缺氧调节蛋白的基质表达是结直肠癌的不良预后因素。

Stromal expression of hypoxia regulated proteins is an adverse prognostic factor in colorectal carcinomas.

作者信息

Cleven Arjen H G, van Engeland Manon, Wouters Bradly G, de Bruïne Adriaan P

机构信息

Departments of Pathology, GROW Research Institute, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands.

出版信息

Cell Oncol. 2007;29(3):229-40. doi: 10.1155/2007/945802.

DOI:10.1155/2007/945802

PMID:17452775

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4617795/

Abstract

BACKGROUND

Hypoxia modifies the phenotype of tumors in a way that promotes tumor aggressiveness and resistance towards chemotherapy and radiotherapy. However, the expression and influence of hypoxia-regulated proteins on tumor biology are not well characterized in colorectal tumors. We studied the role of protein expression of hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, carbonic anhydrase 9 (CA9) and glucose transporter 1 (GLUT1) in patients with colorectal adenocarcinomas.

METHODS

Expression of HIF-1alpha, HIF-2alpha, CA9 and GLUT1 was quantified by immunohistochemistry in 133 colorectal adenocarcinomas. The expression of hypoxia markers was correlated with clinicopathological variables and overall patient survival.

RESULTS

Expression of these hypoxia markers was detected in the epithelial compartment of the tumor cells as well as in tumor-associated stromal cells. Although tumor cells frequently showed expression of one or more of the investigated hypoxia markers, no correlation among these markers or with clinical response was found. However, within the tumor stroma, positive correlations between the hypoxia markers HIF-2alpha, CA9 and GLUT1 were observed. Furthermore expression of HIF-2alpha and CA9 in tumor-associated stroma were both associated with a significantly reduced overall survival. In the Cox proportional hazard model, stromal HIF-2alpha expression was an independent prognostic factor for survival.

CONCLUSION

These observations show, that expression of hypoxia regulated proteins in tumor-associated stromal cells, as opposed to their expression in epithelial tumor cells, is associated with poor outcome in colorectal cancer. This study suggests that tumor hypoxia may influence tumor-associated stromal cells in a way that ultimately contributes to patient prognosis.

摘要

背景

缺氧以促进肿瘤侵袭性以及对化疗和放疗耐药的方式改变肿瘤表型。然而，缺氧调节蛋白在结直肠癌中的表达及其对肿瘤生物学的影响尚未得到充分表征。我们研究了缺氧诱导因子（HIF）-1α、HIF-2α、碳酸酐酶9（CA9）和葡萄糖转运蛋白1（GLUT1）的蛋白表达在结直肠癌患者中的作用。

方法

通过免疫组织化学对133例结直肠癌中的HIF-1α、HIF-2α、CA9和GLUT1表达进行定量分析。将缺氧标志物的表达与临床病理变量及患者总生存期进行关联分析。

结果

在肿瘤细胞的上皮区室以及肿瘤相关基质细胞中均检测到这些缺氧标志物的表达。尽管肿瘤细胞经常显示出一种或多种所研究的缺氧标志物的表达，但未发现这些标志物之间或与临床反应存在相关性。然而，在肿瘤基质中，观察到缺氧标志物HIF-2α、CA9和GLUT1之间呈正相关。此外，肿瘤相关基质中HIF-2α和CA9的表达均与总生存期显著降低相关。在Cox比例风险模型中，基质HIF-2α表达是生存的独立预后因素。