肝素酶在间皮瘤发病机制中的作用：基础方面和临床应用。
Involvement of Heparanase in the Pathogenesis of Mesothelioma: Basic Aspects and Clinical Applications.
机构信息
Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Departments of General Thoracic Surgery, Rambam Health Care Campus, Haifa, Israel.
出版信息
J Natl Cancer Inst. 2018 Oct 1;110(10):1102-1114. doi: 10.1093/jnci/djy032.
BACKGROUND
Mammalian cells express a single functional heparanase, an endoglycosidase that cleaves heparan sulfate and thereby promotes tumor metastasis, angiogenesis, and inflammation. Malignant mesothelioma is highly aggressive and has a poor prognosis because of the lack of markers for early diagnosis and resistance to conventional therapies. The purpose of this study was to elucidate the mode of action and biological significance of heparanase in mesothelioma and test the efficacy of heparanase inhibitors in the treatment of this malignancy.
METHODS
The involvement of heparanase in mesothelioma was investigated by applying mouse models of mesothelioma and testing the effect of heparanase gene silencing (n = 18 mice per experiment; two different models) and heparanase inhibitors (ie, PG545, defibrotide; n = 18 per experiment; six different models). Synchronous pleural effusion and plasma samples from patients with mesothelioma (n = 35), other malignancies (12 non-small cell lung cancer, two small cell lung carcinoma, four breast cancer, three gastrointestinal cancers, two lymphomas), and benign effusions (five patients) were collected and analyzed for heparanase content (enzyme-linked immunosorbent assay). Eighty-one mesothelioma biopsies were analyzed by H-Score for the prognostic impact of heparanase using immunohistochemistry. All statistical tests were two-sided.
RESULTS
Mesothelioma tumor growth, measured by bioluminescence or tumor weight at termination, was markedly attenuated by heparanase gene silencing (P = .02) and by heparanase inhibitors (PG545 and defibrotide; P < .001 and P = .01, respectively). A marked increase in survival of the mesothelioma-bearing mice (P < .001) was recorded. Heparanase inhibitors were more potent in vivo than conventional chemotherapy. Clinically, heparanase levels in patients' pleural effusions could distinguish between malignant and benign effusions, and a heparanase H-score above 90 was associated with reduced patient survival (hazard ratio = 1.89, 95% confidence interval = 1.09 to 3.27, P = .03).
CONCLUSIONS
Our results imply that heparanase is clinically relevant in mesothelioma development. Given these preclinical and clinical data, heparanase appears to be an important mediator of mesothelioma, and heparanase inhibitors are worthy of investigation as a new therapeutic modality in mesothelioma clinical trials.
背景
哺乳动物细胞表达一种单一的功能性肝素酶，这是一种内切糖苷酶，可切割肝素硫酸酯，从而促进肿瘤转移、血管生成和炎症。恶性间皮瘤侵袭性强，预后不良，这是因为缺乏早期诊断的标志物，且对常规疗法具有耐药性。本研究旨在阐明肝素酶在间皮瘤中的作用模式和生物学意义，并测试肝素酶抑制剂治疗这种恶性肿瘤的疗效。
方法
通过应用间皮瘤的小鼠模型，检测肝素酶基因沉默（每组实验 18 只小鼠；两种不同模型）和肝素酶抑制剂（即 PG545、地昔洛肽）的效果，研究肝素酶在间皮瘤中的作用（每组实验 18 只小鼠；六种不同模型）。收集并分析来自间皮瘤患者（35 例）、其他恶性肿瘤患者（12 例非小细胞肺癌、2 例小细胞肺癌、4 例乳腺癌、3 例胃肠道癌、2 例淋巴瘤）和良性渗出液患者（5 例）的同步胸腔积液和血浆样本，以检测肝素酶含量（酶联免疫吸附测定法）。采用免疫组织化学法对 81 例间皮瘤活检样本进行 H 评分，以分析肝素酶的预后影响。所有统计检验均为双侧检验。
结果
通过生物发光或实验结束时的肿瘤重量测量，肝素酶基因沉默（P =.02）和肝素酶抑制剂（PG545 和地昔洛肽；P <.001 和 P =.01）均显著抑制间皮瘤肿瘤生长。荷瘤小鼠的生存时间明显延长（P <.001）。肝素酶抑制剂在体内比常规化疗更有效。临床上，患者胸腔积液中的肝素酶水平可区分恶性和良性渗出液，肝素酶 H 评分高于 90 与患者生存时间缩短相关（风险比 = 1.89，95%置信区间 = 1.09 至 3.27，P =.03）。
结论
我们的研究结果表明肝素酶在间皮瘤发展中具有临床相关性。鉴于这些临床前和临床数据，肝素酶似乎是间皮瘤的一个重要介质，肝素酶抑制剂作为间皮瘤临床试验的一种新治疗方法值得进一步研究。
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