Review ArticleHyaluronan in human malignancies
Introduction
The extracellular matrix (ECM) is composed of an interlocking mesh of fibrous proteins (e.g. collagens) and glycosaminoglycans which are usually attached to proteins to form proteoglycans. Hyaluronan (HA; hyaluronic acid, hyaluronate) is a free unbranched glycosaminoglycan composed of 2000–25,000 repeating disaccharides of N-acetyl-glucosamine (GlcNAc) and glucuronic acid (GlcA) units, with molecular weights ranging from 105 to 107 Da [1], [2]. HA is widely distributed in vertebrate tissues and is also essential for prenatal development. Its physicochemical properties, like the capacity to bind large amounts of water, the formation of viscous gels and the filtering effects on the molecular level enable pliable tissue remodeling in the normal and pathological context. Hyaluronan is capable of forming polyvalent connections with other extracellular macromolecules. Due to these properties, cells are able to modify their biochemical and biomechanical environment by regulating the hyaluronan turnover during inflammation, wound repair and invasion [3].
Hyaluronan is produced by hyaluronan synthases (HAS1–3), which are integral plasma membrane proteins. Newly synthesized HA molecules are extruded directly onto the cell surface for assembly into pericellular or extracellular matrices. They can also be bound to cell surface receptors (CD44 [4], CD168/RHAMM [5], lymphatic vessel endothelial receptor 1 [5], layilin [6] and Toll-like receptor-4 [7]) or can be retained on the cell surface by attachment to the synthase. The interaction between HA and its receptors initiates intracellular signaling transduction and thus forms the basis for tissue homeostasis and cell motility (Fig. 1). Activation of various isoforms of CD44 can modulate cell aggregation, proliferation, migration and angiogenesis [8], [9], [10]. The intracellular part of the receptor interacts with cytoskeletal proteins providing connection between HA and intracellular structures. RHAMM (receptor for hyaluronan-mediated motility) binds HA on the cell surface and is able to activate the protein tyrosine kinases, Src, focal adhesion kinase and Erk kinases. Depending on the cell type, CD44 and RHAMM have different functions in cell signaling processes. For example, CD44 can regulate cell proliferation and RHAMM is required for migration [5].
Hyaluronan is catabolized by hyaluronidases (Hyal-1–3 and PH-20) [11], [12] or reactive oxygen species (ROS) [13], [14]. Hyaluronan fragments may become completely degraded after endocytosis [12], [15] or may be transported via the lymphatic system [16]. The main hyaluronidases involved in HA catabolism in somatic tissues are Hyal-1 and -2, and to lesser extent PH-20. Hyal-3 is widely expressed, but its function is unknown [11]. High molecular weight hyaluronan is degraded within hours of its synthesis by cell surface Hyal-2, generating variously sized fragments of 50–100 saccharides, which are further degraded to tetrasaccharides by lysosomal Hyal-1 after endocytosis. There are abundant fragments of HA in many malignancies and these have properties which are not normally found in the native HA polymer. For instance, depending on the molecular size, the oligosaccharides may have angiogenic or growth suppressing effects [17], [18].
Most types of human cancers have supportive elements, usually a distinct type of connective tissue stroma containing the neovascular structures which support the growth of malignant cells. Hyaluronan is one of the major matrix molecules in human malignancies [19], [20], and the amount of HA in the tumor stroma or in the neoplastic cell compartment impacts on the overall outcome [21], [22]. Hyaluronan, hyaluronan synthases, hyaluronidases and hyaluronan receptors have been shown to be involved in a wide range of carcinomas (breast, lung, skin, urogenital, gynecological, head and neck, gastrointestinal), lymphomas (B-cell and T-cell), melanocytic (malignant melanoma) and neuronal tumors (gliomas). When tumors produce HA, this is associated with invasion [23], host–tumor interactions [24], lymphangiogenesis [25], angiogenesis [26], epithelial–mesenchymal transition [3] and with local and distant metastases [21], [27], [28]. Interestingly, HA may modulate multidrug resistance [29], but it can also be utilized as a drug carrier for the treatment of various cancers [30], [31]. Here we review the mechanisms of malignant transformation and tumor progression associated with HA metabolism.
Section snippets
Increased cell proliferation and evasion of apoptosis
The capability for limitless growth includes self-sufficiency in growth signal, insensitivity to growth-inhibitory signals and evasion of apoptosis. The production of HA and the pericellular HA coating have been shown to correlate positively with the cell proliferation rate in in vivo and in vitro models [32]. HA modifies the environment of the proliferating cells by detaching them from substratum and neighboring cells in the early phase of mitosis [33] and it also separates the daughter cells
Conclusions
The newly formed extracellular matrix with its cellular constituents plays a crucial role in the progress of human malignant tumors. Human tumors originating from the epithelial, mesenchymal, neural and lymphatic tissues contain variable amounts of hyaluronan, which affects cellular proliferation, invasion and angiogenesis. In addition to the native hyaluronan, the catabolic enzymes and the degradation products of this macromolecule have a complex impact on tumor progression. The amount of
Acknowledgments
This work was supported in part by grants from the Finnish Cancer Foundation, The North Savo Cancer Fund, Special Government Funding (EVO) of the Kuopio University Hospital and the Finnish Cultural Foundation.
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