Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
FEBS J. 2013 May;280(10):2180-93. doi: 10.1111/febs.12180. Epub 2013 Mar 4.
Heparan sulfate proteoglycans (HSPGs) have essential functions during embryonic development and throughout postnatal life. To exert these functions, they undergo a series of processing reactions by heparan-sulfate-modifying enzymes (HSMEs), which endows them with highly modified heparan sulfate (HS) domains that provide specific docking sites for a large number of bioactive molecules. The development and antigen-dependent differentiation of normal B lymphocytes, as well as the growth and progression of B-lineage malignancies, are orchestrated by an array of growth factors, cytokines and chemokines many of which display HS binding. As discussed in this review, tightly regulated HSPG expression is a requirement for normal B cell maturation, differentiation and function. In addition, the HSPG syndecan-1 functions as a versatile co-receptor for signals from the bone marrow microenvironment, essential for the survival of long-lived plasma cells and multiple myeloma (MM) plasma cells. Targeting of HSMEs or HS chains on MM cells increases their sensitivity to drugs currently used in MM treatment, including bortezomib, lenalidomide or dexamethasone. Taken together, these findings render the HS biosynthetic machinery a promising target for MM treatment.
硫酸乙酰肝素蛋白聚糖（HSPGs）在胚胎发育和出生后生命中都具有重要功能。为了发挥这些功能，它们通过硫酸乙酰肝素修饰酶（HSMEs）经历一系列的加工反应，这赋予了它们高度修饰的硫酸乙酰肝素（HS）结构域，为大量生物活性分子提供了特定的对接位点。正常 B 淋巴细胞的发育和抗原依赖性分化，以及 B 细胞恶性肿瘤的生长和进展，都是由一系列生长因子、细胞因子和趋化因子调控的，其中许多因子都显示出与 HS 的结合。正如本综述中所讨论的，严格调控的 HSPG 表达是正常 B 细胞成熟、分化和功能的要求。此外，HSPG 连接蛋白聚糖-1 作为骨髓微环境信号的多功能共受体发挥作用，对于长寿浆细胞和多发性骨髓瘤（MM）浆细胞的存活至关重要。针对 MM 细胞上的 HSMEs 或 HS 链进行靶向治疗，可增加其对目前用于 MM 治疗的药物（包括硼替佐米、来那度胺或地塞米松）的敏感性。综上所述，这些发现使 HS 生物合成机制成为 MM 治疗的一个有前途的靶点。
