Department of Biochemistry, Western University, London, ON, Canada.
London Regional Cancer Program, Lawson Health Research Institute, London, ON, Canada.
Front Immunol. 2019 May 10;10:947. doi: 10.3389/fimmu.2019.00947. eCollection 2019.
Hyaluronan (HA) is a glycosaminoglycan with a simple structure but diverse and often opposing functions. The biological activities of this polysaccharide depend on its molecular weight and the identity of interacting receptors. HA is initially synthesized as high molecular-weight (HMW) polymers, which maintain homeostasis and restrain cell proliferation and migration in normal tissues. These HMW-HA functions are mediated by constitutively expressed receptors including CD44, LYVE-1, and STABILIN2. During normal processes such as tissue remodeling and wound healing, HMW-HA is fragmented into low molecular weight polymers (LMW-HA) by hyaluronidases and free radicals, which promote inflammation, immune cell recruitment and the epithelial cell migration. These functions are mediated by RHAMM and TLR2,4, which coordinate signaling with CD44 and other HA receptors. Tumor cells hijack the normally tightly regulated HA production/fragmentation associated with wound repair/remodeling, and these HA functions participate in driving and maintaining malignant progression. However, elevated HMW-HA production in the absence of fragmentation is linked to cancer resistance. The controlled production of HA polymer sizes and their functions are predicted to be key to dissecting the role of microenvironment in permitting or restraining the oncogenic potential of tissues. This review focuses on the dual nature of HA in cancer initiation vs. resistance, and the therapeutic potential of HA for chemo-prevention and as a target for cancer management.
透明质酸（HA）是一种具有简单结构但功能多样且常常相反的糖胺聚糖。这种多糖的生物活性取决于其分子量和相互作用的受体的身份。HA 最初被合成具有高分子量（HMW）的聚合物，这些聚合物在正常组织中维持内稳态并抑制细胞增殖和迁移。这些 HMW-HA 的功能是由包括 CD44、LYVE-1 和 STABILIN2 在内的组成型表达受体介导的。在组织重塑和伤口愈合等正常过程中，HMW-HA 被透明质酸酶和自由基分解成低分子量聚合物（LMW-HA），促进炎症、免疫细胞募集和上皮细胞迁移。这些功能由 RHAMM 和 TLR2、4 介导，它们与 CD44 和其他 HA 受体一起协调信号转导。肿瘤细胞劫持了与伤口修复/重塑相关的通常受到严格调控的 HA 产生/片段化过程，这些 HA 功能参与驱动和维持恶性进展。然而，在没有片段化的情况下，HMW-HA 的产生增加与癌症耐药性有关。HA 聚合物大小的受控产生及其功能预计是剖析微环境在允许或抑制组织致癌潜能方面的关键。这篇综述重点介绍了 HA 在癌症起始与耐药性方面的双重性质，以及 HA 在化学预防和作为癌症管理靶点方面的治疗潜力。
