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 physio-pathological 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.

乙酰肝素酶是唯一降解硫酸乙酰肝素的内切糖苷酶，可调节多种生物活性，从而增强肿瘤的生长，血管生成和转移。在几乎所有检查的癌症中，包括各种癌，肉瘤和血液系统恶性肿瘤中，乙酰肝素酶的表达均得到增强。大量临床协会研究一致表明，乙酰肝素酶表达的上调与肿瘤大小增加，肿瘤血管生成，转移增加和预后不良有关。相反，敲除乙酰肝素酶或用抑制乙酰肝素酶的化合物治疗荷瘤小鼠显着减弱了肿瘤的进展，进一步强调了抗乙酰肝素酶治疗多种类型癌症的潜力。乙酰肝素酶中和性单克隆抗体可阻断骨髓瘤和淋巴瘤肿瘤的生长和扩散；这归因于对肿瘤细胞和/或肿瘤微环境的细胞的联合作用。实际上，乙酰肝素酶对肿瘤进展的许多影响与其在介导肿瘤-宿主串扰，启动肿瘤微环境以更好地支持肿瘤生长，转移和化学耐药性方面的功能有关。乙酰肝素酶的生理病理活动范围正在扩大。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，促进外来体和自噬体的形成，并通过酶促和非酶促活性刺激信号转导途径。这些效应动态影响多种调节途径，共同驱动炎症反应，肿瘤存活，生长，扩散和耐药性。但同时 可能履行一些正常功能，例如与水泡交通，基于溶酶体的分泌，应激反应和硫酸乙酰肝素更新有关。肝癌中的乙酰肝素酶响应于化学疗法而被上调，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，肝素酶抑制剂与化学治疗药物联用克服了最初的化学抗性，为结合常规抗癌药物应用抗肝素酶治疗提供了有力的依据。在各种类型的癌症的临床试验中，正在评估抑制肝素酶活性的类肝素化合物。临床前研究正在评估乙酰肝素酶中和性单克隆抗体，基于乙酰肝素酶蛋白的最近解析的晶体结构，正在开发抑制肝素酶和肝素酶抑制作用的小分子。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剂，这是导致癌症患者不良结局的重要原因和治疗的主要目标。