生长过程中，肿瘤依赖于进一步诱导血管发育以获得充足的氧气和营养供应。如果氧气供应不足，由此产生的缺氧会通过上调缺氧诱导因子-1α（HIF-1α）和血管内皮生长因子（VEGF）来刺激血管生成。VEGF上调与治疗反应不佳和预后不良相关。本研究的目的是分析肿瘤生长过程中缺氧与血管生成之间的相互关系。因此，在肿瘤生长的后续阶段，研究了肿瘤血管结构和血管的功能特性与缺氧及VEGF表达的关系。将源自人多形性胶质母细胞瘤肿瘤系E106的肿瘤移植到无胸腺小鼠体内。在移植后2天以及肿瘤平均大小达到2、4、6、8和10毫米时收获肿瘤。VEGF在血管生成开始时就已存在，与HIF-1α无关。在肿瘤生长过程中，通过酶联免疫吸附测定法（ELISA）评估，VEGF从0.94纳克/毫克增加到7.27纳克/毫克。然而，肿瘤结构中的瘤内异质性不断增加，即使在最大的肿瘤中，也检测到小的氧合良好区域，类似于最小肿瘤相对有序的结构。肿瘤血管在早期常氧条件下发育，后期在缺氧条件下发育，且在较大肿瘤中两种条件并存，这一观察结果表明抗血管生成治疗应针对HIF-1α依赖性和HIF-1α非依赖性途径。
