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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

Exploitation of HA-CD44 interaction for anticancer therapy. Left panel represents the internalization of HA-drug conjugate that ultimately releases the drug that inhibits DNA synthesis of cancer cells. CD44 on the cell membrane binds the HA-drug conjugate and is internalized by endocytosis. The endosome formed is moved to the lysosome and fused. Here the HA in the conjugate is degraded first by hyaluronidase 1 (Hyal-1) into small HA oligosaccharides and next by lysosomal glycosidases to monosaccharides followed by release of the drug. The drug inhibits the DNA synthesis in the nucleus. Right panel exemplifies the steps that target the CD44v6mRNA in cancer cells by CD44v6shRNA. Plasmids producing CD44v6shRNA are coated with transferrin containing nanoparticles to target transferrin receptors of the cells. The particles are then internalized and form an endosome from which the plasmids are released to the nucleus where activation of DNA pol III occurs that results in CD44v6shRNA production. Through exportin, the newly produced CD44v6shRNA come out into cytoplasm where it is converted into CD44v6siRNA by dicer enzyme. One of the strands of siRNA will bind to CD44v6mRNA and forms RNA-induced silencing complex (RISC) which is ultimately degraded.
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fig9: Exploitation of HA-CD44 interaction for anticancer therapy. Left panel represents the internalization of HA-drug conjugate that ultimately releases the drug that inhibits DNA synthesis of cancer cells. CD44 on the cell membrane binds the HA-drug conjugate and is internalized by endocytosis. The endosome formed is moved to the lysosome and fused. Here the HA in the conjugate is degraded first by hyaluronidase 1 (Hyal-1) into small HA oligosaccharides and next by lysosomal glycosidases to monosaccharides followed by release of the drug. The drug inhibits the DNA synthesis in the nucleus. Right panel exemplifies the steps that target the CD44v6mRNA in cancer cells by CD44v6shRNA. Plasmids producing CD44v6shRNA are coated with transferrin containing nanoparticles to target transferrin receptors of the cells. The particles are then internalized and form an endosome from which the plasmids are released to the nucleus where activation of DNA pol III occurs that results in CD44v6shRNA production. Through exportin, the newly produced CD44v6shRNA come out into cytoplasm where it is converted into CD44v6siRNA by dicer enzyme. One of the strands of siRNA will bind to CD44v6mRNA and forms RNA-induced silencing complex (RISC) which is ultimately degraded.

Mentions: Among various GAGs and PGs, much research has demonstrated the ability of HA to target cancer cells overexpressing the HA receptor CD44, in particular its variants, and that HA interaction with CD44v augments cancer pathobiology (Figure 9). Thus, interference with the function of HA-CD44 can inhibit the malignant process at multiple stages. This can be accomplished by perturbation of HA-CD44 signaling pathways and disruption of the HA matrix with hyaluronidases to facilitate passive carrier uptake, targeting the HA tumor matrix and providing sustained source of drug to the tumor site or by targeting CD44 receptor by CD44 blocking antibody or tissue specific targeting of specific variants of CD44 that are overexpressed in tumors. Cancer is a disease of the organism and is the subject of intense research around the world, but many questions about how the disease works remain unanswered. However, the multifaceted functions of GAGs and PGs require careful, context-dependent therapeutic applications because they have dual functions; and targeting ECM GAGs and PGs may promote escape of tumor cells from the primary tumor by inhibiting cancer cell attachment and increasing distant metastatic migration of tumor cells. Alternative viable and beneficial approaches are targeting the tumor ECM to disrupt HA-CD44v signaling pathways, keeping the function of CD44s intact. Thus, our validated tumor specific delivery of CD44 variant-shRNA has considerable advantage versus other therapeutic strategies. First, this technique avoids multiple chemical steps to prepare HA conjugated cytotoxic drugs and conjugation to nanocarriers. Second, it abolishes the CD44v variants in the cancer cells only. Third, a number of cell types in normal tissues that express CD44s or the hematopoietic form will not be affected because these are not activated. Fourth, although inflammation-associated cancers accumulate activated immune cells with upregulated transferrin receptors and CD44 variants and may take up the Tf-PEG-PEI-nanoparticles, there will be no deletion of CD44 variant because the promoter is not lymphocyte specific. To target activated lymphocytes, specific lymphocyte promoter driven-Cre plasmids would have to be used. Fifth, accumulation of antibody in nontumor areas is a major limitation of anti-CD44 antibody therapy. Experiments so far have not shown any such effect in shRNA delivery. The HA-CD44 interaction system is illustrated in Figure 9 where we specify alternatives for cancer therapeutical aspects (discussed in this review) that specifically perturb HA-CD44 signaling pathways.


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)

Exploitation of HA-CD44 interaction for anticancer therapy. Left panel represents the internalization of HA-drug conjugate that ultimately releases the drug that inhibits DNA synthesis of cancer cells. CD44 on the cell membrane binds the HA-drug conjugate and is internalized by endocytosis. The endosome formed is moved to the lysosome and fused. Here the HA in the conjugate is degraded first by hyaluronidase 1 (Hyal-1) into small HA oligosaccharides and next by lysosomal glycosidases to monosaccharides followed by release of the drug. The drug inhibits the DNA synthesis in the nucleus. Right panel exemplifies the steps that target the CD44v6mRNA in cancer cells by CD44v6shRNA. Plasmids producing CD44v6shRNA are coated with transferrin containing nanoparticles to target transferrin receptors of the cells. The particles are then internalized and form an endosome from which the plasmids are released to the nucleus where activation of DNA pol III occurs that results in CD44v6shRNA production. Through exportin, the newly produced CD44v6shRNA come out into cytoplasm where it is converted into CD44v6siRNA by dicer enzyme. One of the strands of siRNA will bind to CD44v6mRNA and forms RNA-induced silencing complex (RISC) which is ultimately degraded.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4581573&req=5

fig9: Exploitation of HA-CD44 interaction for anticancer therapy. Left panel represents the internalization of HA-drug conjugate that ultimately releases the drug that inhibits DNA synthesis of cancer cells. CD44 on the cell membrane binds the HA-drug conjugate and is internalized by endocytosis. The endosome formed is moved to the lysosome and fused. Here the HA in the conjugate is degraded first by hyaluronidase 1 (Hyal-1) into small HA oligosaccharides and next by lysosomal glycosidases to monosaccharides followed by release of the drug. The drug inhibits the DNA synthesis in the nucleus. Right panel exemplifies the steps that target the CD44v6mRNA in cancer cells by CD44v6shRNA. Plasmids producing CD44v6shRNA are coated with transferrin containing nanoparticles to target transferrin receptors of the cells. The particles are then internalized and form an endosome from which the plasmids are released to the nucleus where activation of DNA pol III occurs that results in CD44v6shRNA production. Through exportin, the newly produced CD44v6shRNA come out into cytoplasm where it is converted into CD44v6siRNA by dicer enzyme. One of the strands of siRNA will bind to CD44v6mRNA and forms RNA-induced silencing complex (RISC) which is ultimately degraded.
Mentions: Among various GAGs and PGs, much research has demonstrated the ability of HA to target cancer cells overexpressing the HA receptor CD44, in particular its variants, and that HA interaction with CD44v augments cancer pathobiology (Figure 9). Thus, interference with the function of HA-CD44 can inhibit the malignant process at multiple stages. This can be accomplished by perturbation of HA-CD44 signaling pathways and disruption of the HA matrix with hyaluronidases to facilitate passive carrier uptake, targeting the HA tumor matrix and providing sustained source of drug to the tumor site or by targeting CD44 receptor by CD44 blocking antibody or tissue specific targeting of specific variants of CD44 that are overexpressed in tumors. Cancer is a disease of the organism and is the subject of intense research around the world, but many questions about how the disease works remain unanswered. However, the multifaceted functions of GAGs and PGs require careful, context-dependent therapeutic applications because they have dual functions; and targeting ECM GAGs and PGs may promote escape of tumor cells from the primary tumor by inhibiting cancer cell attachment and increasing distant metastatic migration of tumor cells. Alternative viable and beneficial approaches are targeting the tumor ECM to disrupt HA-CD44v signaling pathways, keeping the function of CD44s intact. Thus, our validated tumor specific delivery of CD44 variant-shRNA has considerable advantage versus other therapeutic strategies. First, this technique avoids multiple chemical steps to prepare HA conjugated cytotoxic drugs and conjugation to nanocarriers. Second, it abolishes the CD44v variants in the cancer cells only. Third, a number of cell types in normal tissues that express CD44s or the hematopoietic form will not be affected because these are not activated. Fourth, although inflammation-associated cancers accumulate activated immune cells with upregulated transferrin receptors and CD44 variants and may take up the Tf-PEG-PEI-nanoparticles, there will be no deletion of CD44 variant because the promoter is not lymphocyte specific. To target activated lymphocytes, specific lymphocyte promoter driven-Cre plasmids would have to be used. Fifth, accumulation of antibody in nontumor areas is a major limitation of anti-CD44 antibody therapy. Experiments so far have not shown any such effect in shRNA delivery. The HA-CD44 interaction system is illustrated in Figure 9 where we specify alternatives for cancer therapeutical aspects (discussed in this review) that specifically perturb HA-CD44 signaling pathways.

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