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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

Alternative splicing in CD44 pre-mRNA. CD44 pre-mRNA is encoded by 20 exons. The common CD44s (hematopoietic) form contains no extra exons, and the protein may have a serine motif encoded in exon 5 that initiates synthesis of a chondroitin sulfate or dermatan sulfate chain. Alternative splicing of CD44 predominantly involves variable insertion of 10 extra exons with combinations of exons 6–15 and spliced in v1–v10 into the stem region, of which v3 encodes a substitution site for a heparan sulfate chain. Variable numbers of the v exons can be spliced in epithelial cells, endothelial cells, and inflammatory monocytes and also upregulated commonly on neoplastic transformation depending on the tissue.
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fig4: Alternative splicing in CD44 pre-mRNA. CD44 pre-mRNA is encoded by 20 exons. The common CD44s (hematopoietic) form contains no extra exons, and the protein may have a serine motif encoded in exon 5 that initiates synthesis of a chondroitin sulfate or dermatan sulfate chain. Alternative splicing of CD44 predominantly involves variable insertion of 10 extra exons with combinations of exons 6–15 and spliced in v1–v10 into the stem region, of which v3 encodes a substitution site for a heparan sulfate chain. Variable numbers of the v exons can be spliced in epithelial cells, endothelial cells, and inflammatory monocytes and also upregulated commonly on neoplastic transformation depending on the tissue.

Mentions: To understand the role of the HA receptor CD44 in modifying malignant properties, it is essential to recognize its structures. Due to paucity of studies regarding involvement of CD44 variants in tumor angiogenesis and cancer stem cells, we discuss its functions in tumor cells in general and how cell-specific perturbation of HA-CD44v interaction can be used to inhibit cancer growth. CD44 (Figure 4) is a transmembrane protein encoded by a single gene. Due to alternative splicing, multiple forms of CD44v are generated that are further modified by N- and O-linked glycosylations. The smallest CD44 isoform that lacks variant exons, designated CD44s, contains an N-terminal signal sequence (exon 1), a link module that binds to HA (exons 2 and 3), a stem region (exons 4, 5, 16, and 17), a single-pass transmembrane domain (exon 18), and a cytoplasmic domain (exon 20). In all forms of CD44 cDNAs, exon 19 is spliced out so that the transmembrane domain encoded by exon 18 is followed by the cytoplasmic domain encoded by exon 20, producing the 73 amino acid cytoplasmic domain. CD44s can be a proteoglycan with a potential CS or DS substitution. Insertion of the v3 exon includes the potential for HS chain substitution [70], which can influence ligand binding and cell behavior by allowing CD44 to be a coreceptor for HGF with c-met [71]. The affinity of CD44 for these GAG substitutions depends on posttranslational modifications, such as modification in glycosylation [72] during alternate splicing of variant exons, and this function depends on cell type and growth condition. Isoforms that contain a variable number of exon insertions (v1–v10) at the proximal plasma membrane external region are expressed primarily on tumor cells [43, 70, 73].


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)

Alternative splicing in CD44 pre-mRNA. CD44 pre-mRNA is encoded by 20 exons. The common CD44s (hematopoietic) form contains no extra exons, and the protein may have a serine motif encoded in exon 5 that initiates synthesis of a chondroitin sulfate or dermatan sulfate chain. Alternative splicing of CD44 predominantly involves variable insertion of 10 extra exons with combinations of exons 6–15 and spliced in v1–v10 into the stem region, of which v3 encodes a substitution site for a heparan sulfate chain. Variable numbers of the v exons can be spliced in epithelial cells, endothelial cells, and inflammatory monocytes and also upregulated commonly on neoplastic transformation depending on the tissue.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4581573&req=5

fig4: Alternative splicing in CD44 pre-mRNA. CD44 pre-mRNA is encoded by 20 exons. The common CD44s (hematopoietic) form contains no extra exons, and the protein may have a serine motif encoded in exon 5 that initiates synthesis of a chondroitin sulfate or dermatan sulfate chain. Alternative splicing of CD44 predominantly involves variable insertion of 10 extra exons with combinations of exons 6–15 and spliced in v1–v10 into the stem region, of which v3 encodes a substitution site for a heparan sulfate chain. Variable numbers of the v exons can be spliced in epithelial cells, endothelial cells, and inflammatory monocytes and also upregulated commonly on neoplastic transformation depending on the tissue.
Mentions: To understand the role of the HA receptor CD44 in modifying malignant properties, it is essential to recognize its structures. Due to paucity of studies regarding involvement of CD44 variants in tumor angiogenesis and cancer stem cells, we discuss its functions in tumor cells in general and how cell-specific perturbation of HA-CD44v interaction can be used to inhibit cancer growth. CD44 (Figure 4) is a transmembrane protein encoded by a single gene. Due to alternative splicing, multiple forms of CD44v are generated that are further modified by N- and O-linked glycosylations. The smallest CD44 isoform that lacks variant exons, designated CD44s, contains an N-terminal signal sequence (exon 1), a link module that binds to HA (exons 2 and 3), a stem region (exons 4, 5, 16, and 17), a single-pass transmembrane domain (exon 18), and a cytoplasmic domain (exon 20). In all forms of CD44 cDNAs, exon 19 is spliced out so that the transmembrane domain encoded by exon 18 is followed by the cytoplasmic domain encoded by exon 20, producing the 73 amino acid cytoplasmic domain. CD44s can be a proteoglycan with a potential CS or DS substitution. Insertion of the v3 exon includes the potential for HS chain substitution [70], which can influence ligand binding and cell behavior by allowing CD44 to be a coreceptor for HGF with c-met [71]. The affinity of CD44 for these GAG substitutions depends on posttranslational modifications, such as modification in glycosylation [72] during alternate splicing of variant exons, and this function depends on cell type and growth condition. Isoforms that contain a variable number of exon insertions (v1–v10) at the proximal plasma membrane external region are expressed primarily on tumor cells [43, 70, 73].

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