Daponte Alexandros, Ioannou Maria, Mylonis Ilias, Simos George, Minas Marcos, Messinis Ioannis E, Koukoulis George
Department of Obstetrics & Gynaecology, University of Thessalia, Larissa, Greece.
BMC Cancer. 2008 Nov 16;8:335. doi: 10.1186/1471-2407-8-335.
The hypoxia-inducible factor (HIF) has emerged as an attractive target for cancer therapy. The few publications addressing the prognostic significance of Hypoxia-Inducible Factor 1 alpha (HIF-1 alpha) cellular expression in ovarian cancer produced contradictory findings which are not permissible to widely acceptable conclusions and clinical applications. Our study was designed to investigate this by including a comparatively large number of cases and by using a combination of antibodies to analyze immunohistochemically the expression of HIF-1 alpha.
One hundred (n = 100) neoplastic and 20 benign (controls) pathological samples from paraffin-embedded tissue were included. They were classified after surgery as stage I (n = 23) and stage III G3 (n = 55). Also 22 borderline serous adenocarcinoma patients and 20 benign controls were stained. The mean follow up was 3 years. Only patients with the diagnosis of serous carcinoma of stage III, G3 who received 6 cycles of postoperative TC (175-180 mg/m2 paclitaxel and carboplatin after calculating the area under the concentration curve) with complete medical records (n = 55) were selected for survival analysis. The survival analysis of the samples compared two groups after the patients were dichotomized by HIF-1 alpha final score to positive and negative.
The frequency of the nuclear expression of HIF-1 alpha in benign tumours was significantly lower (median: no expression) than in borderline and ovarian cancer tumours combined (p < 0.001). HIF-1 alpha expression in serous ovarian carcinoma was not stage dependent. The overall survival of patients with tumours that stained strongly for HIF-1 alpha was significantly shorter than that of patients with tumours that stained weakly or were negative for HIF-1 alpha (p = 0.01). Kaplan-Meier survival curves confirmed that HIF-1 alpha "positive" had decreased overall survival compared to HIF-1 alpha "negative" patients (p = 0.003) and this was an independent adverse prognostic factor (multivariable analysis p = 0.006). HIF-1 alpha "positive" patients displayed a shorter median progress free interval (PFI) (not statistically significant p > 0.05). Interestingly the overall PFI of the subgroup of patients that have undergone suboptimal cytoreduction at primary surgery (n = 21) with tumours that stained strongly for HIF-1 alpha was significantly worse than that of patients with tumours that stained weakly or were negative for HIF- 1 alpha (p = 0.03).
Our report confirms the prognostic value of HIF-1 alpha when restricted to poorly differentiated serous ovarian carcinoma. In addition it shows that this association is elusive, since it is not only methodology-related but it can be antibody-depended. There is adequate evidence to speculate that targeting HIF-1 alpha could improve the long-term prognosis of these patients In order to increase the overall sensitivity of the immunoassay, maintaining acceptable levels of specificity, a panel of antibodies should be used.
缺氧诱导因子（HIF）已成为癌症治疗中一个有吸引力的靶点。少数关于缺氧诱导因子1α（HIF-1α）细胞表达在卵巢癌中的预后意义的出版物得出了相互矛盾的结果，这些结果无法得出广泛认可的结论和临床应用。我们的研究旨在通过纳入相对大量的病例并使用抗体组合来免疫组织化学分析HIF-1α的表达，对此进行调查。
纳入了100份来自石蜡包埋组织的肿瘤病理样本和20份良性（对照）病理样本。术后将它们分为I期（n = 23）和III期G3（n = 55）。还对22例交界性浆液性腺癌患者和20例良性对照进行了染色。平均随访时间为3年。仅选择诊断为III期G3浆液性癌且接受6个周期术后TC（计算浓度曲线下面积后为175 - 180 mg/m²紫杉醇和卡铂）且有完整病历的患者（n = 55）进行生存分析。样本的生存分析在患者按HIF-1α最终评分分为阳性和阴性两组后比较两组情况。
HIF-1α在良性肿瘤中的核表达频率显著低于交界性肿瘤和卵巢癌肿瘤合并组（中位数：无表达）（p < 0.001）。浆液性卵巢癌中HIF-1α的表达与分期无关。HIF-1α染色强的肿瘤患者的总生存期显著短于HIF-1α染色弱或阴性的肿瘤患者（p = 0.01）。Kaplan-Meier生存曲线证实，与HIF-1α“阴性”患者相比，HIF-1α“阳性”患者的总生存期降低（p = 0.003），这是一个独立的不良预后因素（多变量分析p = 0.006）。HIF-1α“阳性”患者的无进展生存期（PFI）中位数较短（无统计学意义，p > 0.05）。有趣的是，在初次手术时接受了次优细胞减灭术的患者亚组（n = 21）中，HIF-1α染色强的肿瘤患者的总体PFI显著差于HIF-1α染色弱或阴性的肿瘤患者（p = 0.03）。
我们的报告证实了HIF-1α在低分化浆液性卵巢癌中的预后价值。此外，它表明这种关联难以捉摸，因为它不仅与方法学有关，还可能取决于抗体。有充分证据推测靶向HIF-1α可以改善这些患者的长期预后。为了提高免疫测定的总体敏感性并保持可接受的特异性水平，应使用一组抗体。
