Involvement of Heparanase in the Pathogenesis of Mesothelioma: Basic Aspects and Clinical Applications
Involvement of Heparanase in the Pathogenesis of Mesothelioma: Basic Aspects and Clinical Applications
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DOI：
10.1093/jnci/djy032
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发表时间：
2018-10-01
影响因子：
10.3
通讯作者：
Vlodavsky, Israel
中科院分区：
文献类型：
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作者：
Barash, Uri;Lapidot, Moshe;Vlodavsky, Israel
背景资料：哺乳动物细胞表达单一功能性乙酰肝素酶，一种内切糖苷酶，其切割硫酸乙酰肝素，从而促进肿瘤转移、血管生成和炎症。恶性间皮瘤是高度侵袭性的，由于缺乏早期诊断的标志物和对常规治疗的抵抗，预后不良。本研究旨在阐明乙酰肝素酶在间皮瘤中的作用机制和生物学意义，并检测乙酰肝素酶抑制剂在间皮瘤治疗中的疗效。方法：应用小鼠间皮瘤模型，检测乙酰肝素酶基因沉默对间皮瘤的影响，探讨乙酰肝素酶在间皮瘤中的作用（每个实验n = 18只小鼠;两种不同的模型）和乙酰肝素酶抑制剂（即，PG 545，去纤维蛋白多核苷酸;每个实验n = 18;六种不同的模型）。收集间皮瘤（n = 35）、其他恶性肿瘤（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）和良性积液（5例患者）患者的同步胸腔积液和血浆样本，并分析乙酰肝素酶含量（酶联免疫吸附测定法）。81例间皮瘤活检标本采用免疫组化法通过H评分分析乙酰肝素酶对预后的影响。结果：间皮瘤肿瘤生长，通过生物发光或肿瘤重量在终止时测量，显着减弱乙酰肝素酶基因沉默（P = 0.02）和乙酰肝素酶抑制剂（PG 545和去纤维蛋白肽; P <0.001和P = 0.01，分别）。记录到携带间皮瘤的小鼠的存活率显著增加（P <0.001）。乙酰肝素酶抑制剂在体内比常规化疗更有效。临床上，患者胸腔积液中的乙酰肝素酶水平可以区分恶性和良性积液，乙酰肝素酶H评分高于90与患者生存率降低相关（风险比= 1.89，95%置信区间= 1.09至3.27，P = 0.03）。鉴于这些临床前和临床数据，乙酰肝素酶似乎是间皮瘤的重要介质，乙酰肝素酶抑制剂作为间皮瘤临床试验中的一种新的治疗方式值得研究。
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.