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Key Roles of Hyaluronan and Its CD44 Receptor in the Stemness and Survival of Cancer Stem Cells.

Chanmee T, Ontong P, Kimata K, Itano N - Front Oncol (2015)

Bottom Line: For instance, HA in the tumor microenvironment modulates the function of tumor-associated macrophages to support CSC self-renewal, and excessive HA production promotes the acquisition of CSC signatures through epithelial-to-mesenchymal transition.CD44 also plays a critical role in the preservation and multidrug resistance (MDR) of CSCs by transmitting survival and anti-apoptotic signals.We also discuss the involvement of CD44 in the oxidative stress and MDR of CSCs.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University , Kyoto , Japan.

ABSTRACT
Cancer stem cells (CSCs) represent a unique subpopulation of self-renewing oncogenic cells that drive cancer initiation and progression. CSCs often acquire multidrug and oxidative stress resistance and are thereby thought to be responsible for tumor recurrence following treatment and remission. Although the mechanisms responsible for CSC generation, maintenance, and expansion have become a major focus in cancer research, the molecular characteristics of CSCs remain poorly understood. The stemness and subsequent expansion of CSCs are believed to be highly influenced by changes in microenvironmental signals as well as genetic and epigenetic alterations. Hyaluronan (HA), a major component of the extracellular matrix, has recently been demonstrated to provide a favorable microenvironment for the self-renewal and maintenance of stem cells. HA directly and indirectly affects CSC self-renewal by influencing the behavior of both cancer and stromal cells. For instance, HA in the tumor microenvironment modulates the function of tumor-associated macrophages to support CSC self-renewal, and excessive HA production promotes the acquisition of CSC signatures through epithelial-to-mesenchymal transition. The importance of HA in mediating CSC self-renewal has been strengthened by the finding that interactions between HA and its receptor, CD44, propagate the stemness of CSCs. HA-CD44 interactions evoke a wide range of signals required for CSC self-renewal and maintenance. CD44 also plays a critical role in the preservation and multidrug resistance (MDR) of CSCs by transmitting survival and anti-apoptotic signals. Thus, a better understanding of the molecular mechanisms involved in HA and CD44 control of CSC stemness may help in the design of more effective therapies for cancer patients. In this review, we address the key roles of HA and CD44 in CSC self-renewal and maintenance. We also discuss the involvement of CD44 in the oxidative stress and MDR of CSCs.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram of HA and CD44 structures. (A) HA is a linear polysaccharide composed of repeating disaccharide units of glucuronic acid and N-acetylglucosamine. (B) The CD44 protein consists of an N-terminal HA-binding link-homology module, stem region, transmembrane domain, and short C-terminal cytoplasmic domain. (C) CD44 is encoded by 20 exons, among which exons 1–5 and 16–18 are constant regions contained in all CD44 isoforms. Exon 19 encodes an alternatively spliced short form that spliced out in most CD44 isoforms. Exons 6–15 are variant exons, typically identified as vl–v10, which can be alternatively spliced and give rise to multiple variant CD44. In human, exon 6 (exon v1) encodes a stop codon and is not expressed. CD44 variant can contain one or more variant regions, such as CD44v3, CD44v3–10, CD44v4–10, or CD44v8–10.
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Figure 1: Schematic diagram of HA and CD44 structures. (A) HA is a linear polysaccharide composed of repeating disaccharide units of glucuronic acid and N-acetylglucosamine. (B) The CD44 protein consists of an N-terminal HA-binding link-homology module, stem region, transmembrane domain, and short C-terminal cytoplasmic domain. (C) CD44 is encoded by 20 exons, among which exons 1–5 and 16–18 are constant regions contained in all CD44 isoforms. Exon 19 encodes an alternatively spliced short form that spliced out in most CD44 isoforms. Exons 6–15 are variant exons, typically identified as vl–v10, which can be alternatively spliced and give rise to multiple variant CD44. In human, exon 6 (exon v1) encodes a stop codon and is not expressed. CD44 variant can contain one or more variant regions, such as CD44v3, CD44v3–10, CD44v4–10, or CD44v8–10.

Mentions: HA is a linear polysaccharide that belongs to the glycosaminoglycan family. It is composed of repeating disaccharide units of glucuronic acid and N-acetylglucosamine (Figure 1A) and has a molecular mass ranging from 103 to 107 Da, depending on tissue type and physiological condition. HA is ubiquitously found in the extracellular matrix (ECM) of vertebrate tissues and is known to contribute to cell proliferation, migration, and adhesion (30). A wide variety of HA-binding molecules also participate in the assembly of pericellular HA–ECM to regulate HA function. Despite its relatively simple chemical composition, HA mediates many important processes during embryonic morphogenesis, tissue regeneration, and wound healing (31). Abnormalities in HA metabolism have been implicated in numerous conditions, including inflammatory disorders, cardiovascular diseases, and cancer. The biosynthesis and degradation processes of HA are tightly regulated by three HA synthases (HAS1–3) and several hyaluronidases, respectively. HAS possesses a glycosyltransferase ability that catalyzes the polymerization of glucuronic acid and N-acetylglucosamine to the nascent HA chain. Each HAS isoform exhibits different enzymatic properties with regard to stability, enzyme kinetics, and rate of chain elongation (32).


Key Roles of Hyaluronan and Its CD44 Receptor in the Stemness and Survival of Cancer Stem Cells.

Chanmee T, Ontong P, Kimata K, Itano N - Front Oncol (2015)

Schematic diagram of HA and CD44 structures. (A) HA is a linear polysaccharide composed of repeating disaccharide units of glucuronic acid and N-acetylglucosamine. (B) The CD44 protein consists of an N-terminal HA-binding link-homology module, stem region, transmembrane domain, and short C-terminal cytoplasmic domain. (C) CD44 is encoded by 20 exons, among which exons 1–5 and 16–18 are constant regions contained in all CD44 isoforms. Exon 19 encodes an alternatively spliced short form that spliced out in most CD44 isoforms. Exons 6–15 are variant exons, typically identified as vl–v10, which can be alternatively spliced and give rise to multiple variant CD44. In human, exon 6 (exon v1) encodes a stop codon and is not expressed. CD44 variant can contain one or more variant regions, such as CD44v3, CD44v3–10, CD44v4–10, or CD44v8–10.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
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Figure 1: Schematic diagram of HA and CD44 structures. (A) HA is a linear polysaccharide composed of repeating disaccharide units of glucuronic acid and N-acetylglucosamine. (B) The CD44 protein consists of an N-terminal HA-binding link-homology module, stem region, transmembrane domain, and short C-terminal cytoplasmic domain. (C) CD44 is encoded by 20 exons, among which exons 1–5 and 16–18 are constant regions contained in all CD44 isoforms. Exon 19 encodes an alternatively spliced short form that spliced out in most CD44 isoforms. Exons 6–15 are variant exons, typically identified as vl–v10, which can be alternatively spliced and give rise to multiple variant CD44. In human, exon 6 (exon v1) encodes a stop codon and is not expressed. CD44 variant can contain one or more variant regions, such as CD44v3, CD44v3–10, CD44v4–10, or CD44v8–10.
Mentions: HA is a linear polysaccharide that belongs to the glycosaminoglycan family. It is composed of repeating disaccharide units of glucuronic acid and N-acetylglucosamine (Figure 1A) and has a molecular mass ranging from 103 to 107 Da, depending on tissue type and physiological condition. HA is ubiquitously found in the extracellular matrix (ECM) of vertebrate tissues and is known to contribute to cell proliferation, migration, and adhesion (30). A wide variety of HA-binding molecules also participate in the assembly of pericellular HA–ECM to regulate HA function. Despite its relatively simple chemical composition, HA mediates many important processes during embryonic morphogenesis, tissue regeneration, and wound healing (31). Abnormalities in HA metabolism have been implicated in numerous conditions, including inflammatory disorders, cardiovascular diseases, and cancer. The biosynthesis and degradation processes of HA are tightly regulated by three HA synthases (HAS1–3) and several hyaluronidases, respectively. HAS possesses a glycosyltransferase ability that catalyzes the polymerization of glucuronic acid and N-acetylglucosamine to the nascent HA chain. Each HAS isoform exhibits different enzymatic properties with regard to stability, enzyme kinetics, and rate of chain elongation (32).

Bottom Line: For instance, HA in the tumor microenvironment modulates the function of tumor-associated macrophages to support CSC self-renewal, and excessive HA production promotes the acquisition of CSC signatures through epithelial-to-mesenchymal transition.CD44 also plays a critical role in the preservation and multidrug resistance (MDR) of CSCs by transmitting survival and anti-apoptotic signals.We also discuss the involvement of CD44 in the oxidative stress and MDR of CSCs.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University , Kyoto , Japan.

ABSTRACT
Cancer stem cells (CSCs) represent a unique subpopulation of self-renewing oncogenic cells that drive cancer initiation and progression. CSCs often acquire multidrug and oxidative stress resistance and are thereby thought to be responsible for tumor recurrence following treatment and remission. Although the mechanisms responsible for CSC generation, maintenance, and expansion have become a major focus in cancer research, the molecular characteristics of CSCs remain poorly understood. The stemness and subsequent expansion of CSCs are believed to be highly influenced by changes in microenvironmental signals as well as genetic and epigenetic alterations. Hyaluronan (HA), a major component of the extracellular matrix, has recently been demonstrated to provide a favorable microenvironment for the self-renewal and maintenance of stem cells. HA directly and indirectly affects CSC self-renewal by influencing the behavior of both cancer and stromal cells. For instance, HA in the tumor microenvironment modulates the function of tumor-associated macrophages to support CSC self-renewal, and excessive HA production promotes the acquisition of CSC signatures through epithelial-to-mesenchymal transition. The importance of HA in mediating CSC self-renewal has been strengthened by the finding that interactions between HA and its receptor, CD44, propagate the stemness of CSCs. HA-CD44 interactions evoke a wide range of signals required for CSC self-renewal and maintenance. CD44 also plays a critical role in the preservation and multidrug resistance (MDR) of CSCs by transmitting survival and anti-apoptotic signals. Thus, a better understanding of the molecular mechanisms involved in HA and CD44 control of CSC stemness may help in the design of more effective therapies for cancer patients. In this review, we address the key roles of HA and CD44 in CSC self-renewal and maintenance. We also discuss the involvement of CD44 in the oxidative stress and MDR of CSCs.

No MeSH data available.


Related in: MedlinePlus