Leo Cornelia, Horn Lars-Christian, Rauscher Cora, Hentschel Bettina, Richter Christine E, Schütz Alexander, Leo Chandra Paul, Höckel Michael
Department of Gynecology, Leipzig University, Leipzig, Germany.
Clin Cancer Res. 2007 Feb 15;13(4):1149-53. doi: 10.1158/1078-0432.CCR-06-2371.
Clinical observations suggest that intratumoral hypoxia increases the aggressiveness of tumors through clonal selection of cancer cells that have lost their apoptotic potential. The aim of this study, therefore, was to investigate the expression of the proapoptotic protein apoptotic protease activating factor-1 (Apaf-1) in cervical cancers and to analyze its relation to intratumoral hypoxia and apoptosis. Furthermore, the effect of hypoxia and apoptosis on survival was examined.
In 56 patients, intratumoral oxygenation measurements and subsequent needle biopsies were done. The obtained tissue was analyzed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assays and by immunohistochemistry with an Apaf-1 antibody.
Apaf-1 was expressed in 86% of cancers. The median apoptosis rate was 1.0%. There was no correlation between Apaf-1 expression and intratumoral hypoxia. However, Apaf-1 expression was negative in 37.5% of hypoxic cervical cancers (pO(2) <or= 10 mmHg) with low apoptosis rates (<or=1.0%) compared with only 5.0% in nonhypoxic cancers and hypoxic cancers with high apoptosis (P = 0.005; Fisher's exact test). With a median follow-up period of 44 months, there was a nonsignificant trend toward worse prognosis in the hypoxic low-apoptotic group (P = 0.08).
Although Apaf-1 is expressed in the vast majority of cervical cancers, a significant proportion of tumors with low apoptosis rates despite intratumoral hypoxia showed a lack of Apaf-1 expression. This finding suggests that loss of Apaf-1 expression is a mechanism by which hypoxic cervical cancers acquire resistance to apoptosis. Thus, low Apaf-1 expression in hypoxic tumors may be an unfavorable prognostic factor.
临床观察表明，肿瘤内缺氧通过对失去凋亡潜能的癌细胞进行克隆选择，增加了肿瘤的侵袭性。因此，本研究的目的是调查促凋亡蛋白凋亡蛋白酶激活因子-1（Apaf-1）在宫颈癌中的表达，并分析其与肿瘤内缺氧及凋亡的关系。此外，还研究了缺氧和凋亡对生存率的影响。
对56例患者进行了肿瘤内氧合测量及随后的针吸活检。通过末端脱氧核苷酸转移酶介导的dUTP缺口末端标记试验和使用Apaf-1抗体的免疫组织化学分析所获得的组织。
86%的癌症中表达Apaf-1。凋亡率中位数为1.0%。Apaf-1表达与肿瘤内缺氧之间无相关性。然而，在凋亡率低（≤1.0%）的37.5%的缺氧宫颈癌（pO₂≤10 mmHg）中Apaf-1表达为阴性，相比之下，在非缺氧癌症和高凋亡的缺氧癌症中仅为5.0%（P = 0.005；Fisher精确检验）。中位随访期为44个月，缺氧低凋亡组预后较差，但无显著趋势（P = 0.08）。
尽管Apaf-1在绝大多数宫颈癌中表达，但相当一部分肿瘤尽管肿瘤内缺氧但凋亡率低，却显示Apaf-1表达缺失。这一发现表明，Apaf-1表达缺失是缺氧宫颈癌获得凋亡抗性的一种机制。因此，缺氧肿瘤中Apaf-1低表达可能是一个不利的预后因素。
