Yoo Heon, Baia Gilson S, Smith Justin S, McDermott Michael W, Bollen Andrew W, Vandenberg Scott R, Lamborn Kathleen R, Lal Anita
Brain Tumor Research Center, Department of Neurological Surgery, University of California, San Francisco, California 94143, USA.
Clin Cancer Res. 2007 Jan 1;13(1):68-75. doi: 10.1158/1078-0432.CCR-06-1377.
Hypoxia in the tumor microenvironment triggers a variety of genetic and adaptive responses that regulate tumor growth. Tumor hypoxia is often associated with more malignant phenotypes, resistance to therapy, and poor survival. The purpose of this study was to evaluate the prevalence of hypoxia in meningiomas using the endogenous hypoxia marker carbonic anhydrase 9 (CA9) and to relate the expression of CA9 to tumor vascularity, histopathologic grade, and clinical variables, such as recurrent tumor status.
Expression of CA9 and CD34, an endothelial cell marker, was examined in serial paraffin-embedded sections by immunohistochemistry in 25 grade 1, 17 grade 2, and 20 grade 3 meningiomas. Areas of immunoreactivity were semiquantitatively scored and correlated to clinical variables using Statistical Analysis System statistical software.
Approximately 50% (29 of 62) of all meningiomas contained regions of hypoxia as judged by expression of CA9, and this expression was significantly associated with higher-grade histology (P = 0.001). In contrast, vascularity, as assessed by the percentage of vascular hotspots, was inversely associated with tumor grade (P = 0.023) and was not associated with CA9 expression. Among lower-grade meningiomas, CA9 expression tended to be more common in recurrent tumors.
Tumor hypoxia is an endogenous feature of meningiomas, and therapeutic regimens should include strategies to target the subpopulation of hypoxic as well as the normoxic cells within the tumor. Hypoxia in meningiomas is associated with an aggressive phenotype. Further studies to define the contribution of hypoxia to meningioma pathophysiology are warranted.
肿瘤微环境中的缺氧会引发多种调节肿瘤生长的基因和适应性反应。肿瘤缺氧常与更恶性的表型、对治疗的抗性及较差的生存率相关。本研究的目的是使用内源性缺氧标志物碳酸酐酶9（CA9）评估脑膜瘤中缺氧的发生率，并将CA9的表达与肿瘤血管生成、组织病理学分级及临床变量（如肿瘤复发状态）相关联。
通过免疫组织化学在25例1级、17例2级和20例3级脑膜瘤的系列石蜡包埋切片中检测CA9和内皮细胞标志物CD34的表达。使用统计分析系统统计软件对免疫反应区域进行半定量评分，并与临床变量相关联。
根据CA9的表达判断，所有脑膜瘤中约50%（62例中的29例）含有缺氧区域，且这种表达与更高分级的组织学显著相关（P = 0.00）。相比之下，通过血管热点百分比评估的血管生成与肿瘤分级呈负相关（P = 0.023），且与CA9表达无关。在低级别脑膜瘤中，CA9表达在复发肿瘤中往往更常见。
肿瘤缺氧是脑膜瘤的一个内源性特征，治疗方案应包括针对肿瘤内缺氧细胞亚群以及正常氧细胞的策略。脑膜瘤中的缺氧与侵袭性表型相关。有必要进一步研究以确定缺氧对脑膜瘤病理生理学的影响。
