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Utilization of Glycosaminoglycans/Proteoglycans as Carriers for Targeted Therapy Delivery.

Misra S, Hascall VC, Atanelishvili I, Moreno Rodriguez R, Markwald RR, Ghatak S - Int J Cell Biol (2015)

Bottom Line: The outcome of patients with cancer has improved significantly in the past decade with the incorporation of drugs targeting cell surface adhesive receptors, receptor tyrosine kinases, and modulation of several molecules of extracellular matrices (ECMs), the complex composite of collagens, glycoproteins, proteoglycans, and glycosaminoglycans that dictates tissue architecture.In this review, we describe how the ECM components, proteoglycans and glycosaminoglycans, influence tumor cell signaling.In particular this review describes how the glycosaminoglycan hyaluronan (HA) and its major receptor CD44 impact invasive behavior of tumor cells, and provides useful insight when designing new therapeutic strategies in the treatment of cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.

ABSTRACT
The outcome of patients with cancer has improved significantly in the past decade with the incorporation of drugs targeting cell surface adhesive receptors, receptor tyrosine kinases, and modulation of several molecules of extracellular matrices (ECMs), the complex composite of collagens, glycoproteins, proteoglycans, and glycosaminoglycans that dictates tissue architecture. Cancer tissue invasive processes progress by various oncogenic strategies, including interfering with ECM molecules and their interactions with invasive cells. In this review, we describe how the ECM components, proteoglycans and glycosaminoglycans, influence tumor cell signaling. In particular this review describes how the glycosaminoglycan hyaluronan (HA) and its major receptor CD44 impact invasive behavior of tumor cells, and provides useful insight when designing new therapeutic strategies in the treatment of cancer.

No MeSH data available.


Related in: MedlinePlus

Diagram of part of an aggrecan aggregate. G1, G2, and G3 are globular, folded regions of the central core protein. Proteoglycan aggrecan showing the noncovalent binding of proteoglycan to HA with the link proteins.
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fig2: Diagram of part of an aggrecan aggregate. G1, G2, and G3 are globular, folded regions of the central core protein. Proteoglycan aggrecan showing the noncovalent binding of proteoglycan to HA with the link proteins.

Mentions: Proteoglycans (PGs) (Figures 1 and 2) are proteins with a variable number of glycosaminoglycan (GAG) side chains [3]. The three classes of PGs with GAG chains and core proteins are (i) chondroitin/dermatan sulfate (CS/DS) PGs; (ii) heparin/heparan sulfate (Hep/HS) PGs; and (iii) keratan sulfate (KS) PGs [4, 5]. Hyaluronan (HA), a GAG, is synthesized without a core protein [6]. As indicated by their names (Figures 1 and 2), the GAGs other than HA are sulfated. GAGs have a critical role in assembling protein-protein complexes such as growth factor-receptor or enzyme-inhibitor interactions on the cell surface and in the extracellular matrix. These interactions can transduce signals by formation of ternary complexes of ligand, receptor, and PG for initiating cell signaling events or inhibiting biochemical pathways (Figure 3). Thus, GAGs can potentially sequester proteins and enzymes and present them to the appropriate site for activation. For a given high-affinity GAG-protein interaction, the positioning of the protein binding oligosaccharide motifs along the GAG chain determines if an active signaling complex is assembled at the cell surface or an inactive complex is sequestered in the matrix [7–9]. Overexpression of HA synthase 2 (HAS2) increases receptor tyrosine kinase-dependent signaling in breast and colon cancer cells [10–13], whereas antisense-mediated suppression of HAS2 inhibits tumorigenesis and progression of breast and prostate cancers [14, 15]. PGs and GAGs can have various physiological functions in different organs as well as roles in various pathologies. The details of these properties of GAGs and PGs are beyond the scope of this chapter. The present chapter will review the works that describe the utilization of GAGs in delivery of molecules for therapeutic purposes and highlights new possibilities for modulating HA interactions with CD44 variants (CD44v) for therapeutic control of cancer.


Utilization of Glycosaminoglycans/Proteoglycans as Carriers for Targeted Therapy Delivery.

Misra S, Hascall VC, Atanelishvili I, Moreno Rodriguez R, Markwald RR, Ghatak S - Int J Cell Biol (2015)

Diagram of part of an aggrecan aggregate. G1, G2, and G3 are globular, folded regions of the central core protein. Proteoglycan aggrecan showing the noncovalent binding of proteoglycan to HA with the link proteins.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4581573&req=5

fig2: Diagram of part of an aggrecan aggregate. G1, G2, and G3 are globular, folded regions of the central core protein. Proteoglycan aggrecan showing the noncovalent binding of proteoglycan to HA with the link proteins.
Mentions: Proteoglycans (PGs) (Figures 1 and 2) are proteins with a variable number of glycosaminoglycan (GAG) side chains [3]. The three classes of PGs with GAG chains and core proteins are (i) chondroitin/dermatan sulfate (CS/DS) PGs; (ii) heparin/heparan sulfate (Hep/HS) PGs; and (iii) keratan sulfate (KS) PGs [4, 5]. Hyaluronan (HA), a GAG, is synthesized without a core protein [6]. As indicated by their names (Figures 1 and 2), the GAGs other than HA are sulfated. GAGs have a critical role in assembling protein-protein complexes such as growth factor-receptor or enzyme-inhibitor interactions on the cell surface and in the extracellular matrix. These interactions can transduce signals by formation of ternary complexes of ligand, receptor, and PG for initiating cell signaling events or inhibiting biochemical pathways (Figure 3). Thus, GAGs can potentially sequester proteins and enzymes and present them to the appropriate site for activation. For a given high-affinity GAG-protein interaction, the positioning of the protein binding oligosaccharide motifs along the GAG chain determines if an active signaling complex is assembled at the cell surface or an inactive complex is sequestered in the matrix [7–9]. Overexpression of HA synthase 2 (HAS2) increases receptor tyrosine kinase-dependent signaling in breast and colon cancer cells [10–13], whereas antisense-mediated suppression of HAS2 inhibits tumorigenesis and progression of breast and prostate cancers [14, 15]. PGs and GAGs can have various physiological functions in different organs as well as roles in various pathologies. The details of these properties of GAGs and PGs are beyond the scope of this chapter. The present chapter will review the works that describe the utilization of GAGs in delivery of molecules for therapeutic purposes and highlights new possibilities for modulating HA interactions with CD44 variants (CD44v) for therapeutic control of cancer.

Bottom Line: The outcome of patients with cancer has improved significantly in the past decade with the incorporation of drugs targeting cell surface adhesive receptors, receptor tyrosine kinases, and modulation of several molecules of extracellular matrices (ECMs), the complex composite of collagens, glycoproteins, proteoglycans, and glycosaminoglycans that dictates tissue architecture.In this review, we describe how the ECM components, proteoglycans and glycosaminoglycans, influence tumor cell signaling.In particular this review describes how the glycosaminoglycan hyaluronan (HA) and its major receptor CD44 impact invasive behavior of tumor cells, and provides useful insight when designing new therapeutic strategies in the treatment of cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.

ABSTRACT
The outcome of patients with cancer has improved significantly in the past decade with the incorporation of drugs targeting cell surface adhesive receptors, receptor tyrosine kinases, and modulation of several molecules of extracellular matrices (ECMs), the complex composite of collagens, glycoproteins, proteoglycans, and glycosaminoglycans that dictates tissue architecture. Cancer tissue invasive processes progress by various oncogenic strategies, including interfering with ECM molecules and their interactions with invasive cells. In this review, we describe how the ECM components, proteoglycans and glycosaminoglycans, influence tumor cell signaling. In particular this review describes how the glycosaminoglycan hyaluronan (HA) and its major receptor CD44 impact invasive behavior of tumor cells, and provides useful insight when designing new therapeutic strategies in the treatment of cancer.

No MeSH data available.


Related in: MedlinePlus