Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer
Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer
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DOI：
10.1016/s0360-3016(02)02848-1
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发表时间：
2002-08-01
影响因子：
7
通讯作者：
Harris, AL
中科院分区：
文献类型：
--
作者：
Koukourakis, MI;Giatromanolaki, A;Harris, AL
目的：低氧诱导因子HIF 1 α和HIF 2 α（HIF α）调节多种编码与血管生成和暴露于低氧应激的细胞的无氧代谢相关的蛋白质的基因的表达。它们作为临床相关缺氧标志物的假定作用，因此，作为对放化疗反应的预测因素，在此检查。患者和方法：使用免疫组织化学，我们评估了HIF α在正常头颈部粘膜和75例局部晚期鳞状细胞头颈部癌（SCHNC）患者的癌标本中的表达，这些患者同时接受卡铂放化疗。正常人的头颈部粘膜未显示任何HIF 1 α或HIF 2 α反应性。SCHNC表现出不同的HIF表达，范围从阴性反应，到弱或局部强细胞质反应，或到强弥漫性细胞质/核反应。52%和33%的癌症样本分别显示了HIF 1 α和HIF 2 α的后一种表达模式，并被认为具有“高”HIF反应性。骨/软骨受累在HIF 1 α高表达的肿瘤中更常见（p = 0.05）。HIF 1 α和HIF 2 α过表达与高微血管密度（分别为p = 0.002和0.02）和VEGF表达（分别为p = 0.01和0.005）显著相关。HIF 1 α与胸苷磷酸化酶高表达相关（p = 0.03），而VEGF/KDR激活的肿瘤血管系统在HIF 2 α过表达的肿瘤中明显更常见（p = 0.02）。高HIF 1 α和HIF 2 α与放化疗不完全应答相关（分别为p = 0.007和p = 0.02）。在单变量分析中，HIF 1 α和HIF 2 α高表达与局部无复发生存率（分别为p = 0.003和0.003）和总生存率（分别为p = 0.05和0.001）显著相关。在多变量模型中，HIF 2 α表达是一个独立的预后因素。在活检后进行的交付20戈伊的放射治疗，上调HIF α注意到在某些cases.Conclusions：它的结论是过度表达的HIF α在SCHNC是有关的局部侵略性行为，血管生成的加剧，和一个重要的耐卡铂放化疗。(C)2002年爱思唯尔科技有限公司
Purpose: Hypoxia-inducible factors HIF1alpha and HIF2alpha (HIFalphas) regulate the expression of a variety of genes encoding proteins related to angiogenesis and to anaerobic metabolism of cells exposed to hypoxic stress. Their putative role as markers of clinically relevant hypoxia and, therefore, as predictors of response to chemoradiotherapy is herein examined.Patients and Methods: Using immunohistochemistry, we assessed the expression of HIFalphas in normal head-neck mucosa and in 75 cancer specimens from patients with locally advanced squamous cell head-and-neck cancer (SCHNC), treated with concurrent carboplatin chemoradiotherapy.Results: Head-and-neck mucosa from normal individuals did not show any HIF1alpha or HIF2alpha reactivity. SCHNC showed a varying expression of HIFas ranging through negative reactivity, to weak or focally strong cytoplasmic reactivity, or to strong diffuse cytoplasmic/nuclear reactivity. Fifty-two percent and 33% of cancer samples showed the latter expression pattern for HIF1alpha and HIF2alpha, respectively, and were considered to bear "high" HIF reactivity. Bone/cartilage involvement was more frequent in tumors with high HIF1alpha expression (p = 0.05). HIF1alpha and HIF2alpha overexpression were significantly associated with high microvessel density (p = 0.002 and 0.02, respectively) and with VEGF expression (p = 0.01 and 0.005, respectively). HIF1alpha was related to high thymidine phosphorylase expression (p = 0.03), whereas VEGF/KDR-activated tumor vasculature was significantly more frequent in HIF2alpha-overexpressing tumors (p = 0.02). High HIF1alpha and HIF2alpha were associated with incomplete response to chemoradiation (p = 0.007 and p = 0.02, respectively). In univariate analysis, high HIF1alpha and HIF2alpha expression were significantly associated with poor local relapse-free survival (p = 0.003 and 0.003, respectively) and with poor overall survival (p = 0.05 and 0.001, respectively). In multivariate models, HIF2alpha expression was an independent prognostic factor. In biopsies performed after the delivery of 20 Gy of radiotherapy, upregulation of HIFalphas was noted in some cases.Conclusions: It is concluded that the overexpression of HIFas in SCHNC is related to locally aggressive behavior, to intensification of angiogenesis, and to an important resistance to carboplatin chemoradiotherapy. (C) 2002 Elsevier Science Inc.