透明质酸及其受体（CD44，RHAMM）之间的相互作用调节炎症和癌症的活动。,Frontiers in Immunology

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透明质酸及其受体（CD44，RHAMM）之间的相互作用调节炎症和癌症的活动。
Frontiers in Immunology ( IF 5.7 ) Pub Date : 2015-05-23 , DOI: 10.3389/fimmu.2015.00201
Suniti Misra ₁ , Vincent C Hascall ₂ , Roger R Markwald ₁ , Shibnath Ghatak ₁

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已经提出糖胺聚糖透明质酸（HA），细胞外基质的主要成分，以及HA的细胞表面受体在细胞增殖，迁移和侵袭中具有关键作用，这对于炎症和癌症的发展是必不可少的。CD44和HA介导的运动受体（RHAMM）是两个主要的HA受体，已经全面研究了其在人和鼠炎症和肿瘤细胞中的生物学功能。HA最初被认为只是结缔组织的惰性成分，但现在被称为“动态”分子，通过涉及各种大小的HA分子的快速代谢，在许多组织中具有恒定的更新率：高分子量HA（HMW HA），低分子量HA和寡糖。HA与CD44和RHAMM相互作用引发的细胞内信号转导通路导致炎症反应和致瘤反应很复杂。有趣的是，这些分子在炎症和肿瘤发生中具有双重功能。例如，关节炎小鼠的发病过程中涉及CD44的存在，而关节炎小鼠模型中由于基因缺失引起的CD44的缺乏增加而不是降低了疾病的严重程度。CD44在癌症的发生和发展中也存在类似的双重功能。RHAMM的过表达最常与癌症进展相关，而RHAMM的丧失与恶性周围神经鞘瘤的生长有关。HA可以类似地执行双重功能。大量的HMW HA可以促进恶性细胞增殖和癌症的发展，而HA-CD44信号转导的拮抗剂通过干扰HMW HA-CD44相互作用，在体外和体内抑制肿瘤细胞的生长。这篇综述描述了HA与CD44和RHAMM相互作用在炎症反应和肿瘤发展/进展中的作用，以及如何在啮齿动物和人类疾病中开发出阻断这些关键炎症/致瘤过程的治疗策略。

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Interactions between Hyaluronan and Its Receptors (CD44, RHAMM) Regulate the Activities of Inflammation and Cancer.

The glycosaminoglycan hyaluronan (HA), a major component of extracellular matrices, and cell surface receptors of HA have been proposed to have pivotal roles in cell proliferation, migration, and invasion, which are necessary for inflammation and cancer progression. CD44 and receptor for HA-mediated motility (RHAMM) are the two main HA-receptors whose biological functions in human and murine inflammations and tumor cells have been investigated comprehensively. HA was initially considered to be only an inert component of connective tissues, but is now known as a "dynamic" molecule with a constant turnover in many tissues through rapid metabolism that involves HA molecules of various sizes: high molecular weight HA (HMW HA), low molecular weight HA, and oligosaccharides. The intracellular signaling pathways initiated by HA interactions with CD44 and RHAMM that lead to inflammatory and tumorigenic responses are complex. Interestingly, these molecules have dual functions in inflammations and tumorigenesis. For example, the presence of CD44 is involved in initiation of arthritis, while the absence of CD44 by genetic deletion in an arthritis mouse model increases rather than decreases disease severity. Similar dual functions of CD44 exist in initiation and progression of cancer. RHAMM overexpression is most commonly linked to cancer progression, whereas loss of RHAMM is associated with malignant peripheral nerve sheath tumor growth. HA may similarly perform dual functions. An abundance of HMW HA can promote malignant cell proliferation and development of cancer, whereas antagonists to HA-CD44 signaling inhibit tumor cell growth in vitro and in vivo by interfering with HMW HA-CD44 interaction. This review describes the roles of HA interactions with CD44 and RHAMM in inflammatory responses and tumor development/progression, and how therapeutic strategies that block these key inflammatory/tumorigenic processes may be developed in rodent and human diseases.

更新日期：2019-11-01

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