The Role of Heparanase and Sulfatases in the Modification of Heparan Sulfate Proteoglycans within the Tumor Microenvironment and Opportunities for Novel Cancer Therapeutics.
The Role of Heparanase and Sulfatases in the Modification of Heparan Sulfate Proteoglycans within the Tumor Microenvironment and Opportunities for Novel Cancer Therapeutics.
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DOI：
10.3389/fonc.2014.00195
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发表时间：
2014
影响因子：
4.7
通讯作者：
Dredge K
中科院分区：
文献类型：
--
作者：
Hammond E;Khurana A;Shridhar V;Dredge K
硫酸乙酰肝素蛋白多糖(HSPGs)是细胞表面和细胞外基质中正常组织结构中不可或缺的动态部分。众所周知，肿瘤微环境中HSPGs的修饰不仅会导致结构上的后果，还会导致功能上的后果，从而显著影响癌症的进展。作为关键酶硫酸酯酶和肝素酶的底物，HSPGS的修饰通常是通过内切-6-O-硫酸酯酶(Sulf1和Sulf2)或乙酰肝素酶(一种内切糖苷酶，裂解HS聚合物，从HSPG复合体中释放出较小的片段)降解乙酰肝素硫酸酯(HS)链/硫化模式。大量研究表明，这些酶是如何积极影响癌细胞的增殖、信号、侵袭和转移的。据报道，这些酶的活性或表达在各种癌症中被修饰。这些观察结果与正常结构和基底膜的退化是一致的，而正常结构和基底膜在转移性疾病中通常是受损的。此外，最近的研究阐明了这些蛋白质在肿瘤发生和发展中的需求，举例说明了它们在癌症发生和发展中的重要性。因此，随着肿瘤微环境在癌症进展中的影响变得更加明显，对降解HSPG的靶向酶的关注突出了一种维持正常组织结构、抑制肿瘤进展和阻止转移的方法。这篇综述讨论了这些酶在肿瘤微环境中的作用，以及它们作为癌症治疗靶点的前景。
Heparan sulfate proteoglycans (HSPGs) are an integral and dynamic part of normal tissue architecture at the cell surface and within the extracellular matrix. The modification of HSPGs in the tumor microenvironment is known to result not just in structural but also functional consequences, which significantly impact cancer progression. As substrates for the key enzymes sulfatases and heparanase, the modification of HSPGs is typically characterized by the degradation of heparan sulfate (HS) chains/sulfation patterns via the endo-6-O-sulfatases (Sulf1 and Sulf2) or by heparanase, an endo-glycosidase that cleaves the HS polymers releasing smaller fragments from HSPG complexes. Numerous studies have demonstrated how these enzymes actively influence cancer cell proliferation, signaling, invasion, and metastasis. The activity or expression of these enzymes has been reported to be modified in a variety of cancers. Such observations are consistent with the degradation of normal architecture and basement membranes, which are typically compromised in metastatic disease. Moreover, recent studies elucidating the requirements for these proteins in tumor initiation and progression exemplify their importance in the development and progression of cancer. Thus, as the influence of the tumor microenvironment in cancer progression becomes more apparent, the focus on targeting enzymes that degrade HSPGs highlights one approach to maintain normal tissue architecture, inhibit tumor progression, and block metastasis. This review discusses the role of these enzymes in the context of the tumor microenvironment and their promise as therapeutic targets for the treatment of cancer.