Turning-Off Signaling by Siglecs, Selectins, and Galectins: Chemical Inhibition of Glycan-Dependent Interactions in Cancer.
Turning-Off Signaling by Siglecs, Selectins, and Galectins: Chemical Inhibition of Glycan-Dependent Interactions in Cancer.
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DOI：
10.3389/fonc.2016.00109
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发表时间：
2016
影响因子：
4.7
通讯作者：
Mariño KV
中科院分区：
文献类型：
--
作者：
Cagnoni AJ;Pérez Sáez JM;Rabinovich GA;Mariño KV
异常糖基化是与恶性肿瘤相关的常见特征，与癌症进展过程中的重要事件有关。在过去的几年里，我们对聚糖在癌症中的作用的理解呈指数级增长，同时在糖组学和糖蛋白质组学技术方面取得了重要进展，为验证许多聚糖结构作为潜在的糖生物标志物铺平了道路。然而，癌症相关聚糖修饰的分子基础仍然远未被理解。聚糖具有天然的异质性，这对于其作为生物相关信息的特定载体的多种功能作用至关重要。这种信息由称为凝集素的蛋白质家族解码，包括唾液酸结合免疫球蛋白（IG）样凝集素（siglecs）、C型凝集素受体（CLR）和半乳糖凝集素。Siglecs主要在免疫细胞的表面上表达，并且差异地控制先天性和适应性免疫应答。在CLR中，选择素是介导癌细胞与血小板、白细胞和内皮细胞之间的相互作用的细胞粘附分子家族，从而促进肿瘤细胞侵袭和转移。半乳糖凝集素是结合含β-半乳糖苷的聚糖的可溶性蛋白质家族，其参与与癌症生物学相关的多种事件，如细胞凋亡、同型细胞聚集、血管生成、细胞迁移和肿瘤免疫逃逸。因此，这些凝集素家族的个体成员已成为设计新型抗癌疗法的有希望的靶点。在过去的十年中，已经开发了许多凝集素-聚糖相互作用的抑制剂，包括小分子抑制剂、多价糖配体，并且最近肽和肽模拟物提供了解决肿瘤进展的替代方案。在这篇文章中，我们回顾了化学凝集素抑制剂的发现和发展的现状，并讨论了通过靶向凝集素-聚糖相互作用来限制癌症进展的新策略。
Aberrant glycosylation, a common feature associated with malignancy, has been implicated in important events during cancer progression. Our understanding of the role of glycans in cancer has grown exponentially in the last few years, concurrent with important advances in glycomics and glycoproteomic technologies, paving the way for the validation of a number of glycan structures as potential glycobiomarkers. However, the molecular bases underlying cancer-associated glycan modifications are still far from understood. Glycans exhibit a natural heterogeneity, crucial for their diverse functional roles as specific carriers of biologically relevant information. This information is decoded by families of proteins named lectins, including sialic acid-binding immunoglobulin (Ig)-like lectins (siglecs), C-type lectin receptors (CLRs), and galectins. Siglecs are primarily expressed on the surface of immune cells and differentially control innate and adaptive immune responses. Among CLRs, selectins are a family of cell adhesion molecules that mediate interactions between cancer cells and platelets, leukocytes, and endothelial cells, thus facilitating tumor cell invasion and metastasis. Galectins, a family of soluble proteins that bind β-galactoside-containing glycans, have been implicated in diverse events associated with cancer biology such as apoptosis, homotypic cell aggregation, angiogenesis, cell migration, and tumor-immune escape. Consequently, individual members of these lectin families have become promising targets for the design of novel anticancer therapies. During the past decade, a number of inhibitors of lectin–glycan interactions have been developed including small-molecule inhibitors, multivalent saccharide ligands, and more recently peptides and peptidomimetics have offered alternatives for tackling tumor progression. In this article, we review the current status of the discovery and development of chemical lectin inhibitors and discuss novel strategies to limit cancer progression by targeting lectin–glycan interactions.