Nagarajan Arvindhan, Malvi Parmanand, Wajapeyee Narendra
Department of Pathology, Yale University School of Medicine, New Haven, CT, United States.
Yale Cancer Center, Yale University School of Medicine, New Haven, CT, United States.
Front Endocrinol (Lausanne). 2018 Aug 24;9:483. doi: 10.3389/fendo.2018.00483. eCollection 2018.
Heparan sulfate (HS) are complex unbranched carbohydrate chains that are heavily modified by sulfate and exist either conjugated to proteins or as free, unconjugated chains. Proteins with covalently bound Heparan sulfate chains are termed Heparan Sulfate Proteoglycans (HSPGs). Both HS and HSPGs bind to various growth factors and act as co-receptors for different cell surface receptors. They also modulate the dynamics and kinetics of various ligand-receptor interactions, which in turn can influence the duration and potency of the signaling. HS and HSPGs have also been shown to exert a structural role as a component of the extracellular matrix, thereby altering processes such as cell adhesion, immune cell infiltration and angiogenesis. Previous studies have shown that HS are deregulated in a variety of solid tumors and hematological malignancies and regulate key aspects of cancer initiation and progression. HS deregulation in cancer can occur as a result of changes in the level of HSPGs or due to changes in the levels of HS biosynthesis and remodeling enzymes. Here, we describe the major cell-autonomous (proliferation, apoptosis/senescence and differentiation) and cell-non-autonomous (angiogenesis, immune evasion, and matrix remodeling) roles of HS and HSPGs in cancer. Finally, we discuss therapeutic opportunities for targeting deregulated HS biosynthesis and HSPGs as a strategy for cancer treatment.
硫酸乙酰肝素（HS）是复杂的无分支碳水化合物链，被硫酸大量修饰，以与蛋白质结合或游离、未结合的链的形式存在。带有共价结合硫酸乙酰肝素链的蛋白质被称为硫酸乙酰肝素蛋白聚糖（HSPG）。HS和HSPG都能与多种生长因子结合，并作为不同细胞表面受体的共受体发挥作用。它们还能调节各种配体-受体相互作用的动力学和动力学过程，进而影响信号传导的持续时间和强度。HS和HSPG还被证明作为细胞外基质的组成部分发挥结构作用，从而改变细胞黏附、免疫细胞浸润和血管生成等过程。先前的研究表明，HS在多种实体瘤和血液系统恶性肿瘤中失调，并调节癌症发生和发展的关键方面。癌症中HS失调可能是由于HSPG水平的变化，或者是由于HS生物合成和重塑酶水平的变化。在此，我们描述了HS和HSPG在癌症中的主要细胞自主作用（增殖、凋亡/衰老和分化）和细胞非自主作用（血管生成、免疫逃逸和基质重塑）。最后，我们讨论了将失调的HS生物合成和HSPG作为癌症治疗策略进行靶向治疗的机会。
