Limits...
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

Systemic application of pSicoCD44v6shRNA plasmid in Apc Min/+ mice. Effect of plasmid/nanoparticle treatment on protein expression, RT-PCR analysis, and number of adenomas in Apc Min/+ mice (adapted from [43]). Thirty Apc Min/+ mice were randomly divided into three groups. Group 1 received pSV-β-galactosidase (100 μg/100 μL, intraperitoneally (i.p.)) alone, Group 2 received pSV-β-gal nanoparticles (100 μg/100 μL, i.p.) targeted to the Tf-R, and Group 3 received pSico-CD44v6shRNA (75 μg) plus pFabpl-Cre (25 μg)/nanoparticles i.p. every other day. 10 days after beginning treatment, the animals were sacrificed, and the large (>1 mm) and small (<1 mm) adenomas were counted (a). The tumor and adjacent normal tissues were subsequently processed for (b) western blots for CD44, pErbB2, TErbB2, COX-2, and β-actin and (c) RT-PCR analyses for CD44 variants from total RNA. Total ErbB2 remained unchanged in all the treatment groups (data not shown).
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4581573&req=5

fig8: Systemic application of pSicoCD44v6shRNA plasmid in Apc Min/+ mice. Effect of plasmid/nanoparticle treatment on protein expression, RT-PCR analysis, and number of adenomas in Apc Min/+ mice (adapted from [43]). Thirty Apc Min/+ mice were randomly divided into three groups. Group 1 received pSV-β-galactosidase (100 μg/100 μL, intraperitoneally (i.p.)) alone, Group 2 received pSV-β-gal nanoparticles (100 μg/100 μL, i.p.) targeted to the Tf-R, and Group 3 received pSico-CD44v6shRNA (75 μg) plus pFabpl-Cre (25 μg)/nanoparticles i.p. every other day. 10 days after beginning treatment, the animals were sacrificed, and the large (>1 mm) and small (<1 mm) adenomas were counted (a). The tumor and adjacent normal tissues were subsequently processed for (b) western blots for CD44, pErbB2, TErbB2, COX-2, and β-actin and (c) RT-PCR analyses for CD44 variants from total RNA. Total ErbB2 remained unchanged in all the treatment groups (data not shown).

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)

Systemic application of pSicoCD44v6shRNA plasmid in Apc Min/+ mice. Effect of plasmid/nanoparticle treatment on protein expression, RT-PCR analysis, and number of adenomas in Apc Min/+ mice (adapted from [43]). Thirty Apc Min/+ mice were randomly divided into three groups. Group 1 received pSV-β-galactosidase (100 μg/100 μL, intraperitoneally (i.p.)) alone, Group 2 received pSV-β-gal nanoparticles (100 μg/100 μL, i.p.) targeted to the Tf-R, and Group 3 received pSico-CD44v6shRNA (75 μg) plus pFabpl-Cre (25 μg)/nanoparticles i.p. every other day. 10 days after beginning treatment, the animals were sacrificed, and the large (>1 mm) and small (<1 mm) adenomas were counted (a). The tumor and adjacent normal tissues were subsequently processed for (b) western blots for CD44, pErbB2, TErbB2, COX-2, and β-actin and (c) RT-PCR analyses for CD44 variants from total RNA. Total ErbB2 remained unchanged in all the treatment groups (data not shown).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4581573&req=5

fig8: Systemic application of pSicoCD44v6shRNA plasmid in Apc Min/+ mice. Effect of plasmid/nanoparticle treatment on protein expression, RT-PCR analysis, and number of adenomas in Apc Min/+ mice (adapted from [43]). Thirty Apc Min/+ mice were randomly divided into three groups. Group 1 received pSV-β-galactosidase (100 μg/100 μL, intraperitoneally (i.p.)) alone, Group 2 received pSV-β-gal nanoparticles (100 μg/100 μL, i.p.) targeted to the Tf-R, and Group 3 received pSico-CD44v6shRNA (75 μg) plus pFabpl-Cre (25 μg)/nanoparticles i.p. every other day. 10 days after beginning treatment, the animals were sacrificed, and the large (>1 mm) and small (<1 mm) adenomas were counted (a). The tumor and adjacent normal tissues were subsequently processed for (b) western blots for CD44, pErbB2, TErbB2, COX-2, and β-actin and (c) RT-PCR analyses for CD44 variants from total RNA. Total ErbB2 remained unchanged in all the treatment groups (data not shown).
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