碳酸酐酶 XII 是胶质瘤中具有临床意义的分子肿瘤亚型特异性治疗靶点，具有对抗脑肿瘤细胞侵袭的潜力,OncoTargets and Therapy

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碳酸酐酶 XII 是胶质瘤中具有临床意义的分子肿瘤亚型特异性治疗靶点，具有对抗脑肿瘤细胞侵袭的潜力
OncoTargets and Therapy ( IF 2.7 ) Pub Date : 2021-03-04 , DOI: 10.2147/ott.s300623
Guanzhang Li ₁ , Ting-Wei Chen ₂ , Ann-Christin Nickel ₂ , Sajjad Muhammad ₂ , Hans-Jakob Steiger ₂ , Theophilos Tzaridis _{3,

4} , Daniel Hänggi ₂ , Reinhard Zeidler ₅ , Wei Zhang _{6,

7,

8} , Ulf Dietrich Kahlert _{1,

2}

Affiliation

背景：代谢酶碳酸酐酶 12 (CA12/CAXII) 正在成为一种有前途的癌症治疗靶点，药物开发项目正在进行中。以前的报告提出了 CA12 在胶质瘤背景下的相关性，但患者数据数量有限，忽略了患者的种族多样性或依赖于半定量的方法，从而过时。此外，关于 CA12 与脑肿瘤干性的关联或抗 CAXII 定向单一疗法对神经胶质瘤干细胞 (GSC) 的影响，特别是它们对间充质分化状态的反应知之甚少。
方法：我们对三个独立的大规模患者数据集进行了计算机分析，这些数据集询问了最先进的分子诊断技术以及临床结果。我们分析了一组 GSC 上的 CAXII 丰度，并在功能上测试了它们对暴露于 CAXII 阻断抗体 6A10 的反应。
结果：与正常组织相比，CA12 在胶质瘤中高表达，预示着肿瘤患者的不良临床病程。胶质母细胞瘤中的 CA12 表达与临床确定的 IDH1 ^{WT分子标记显着相关}DNA，WHO IV 级或没有 1p/19q 染色体臂共缺失。此外，CA12 升高的肿瘤聚集成该疾病的间充质转录亚类。不同 GSC 中的 CAXII 丰度从几乎不存在到高水平不等，并且与干细胞标志物 CD133/AC133 细胞表面表达无关。此外，旨在用抗体 6A10 药理学阻断我们细胞中的 CAXII 仅在一种测试的 GSCs 模型中引起显着的功能反应，其特点是抑制细胞侵袭，同时减少 ZEB1 蛋白和其他干细胞标志物。
结论：CA12 代表临床相关的分子脑肿瘤亚型特异性治疗靶点。我们来自实验和临床样本的相关数据不支持 CA12/CAXII 是 GSC 特异性的。6A10 具有阻止神经胶质瘤细胞侵袭能力的巨大潜力，并支持 CAXII 与癌症 EMT 程序相互作用的新兴概念。然而，需要进一步的机制研究来全面评估 6A10 的治疗潜力并确定 GSCs 的不同耐药机制。

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Carbonic Anhydrase XII is a Clinically Significant, Molecular Tumor-Subtype Specific Therapeutic Target in Glioma with the Potential to Combat Invasion of Brain Tumor Cells

Background: The metabolic enzyme carbonic anhydrase 12 (CA12/CAXII) emerges as a promising cancer therapeutic target with drug development projects underway. Previous reports proposed the relevance of CA12 in the context of glioma but are limited in patient data quantity, ignore ethnic diversity of patients or rely on semi-quantitative, thereby out of date, methodology. Moreover, little is known on the association of CA12 to brain tumor stemness or on the effect of anti-CAXII-directed monotherapies on glioma stem cells (GSCs), in particular their response regarding mesenchymal differentiation status.
Methods: We performed in silico analysis on three independent, large-scale patient datasets interrogating state of the art molecular diagnostics alongside clinical outcomes. We analyzed CAXII abundance on a collection of GSCs and functionally tested their response to exposure to CAXII blocking antibody 6A10.
Results: CA12 is highly expressed in glial tumors compared with normal tissue and predicts for poor clinical course of tumor patients. CA12 expression in glioblastoma significantly correlates with clinically established, molecular markers of IDH1^WT DNA, WHO grade IV or absence of 1p/19q chromosome arm co-deletion. Furthermore, tumors with elevated CA12 cluster into the mesenchymal transcription subclass of the disease. CAXII abundance in different GSCs ranges from almost absent to high levels and does not correlate to stem cell marker CD133/AC133 cell surface expression. Moreover, aiming to pharmacologically block CAXII in our cells with antibody 6A10 caused significant functional response only in one of the tested GSCs models, featuring suppression of cell invasion accompanied by reduction of ZEB1 protein and other stem cell markers.
Conclusion: CA12 represents a clinically relevant and molecular brain tumor-subtype specific therapeutic target. Our correlative data from experimental and clinical samples does not support CA12/CAXII to be GSC specific. 6A10 possesses promising potential to impede the invasive capacity of glioma cells and supports the emerging concept that CAXII interacts with cancer EMT programs. However, further mechanistic studies are required to comprehensively assess the therapeutic potential of 6A10 and to identify different resistance mechanisms of GSCs.

更新日期：2021-04-20

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