Expression of hypoxia-inducible carbonic anhydrases in brain tumors
Expression of hypoxia-inducible carbonic anhydrases in brain tumors
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DOI：
10.1215/s1152851705000025
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发表时间：
2005-10-01
期刊：
影响因子：
15.9
通讯作者：
Merrill, MJ
中科院分区：
文献类型：
--
作者：
Proescholdt, MA;Mayer, C;Merrill, MJ
恶性脑肿瘤表现出独特的代谢特征。尽管乳酸水平很高，但脑肿瘤的细胞内 pH 值比正常大脑更呈碱性。此外，随着恶性肿瘤的增加，脑肿瘤表现出瘤内缺氧。碳酸酐酶 (CA) IX 和 XII 是由组织缺氧诱导的跨膜同工酶。它们通过催化二氧化碳的可逆水合参与 pH 稳态的调节。我们研究的目的是调查与正常脑相比，不同组织学和恶性程度的脑肿瘤是否表达升高水平的 CA IX 和 XII。我们通过免疫组织化学、蛋白质印迹和原位杂交分析了来自脑肿瘤（原发性和转移性）和正常脑的 120 个组织标本的 CA IX 和 XII 表达。虽然正常脑组织显示出最低水平的 CA IX 和 XII 表达，但发现肿瘤中的表达随着恶性肿瘤水平的增加而上调。来自 von Hippel-Lindau 病患者的血管母细胞瘤也表现出高水平的 CA IX 和 XII 表达。 CA IX 和 XII 染色与 HIF-let 染色的比较显示出相似的显微解剖分布，表明缺氧是主要但不是唯一的诱导因素。如 Ki67 标记所示，CA IX 和 XII 染色的程度与细胞增殖相关。结果表明，与正常脑组织相比，CA IX 和 XII 在固有性和转移性脑肿瘤中表达上调。这可能有助于肿瘤特异性酸负荷的管理并提供治疗靶点。
Malignant brain tumors exhibit distinct metabolic characteristics. Despite high levels of lactate, the intracellular pH of brain tumors is more alkaline than normal brain. Additionally, with increasing malignancy, brain tumors display intratumoral hypoxia. Carbonic anhydrase (CA) IX and XII are transmembrane isoenzymes that are induced by tissue hypoxia. They participate in regulation of pH homeostasis by catalyzing the reversible hydration of carbon dioxide. The aim of our study was to investigate whether brain tumors of different histology and grade of malignancy express elevated levels of CA IX and XII as compared to normal brain. We analyzed 120 tissue specimens from brain tumors (primary and metastatic) and normal brain for CA IX and XII expression by immunohistochemistry, Western blot, and in situ hybridization. Whereas normal brain tissue showed minimal levels of CA IX and XII expression, expression in tumors was found to be upregulated with increased level of malignancy. Hemangioblastomas, from patients with von Hippel-Lindau disease, also displayed high levels of CA IX and XII expression. Comparison of CA IX and XII staining with HIF-let staining revealed a similar microanatomical distribution, indicating hypoxia as a major, but not the only, induction factor. The extent of CA IX and XII staining correlated with cell proliferation, as indicated by Ki67 labeling. The results demonstrate that CA IX and XII are upregulated in intrinsic and metastatic brain tumors as compared to normal brain tissue. This may contribute to the management of tumor-specific acid load and provide a therapeutic target.