Heparanase: From basic research to therapeutic applications in cancer and inflammation.
Heparanase: From basic research to therapeutic applications in cancer and inflammation.
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DOI：
10.1016/j.drup.2016.10.001
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发表时间：
2016-11
期刊：
影响因子：
--
通讯作者：
Ilan N
中科院分区：
文献类型：
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作者：
Vlodavsky I;Singh P;Boyango I;Gutter-Kapon L;Elkin M;Sanderson RD;Ilan N
乙酰肝素酶是唯一的硫酸乙酰肝素内切糖苷酶，具有多种生物学活性，可促进肿瘤生长、血管生成和转移。乙酰肝素酶表达在几乎所有检查的癌症中增强，包括各种癌、肉瘤和血液恶性肿瘤。大量临床相关研究一致表明，乙酰肝素酶表达上调与肿瘤大小增加、肿瘤血管生成、转移增强和预后不良相关。相比之下，乙酰肝素酶的敲除或用乙酰肝素酶抑制化合物治疗荷瘤小鼠，显著减弱肿瘤进展，进一步强调了抗乙酰肝素酶治疗多种类型癌症的潜力。乙酰肝素酶中和单克隆抗体阻断骨髓瘤和淋巴瘤肿瘤生长和播散;这归因于对肿瘤细胞和/或肿瘤微环境细胞的联合作用。事实上，乙酰肝素酶对肿瘤进展的大部分影响与其介导肿瘤-宿主串扰，启动肿瘤微环境以更好地支持肿瘤生长，转移和化疗抗性的功能有关。乙酰肝素酶的生理病理学活性的库正在扩大。具体而言，乙酰肝素酶调节基因表达，激活先天免疫系统的细胞，促进外泌体和自噬体的形成，并通过酶和非酶活性刺激信号转导途径。这些作用动态地影响共同驱动炎症反应、肿瘤存活、生长、传播和耐药性的多个调节途径;但同时，可能实现与例如囊泡运输、基于溶酶体的分泌、应激反应和硫酸乙酰肝素周转相关的一些正常功能。乙酰肝素酶在癌症患者中响应于化疗而上调，并且存活的细胞获得化学抗性，这至少部分归因于自噬。因此，与化疗药物串联使用的乙酰肝素酶抑制剂克服了初始的化学抗性，为与常规抗癌药物组合应用抗乙酰肝素酶治疗提供了强有力的理论基础。抑制乙酰肝素酶活性的肝素样化合物正在各种类型癌症的临床试验中进行评估。肝素酶中和单克隆抗体正在临床前研究中进行评估，肝素酶抑制小分子正在根据最近解析的肝素酶蛋白质晶体结构进行开发。总的来说，新出现的前提是，肿瘤细胞、先天免疫细胞、活化的内皮细胞以及肿瘤微环境的其他细胞表达的乙酰肝素酶是癌症侵袭性表型的主要调节因子，是癌症患者预后不良的重要因素。也是治疗的主要目标。
Heparanase, the sole heparan sulfate degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, angiogenesis and metastasis. Heparanase expression is enhanced in almost all cancers examined including various carcinomas, sarcomas and hematological malignancies. Numerous clinical association studies have consistently demonstrated that upregulation of heparanase expression correlates with increased tumor size, tumor angiogenesis, enhanced metastasis and poor prognosis. In contrast, knockdown of heparanase or treatments of tumor-bearing mice with heparanase-inhibiting compounds, markedly attenuate tumor progression further underscoring the potential of anti-heparanase therapy for multiple types of cancer. Heparanase neutralizing monoclonal antibodies block myeloma and lymphoma tumor growth and dissemination; this is attributable to a combined effect on the tumor cells and/or cells of the tumor microenvironment. In fact, much of the impact of heparanase on tumor progression is related to its function in mediating tumor-host crosstalk, priming the tumor microenvironment to better support tumor growth, metastasis and chemoresistance. The repertoire of the physiopathological activities of heparanase is expanding. Specifically, heparanase regulates gene expression, activates cells of the innate immune system, promotes the formation of exosomes and autophagosomes, and stimulates signal transduction pathways via enzymatic and non-enzymatic activities. These effects dynamically impact multiple regulatory pathways that together drive inflammatory responses, tumor survival, growth, dissemination and drug resistance; but in the same time, may fulfill some normal functions associated, for example, with vesicular traffic, lysosomal-based secretion, stress response, and heparan sulfate turnover. Heparanase is upregulated in response to chemotherapy in cancer patients and the surviving cells acquire chemoresistance, attributed, at least in part, to autophagy. Consequently, heparanase inhibitors used in tandem with chemotherapeutic drugs overcome initial chemoresistance, providing a strong rationale for applying anti-heparanase therapy in combination with conventional anti-cancer drugs. Heparin-like compounds that inhibit heparanase activity are being evaluated in clinical trials for various types of cancer. Heparanase neutralizing monoclonal antibodies are being evaluated in pre-clinical studies, and heparanase-inhibiting small molecules are being developed based on the recently resolved crystal structure of the heparanase protein. Collectively, the emerging premise is that heparanase expressed by tumor cells, innate immune cells, activated endothelial cells as well as other cells of the tumor microenvironment is a master regulator of the aggressive phenotype of cancer, an important contributor to the poor outcome of cancer patients and a prime target for therapy.