Le Quynh-Thu, Chen Eunice, Salim Ali, Cao Hongbin, Kong Christina S, Whyte Richard, Donington Jessica, Cannon Walter, Wakelee Heather, Tibshirani Robert, Mitchell John D, Richardson Donna, O'Byrne Ken J, Koong Albert C, Giaccia Amato J
Department of Radiation Oncology, Stanford University Medical Center, Stanford, California 94305-5847, USA.
Clin Cancer Res. 2006 Mar 1;12(5):1507-14. doi: 10.1158/1078-0432.CCR-05-2049.
To directly assess tumor oxygenation in resectable non-small cell lung cancers (NSCLC) and to correlate tumor pO2 and the selected gene and protein expression to treatment outcomes.
Twenty patients with resectable NSCLC were enrolled. Intraoperative measurements of normal lung and tumor pO2 were done with the Eppendorf polarographic electrode. All patients had plasma osteopontin measurements by ELISA. Carbonic anhydrase-IX (CA IX) staining of tumor sections was done in the majority of patients (n = 16), as was gene expression profiling (n = 12) using cDNA microarrays. Tumor pO2 was correlated with CA IX staining, osteopontin levels, and treatment outcomes.
The median tumor pO2 ranged from 0.7 to 46 mm Hg (median, 16.6) and was lower than normal lung pO2 in all but one patient. Because both variables were affected by the completeness of lung deflation during measurement, we used the ratio of tumor/normal lung (T/L) pO2 as a reflection of tumor oxygenation. The median T/L pO2 was 0.13. T/L pO2 correlated significantly with plasma osteopontin levels (r = 0.53, P = 0.02) and CA IX expression (P = 0.006). Gene expression profiling showed that high CD44 expression was a predictor for relapse, which was confirmed by tissue staining of CD44 variant 6 protein. Other variables associated with the risk of relapse were T stage (P = 0.02), T/L pO2 (P = 0.04), and osteopontin levels (P = 0.001).
Tumor hypoxia exists in resectable NSCLC and is associated with elevated expression of osteopontin and CA IX. Tumor hypoxia and elevated osteopontin levels and CD44 expression correlated with poor prognosis. A larger study is needed to confirm the prognostic significance of these factors.
直接评估可切除的非小细胞肺癌（NSCLC）中的肿瘤氧合情况，并将肿瘤pO2与选定的基因和蛋白质表达与治疗结果相关联。
招募了20例可切除的NSCLC患者。使用Eppendorf极谱电极对正常肺组织和肿瘤组织进行术中pO2测量。所有患者均通过酶联免疫吸附测定法检测血浆骨桥蛋白水平。大多数患者（n = 16）对肿瘤切片进行碳酸酐酶IX（CA IX）染色，12例患者使用cDNA微阵列进行基因表达谱分析。将肿瘤pO2与CA IX染色、骨桥蛋白水平及治疗结果相关联。
肿瘤pO2中位数范围为0.7至46 mmHg（中位数为16.6），除1例患者外，所有患者的肿瘤pO2均低于正常肺组织。由于测量期间肺萎陷的完整性会影响这两个变量，因此我们使用肿瘤/正常肺（T/L）pO2比值来反映肿瘤氧合情况。T/L pO2中位数为0.13。T/L pO2与血浆骨桥蛋白水平（r = 0.53，P = 0.02）及CA IX表达（P = 0.006）显著相关。基因表达谱分析显示，CD44高表达是复发的预测指标，CD44变体6蛋白的组织染色证实了这一点。与复发风险相关的其他变量包括T分期（P = 0.02）、T/L pO2（P = 0.04）及骨桥蛋白水平（P = 0.001）。
可切除的NSCLC中存在肿瘤缺氧，且与骨桥蛋白和CA IX的表达升高相关。肿瘤缺氧、骨桥蛋白水平升高及CD44表达与预后不良相关。需要开展更大规模的研究来证实这些因素的预后意义。
