Effect of distributional heterogeneity on the analysis of tumor hypoxia based on carbonic anhydrase IX
Effect of distributional heterogeneity on the analysis of tumor hypoxia based on carbonic anhydrase IX
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DOI：
10.1038/labinvest.3700680
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发表时间：
2007-12-01
影响因子：
5
通讯作者：
Hedley, David W.
中科院分区：
文献类型：
--
作者：
Iakovlev, Vladimir V.;Pintilie, Melania;Hedley, David W.
免疫组织化学 (IHC) 广泛用于评估预后标志物和对新型抗癌药物的敏感性，以及癌症的常规临床评估。然而，尽管众所周知肿瘤具有高度异质性，但组织学标志物测量中产生的采样误差常常被忽视，特别是在基础科学研究中。在本文中，我们测试了这样的假设：优化组织采样以补偿异质性可改善内在缺氧标记物碳酸酐酶 IX (CAIX) 的组织学测量与整体肿瘤氧合状态之间的相关性。该研究以 24 名浸润性宫颈癌患者为研究对象，在直接评估肿瘤内的 pO(2) 时对这些患者进行了多次活检，这是一项研究的一部分。通过对这些活检组织切出的多个深层切片进行图像分析来进行测量，并使用免疫荧光和免疫组织化学技术标记 CAIX，并包括组织微阵列 (TMA) 模拟。方差和相关分析表明，组织样本（活检或TMA核心）的大小是影响样本测量准确性的主要因素。多个活检/核心的采样也改善了整体肿瘤评估，前提是这些在空间上充分分离。采样的优化改善了 CAIX 染色与肿瘤 pO2 测量值的相关性，与假设一致。然而，CAIX 作为患者分层的工具不如 pO2 测量。需要改进分析方法来解释肿瘤内异质性，以提供分子标记的可靠测量。
Immunohistochemistry (IHC) is used extensively to assess markers for prognosis and sensitivity to novel anticancer agents, as well as in the routine clinical assessment of cancers. Yet, although it is well known that tumors are highly heterogeneous, the resulting sampling error in the measurement of histological markers is often ignored, particularly in basic scientific studies. In this paper, we tested the hypothesis that the optimization of tissue sampling to compensate for heterogeneity improves the correlation between histological measurements of the intrinsic hypoxia marker carbonic anhydrase IX (CAIX) and global tumor oxygenation status. The study was based on a group of 24 patients with invasive cervical carcinoma from whom multiple biopsies were obtained at the time of direct pO(2) assessment within the tumor, done as part of a research study. Measurements were made by image analysis of multiple deep sections cut through these biopsies, labeled for CAIX using both immunofluorescence and immunohistochemical techniques, and included tissue microarray (TMA) simulations. Variance and correlation analysis showed that the size of the tissue sample (biopsy or TMA core) was the major factor affecting accuracy of measurement in the sample. Sampling of multiple biopsies/cores also improved the global tumor assessment, provided that these were sufficiently separated in space. Optimization of sampling resulted in an improved correlation of CAIX staining with tumor pO2 measurements, consistent with the hypothesis. However, CAIX was inferior to pO2 measurements as a tool for patient stratification. Improved analytical methods to account for intratumoral heterogeneity are needed to provide reliable measurements of molecular markers.