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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

Uptake of pSV-β-galactosidase/Tf-PEG-PEI (nanoparticles) into target cell. Delivery of pSV-β-gal nanoparticles in colon cancer cells (adapted from [43]). (a) In situ  β-galactosidase expression in the target cell. The Apc10.1-HAS2 clone and the CT26 cells were treated for 48 h with the pSV-β-gal alone (panel 1), with the pSV-β-gal with liposome (panel 2), or with the pSV-β-gal/nanoparticles (35 nm average diameter, 8 μg of pSV-β-gal/mL) (panel 3). The average size of the pSV-β-gal/nanoparticles is ~35 nm ± 20 nm. The transfected cells were fixed in 0.2% glutaraldehyde in PBS and washed twice in PBS. The cells were treated with a β-galactosidase staining solution and digitally photographed. (b) Transferrin-dependent uptake and in situ  β-galactosidase expression in the target cell. The Apc 10.1-HAS2 cells were transfected with the pSV-β-gal with liposome (panel 1), treated with Tf-R antibody and followed by transfection with the pSV-β-gal/nanoparticles (8 μg pSV-β-gal/mL) (panel 2), or treated with the pSV-β-gal/nanoparticles (8 μg pSV-β-gal/mL) alone (panel 3). The transfected cells were fixed in 0.2% glutaraldehyde in PBS and washed twice in PBS. β-galactosidase expressions in the cells were digitally photographed. (c) Cell-free extracts of parallel cultures were prepared in 10 mM CHAPS buffer and assayed for β-galactosidase activity using o-nitrophenyl β-D-galactopyranoside as substrate. The results are expressed as micromoles of o-nitrophenol formed per min/mg protein and represent ± S.D. of triplicate assays from the untransfected, liposome-transfected, or nanoparticles-treated cultures for each cell type.
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fig7: Uptake of pSV-β-galactosidase/Tf-PEG-PEI (nanoparticles) into target cell. Delivery of pSV-β-gal nanoparticles in colon cancer cells (adapted from [43]). (a) In situ  β-galactosidase expression in the target cell. The Apc10.1-HAS2 clone and the CT26 cells were treated for 48 h with the pSV-β-gal alone (panel 1), with the pSV-β-gal with liposome (panel 2), or with the pSV-β-gal/nanoparticles (35 nm average diameter, 8 μg of pSV-β-gal/mL) (panel 3). The average size of the pSV-β-gal/nanoparticles is ~35 nm ± 20 nm. The transfected cells were fixed in 0.2% glutaraldehyde in PBS and washed twice in PBS. The cells were treated with a β-galactosidase staining solution and digitally photographed. (b) Transferrin-dependent uptake and in situ  β-galactosidase expression in the target cell. The Apc 10.1-HAS2 cells were transfected with the pSV-β-gal with liposome (panel 1), treated with Tf-R antibody and followed by transfection with the pSV-β-gal/nanoparticles (8 μg pSV-β-gal/mL) (panel 2), or treated with the pSV-β-gal/nanoparticles (8 μg pSV-β-gal/mL) alone (panel 3). The transfected cells were fixed in 0.2% glutaraldehyde in PBS and washed twice in PBS. β-galactosidase expressions in the cells were digitally photographed. (c) Cell-free extracts of parallel cultures were prepared in 10 mM CHAPS buffer and assayed for β-galactosidase activity using o-nitrophenyl β-D-galactopyranoside as substrate. The results are expressed as micromoles of o-nitrophenol formed per min/mg protein and represent ± S.D. of triplicate assays from the untransfected, liposome-transfected, or nanoparticles-treated cultures for each cell type.

Mentions: This shRNA plasmid delivery approach was tested for transfection of pSV-β-gal/Tf-PEG-PEI-nanoparticles in cellular models (Figure 7). Following this experiment, we successfully demonstrated that the CD44v6shRNA is localized into the colon tumor cells by an end-point assay of CD44v6 expression and by perturbation of HA-CD44v6 interaction as reflected in the reduction in the number of tumors [43] (Figure 8). The tissue specific shRNA delivery was made possible by the use of Cre-recombinase produced in response to a colon tissue specific promoter, which deletes the interruption between the U6 promoter and the CD44v6shRNA oligonucleotide. The newly developed cell-specific shRNA delivery approach by Misra et al. [43] confirmed that targeting the signaling pathways induced by HA-CD44v6 interaction inhibited distant colon tumor growth in Apc Min/+ mice. Our recent unpublished in vivo studies with the C57Bl/6 mice have now shown that systemic delivery of a mixture of two plasmids in Tf-PEG-PEI-nanoparticles (pARR2-Probasin-Cre/Tf-PEG-PEI-nanoparticles and floxed pSico-CD44v9shRNA/Tf-PEG-PEI-nanoparticles) can target both localized and metastatic prostate cancer cells. This novel approach opens up new ways to combat cancer and to understand tumorigenesis in vivo for the following reasons.


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)

Uptake of pSV-β-galactosidase/Tf-PEG-PEI (nanoparticles) into target cell. Delivery of pSV-β-gal nanoparticles in colon cancer cells (adapted from [43]). (a) In situ  β-galactosidase expression in the target cell. The Apc10.1-HAS2 clone and the CT26 cells were treated for 48 h with the pSV-β-gal alone (panel 1), with the pSV-β-gal with liposome (panel 2), or with the pSV-β-gal/nanoparticles (35 nm average diameter, 8 μg of pSV-β-gal/mL) (panel 3). The average size of the pSV-β-gal/nanoparticles is ~35 nm ± 20 nm. The transfected cells were fixed in 0.2% glutaraldehyde in PBS and washed twice in PBS. The cells were treated with a β-galactosidase staining solution and digitally photographed. (b) Transferrin-dependent uptake and in situ  β-galactosidase expression in the target cell. The Apc 10.1-HAS2 cells were transfected with the pSV-β-gal with liposome (panel 1), treated with Tf-R antibody and followed by transfection with the pSV-β-gal/nanoparticles (8 μg pSV-β-gal/mL) (panel 2), or treated with the pSV-β-gal/nanoparticles (8 μg pSV-β-gal/mL) alone (panel 3). The transfected cells were fixed in 0.2% glutaraldehyde in PBS and washed twice in PBS. β-galactosidase expressions in the cells were digitally photographed. (c) Cell-free extracts of parallel cultures were prepared in 10 mM CHAPS buffer and assayed for β-galactosidase activity using o-nitrophenyl β-D-galactopyranoside as substrate. The results are expressed as micromoles of o-nitrophenol formed per min/mg protein and represent ± S.D. of triplicate assays from the untransfected, liposome-transfected, or nanoparticles-treated cultures for each cell type.
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Related In: Results  -  Collection

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fig7: Uptake of pSV-β-galactosidase/Tf-PEG-PEI (nanoparticles) into target cell. Delivery of pSV-β-gal nanoparticles in colon cancer cells (adapted from [43]). (a) In situ  β-galactosidase expression in the target cell. The Apc10.1-HAS2 clone and the CT26 cells were treated for 48 h with the pSV-β-gal alone (panel 1), with the pSV-β-gal with liposome (panel 2), or with the pSV-β-gal/nanoparticles (35 nm average diameter, 8 μg of pSV-β-gal/mL) (panel 3). The average size of the pSV-β-gal/nanoparticles is ~35 nm ± 20 nm. The transfected cells were fixed in 0.2% glutaraldehyde in PBS and washed twice in PBS. The cells were treated with a β-galactosidase staining solution and digitally photographed. (b) Transferrin-dependent uptake and in situ  β-galactosidase expression in the target cell. The Apc 10.1-HAS2 cells were transfected with the pSV-β-gal with liposome (panel 1), treated with Tf-R antibody and followed by transfection with the pSV-β-gal/nanoparticles (8 μg pSV-β-gal/mL) (panel 2), or treated with the pSV-β-gal/nanoparticles (8 μg pSV-β-gal/mL) alone (panel 3). The transfected cells were fixed in 0.2% glutaraldehyde in PBS and washed twice in PBS. β-galactosidase expressions in the cells were digitally photographed. (c) Cell-free extracts of parallel cultures were prepared in 10 mM CHAPS buffer and assayed for β-galactosidase activity using o-nitrophenyl β-D-galactopyranoside as substrate. The results are expressed as micromoles of o-nitrophenol formed per min/mg protein and represent ± S.D. of triplicate assays from the untransfected, liposome-transfected, or nanoparticles-treated cultures for each cell type.
Mentions: This shRNA plasmid delivery approach was tested for transfection of pSV-β-gal/Tf-PEG-PEI-nanoparticles in cellular models (Figure 7). Following this experiment, we successfully demonstrated that the CD44v6shRNA is localized into the colon tumor cells by an end-point assay of CD44v6 expression and by perturbation of HA-CD44v6 interaction as reflected in the reduction in the number of tumors [43] (Figure 8). The tissue specific shRNA delivery was made possible by the use of Cre-recombinase produced in response to a colon tissue specific promoter, which deletes the interruption between the U6 promoter and the CD44v6shRNA oligonucleotide. The newly developed cell-specific shRNA delivery approach by Misra et al. [43] confirmed that targeting the signaling pathways induced by HA-CD44v6 interaction inhibited distant colon tumor growth in Apc Min/+ mice. Our recent unpublished in vivo studies with the C57Bl/6 mice have now shown that systemic delivery of a mixture of two plasmids in Tf-PEG-PEI-nanoparticles (pARR2-Probasin-Cre/Tf-PEG-PEI-nanoparticles and floxed pSico-CD44v9shRNA/Tf-PEG-PEI-nanoparticles) can target both localized and metastatic prostate cancer cells. This novel approach opens up new ways to combat cancer and to understand tumorigenesis in vivo for the following reasons.

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