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

Abstract

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.

Multi-omics Analysis of Serum Samples Demonstrates Reprogramming of Organ Functions Via Systemic Calcium Mobilization and Platelet Activation in Metastatic Melanoma

“…S3; supplemental Table S4 and S5). CD44 antigen is also a transmembrane receptor protein and elevated levels of its soluble form in circulating fluids are known to promote tumor metastasis (30). Complement C4-A (C4A), secreted by macrophages, is part of the innate immune system.…”

The ubiquitous hyaluronan: Functionally implicated in the oviduct?

“…Hyaluronan thus regulates cell proliferation, migration and invasiveness, a matter of utmost relevance during inflammation, wound healing, tissue development or the formation and spreading of tumours [5]. Moreover, hyaluronan is able to control/modulate cell responses by acting as ligand to specific hyaluronan-membrane receptors [6][7][8].…”

Involvement of glycogen debranching enzyme in bladder cancer

“…Two of these cell surface hyaladherins, RHAMM and CD44, are clinically significant in various cancer models (16,19,22). These hyaladherins have been demonstrated to provide multi-drug resistance, assist with anchorage independent growth, and cell motility of cancer cells (23)(24)(25). Since both RHAMM and CD44 serve a major role in tumor progression, the authors investigated whether these proteins were involved in HA driven rapid growth of bladder cancer cells with AGL loss.…”