Hyaluronan–CD44 Interaction Promotes Oncogenic Signaling, microRNA Functions, Chemoresistance, and Radiation Resistance in Cancer Stem Cells Leading to Tumor Progression

Abstract

Hyaluronan (HA), a major component of the extracellular matrix (ECM), is enriched in many types of tumors. There is good evidence linking high levels of HA production in human carcinomas to an aggressive phenotype and tumor metastasis. HA is generally bound to CD44 isoforms (so-called CD44s and CD44v3) which are ubiquitous, abundant, and functionally important cell surface receptors. This chapter describes the evidence for HA/CD44v3-mediated activation of the cytoskeleton (e.g., ankyrin and GTPases) and matrix metalloproteinase (MMP) signaling during tumor progression. A special focus is placed on the role of HA–CD44v3 interaction in cancer stem cells (CSCs). Matrix HA is known to be present in CSC niches. Since CD44v3 serves as a CSC marker, it provides an important physical linkage between matrix HA and various transcription factors that regulate tumor cell functions through distinct signaling pathways. CSCs are known to be chemoresistant and/or radiation resistant and to cause cancer relapse. The purpose of this chapter is to review the most current research on the cellular and molecular biology of CSCs. The emphasis will be placed on both CSC niche and matrix HA-induced microRNA signaling plus various CSC functions (e.g., self-renewal, differentiation, and chemoresistance) during cancer progression. Understanding the regulation of CSCs is critically important for designing CSC-specific therapeutic targets to prevent cancer development and progression.

Up-regulation of Histone Methyltransferase, DOT1L, by Matrix Hyaluronan Promotes MicroRNA-10 Expression Leading to Tumor Cell Invasion and Chemoresistance in Cancer Stem Cells from Head and Neck Squamous Cell Carcinoma

“…The recent discovery of miRNAs in CSCs has broadened the area of gene regulation implicated in tumorigenesis and CSC modulation (35,42,43). In this study, we observed that HA is capable of stimulating DOT1L and H3K79 methylation in CSCs.…”

“…Although certain anti-apoptotic proteins (e.g. Bcl-xL) have been shown to participate in anti-apoptosis and chemoresistance in HA/CD44-activated tumor cells, the involvement of IAPs in HA/CD44-mediated HNSCC cell survival and chemoresistance (10,13,42,43) has only recently started to receive attention. In this study we demonstrated that downregulation of HA/CD44-activated DOT1L signaling (by DOT1L siRNA) and miR-10b production (by anti-miR-10b inhibitor) inhibits the expression of survival proteins (e.g.…”

“…ECM components, including HA, are known to be present in at least one of the stem cell niches (28,29). Because CD44 is a major HA receptor, it provides a physical linkage between matrix HA and various transcription factors that regulate tumor cell functions through distinct signaling pathways (30,42). In fact, both HA and CD44 have been shown to be involved in self-renewal and differentiation of human embryonic stem cells (31,32).…”

Osteoblast-released Matrix Vesicles, Regulation of Activity and Composition by Sulfated and Non-sulfated Glycosaminoglycans

“…However, besides stimulating bone formation and reducing bone resorption, the alteration of GAG concentrations has also been reported to correlate with cancer progression by activating oncogenic pathways (92), promoting invasion and metastasis (93), and accelerating shedding of extracellular vesicles (94,95), which have to be carefully evaluated prior to clinical application. An alternative approach could be provided by dexamethasone, a synthetic glucocorticoid that was also shown to stimulate an osteoblast phenotype in vivo (96).…”

The ubiquitous hyaluronan: Functionally implicated in the oviduct?

“…Hyaluronan is, however, highly dependent on the presence of CD44 in the cells, particularly in cancer stem cells, that survive immune attacks [52,53]. Interestingly, hyaluronan has also shown capacity to induce pro-inflammatory and pro-fibrotic cytokines [54], and to contribute to leukocyte recruitment from the blood circulation [55], indicating an interacting role in immunological systems [56].…”