Department of Pathology, University of Valencia, Medical School, Valencia, Spain.
Clin Cancer Res. 2009 Dec 1;15(23):7130-6. doi: 10.1158/1078-0432.CCR-09-0223. Epub 2009 Nov 10.
Hypoxia is considered to be a major driving force behind tumor angiogenesis. The stabilization and activation at hypoxia of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha and the concomitant induction of expression of vascular endothelial growth factor (VEGF) and other proangiogenic factors provide a molecular frame for hypoxia-driven tumor angiogenesis. This study has investigated how HIF and VEGF protein levels relate to each other with regard to vascularization, tumor stage, and overall survival in neuroblastoma.
Tissue cores taken from tumor specimens representing 93 children with neuroblastoma were arranged on a microarray and stained for HIF-1alpha, HIF-2alpha, VEGF, and CD31 proteins. Both fraction of positive cells and staining intensity were evaluated and protein levels were correlated with each other and with clinical variables.
Although high levels of both HIF-1alpha (P < 0.001) and HIF-2alpha (P < 0.001) correlated positively to VEGF expression, they did not fully correlate with each other. Moreover, HIF-1alpha (P = 0.002) and VEGF (P < 0.001), but not HIF-2alpha, correlated negatively to vascularization as determined by CD31 staining abundance. VEGF expression or degree of vascularization did not correlate with tumor stage or overall survival. High HIF-1alpha levels correlated with low tumor stage (P < 0.001) and were associated with a favorable patient prognosis (P = 0.08).
The discordant results on expression of HIF-1alpha and HIF-2alpha suggest that these two proteins are differentially regulated in vivo, thus reflecting distinctive protein expression/stabilization mechanisms. The association between HIF-1alpha and favorable outcome stresses the importance of discriminating HIF-2alpha from HIF-1alpha expression and has implications for using HIFs as treatment targets.
缺氧被认为是肿瘤血管生成的主要驱动力。在缺氧条件下，缺氧诱导因子 HIF-1α 和 HIF-2α 的稳定和激活，以及血管内皮生长因子（VEGF）和其他促血管生成因子的表达诱导，为缺氧驱动的肿瘤血管生成提供了分子框架。本研究探讨了 HIF 和 VEGF 蛋白水平在神经母细胞瘤血管生成、肿瘤分期和总生存方面的相互关系。
从 93 名神经母细胞瘤患儿的肿瘤标本中取出组织芯，排列在微阵列上，并对 HIF-1α、HIF-2α、VEGF 和 CD31 蛋白进行染色。评估阳性细胞的比例和染色强度，并将蛋白水平相互关联，并与临床变量相关联。
尽管 HIF-1α（P < 0.001）和 HIF-2α（P < 0.001）的高水平均与 VEGF 表达呈正相关，但它们彼此并不完全相关。此外，HIF-1α（P = 0.002）和 VEGF（P < 0.001），但不是 HIF-2α，与 CD31 染色丰度所确定的血管化呈负相关。VEGF 表达或血管化程度与肿瘤分期或总生存无关。高 HIF-1α水平与低肿瘤分期（P < 0.001）相关，与患者预后良好相关（P = 0.08）。
HIF-1α 和 HIF-2α 表达的不一致结果表明，这两种蛋白在体内受到不同的调节，从而反映了不同的蛋白表达/稳定机制。HIF-1α 与良好预后之间的关联强调了区分 HIF-2α 与 HIF-1α 表达的重要性，并对将 HIF 作为治疗靶点具有重要意义。
