Antibody targeting of cathepsin S inhibits angiogenesis and synergistically enhances anti-VEGF.
BACKGROUND: Angiogenesis is a key hallmark of tumourigenesis and its inhibition is a proven strategy for the development of novel anti-cancer therapeutics. An important aspect of early angiogenesis is the co-ordinated migration and invasion of endothelial cells through the hypoxic tumour tissue. Cat...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2010-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2932732?pdf=render |
| _version_ | 1819099045021351936 |
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| author | Claire Ward Diana Kuehn Roberta E Burden Julie A Gormley Thomas J Jaquin Mihaela Gazdoiu Donna Small Roy Bicknell James A Johnston Christopher J Scott Shane A Olwill |
| author_facet | Claire Ward Diana Kuehn Roberta E Burden Julie A Gormley Thomas J Jaquin Mihaela Gazdoiu Donna Small Roy Bicknell James A Johnston Christopher J Scott Shane A Olwill |
| author_sort | Claire Ward |
| collection | DOAJ |
| description | BACKGROUND: Angiogenesis is a key hallmark of tumourigenesis and its inhibition is a proven strategy for the development of novel anti-cancer therapeutics. An important aspect of early angiogenesis is the co-ordinated migration and invasion of endothelial cells through the hypoxic tumour tissue. Cathepsin S has been shown to play an important role in angiogenesis as has vascular endothelial growth factor (VEGF). We sought to assess the anti-angiogenic effect of Fsn0503, a novel cathepsin S inhibitory antibody, when combined with anti-VEGF on vascular development. METHODOLOGY/PRINCIPAL FINDINGS: Cathepsin S expression and secretion from endothelial cells was characterised using RT-PCR and western blotting. We further show that cathepsin S promotes pericellular hydrolysis of extracellular matrix components in the tumour microenvironment and facilitates endothelial invasion. The cathepsin S inhibitory antibody, Fsn0503, blocks extracellular proteolysis, inhibiting endothelial invasion and tube formation in cell-based assays. The anti-angiogenic effects of Fsn0503 were also shown in vivo where it significantly retarded the development of vasculature in human xenograft models. Furthermore, when Fsn0503 was combined with an anti-VEGF antibody, a synergistic inhibition of microvascular development was observed. CONCLUSIONS/SIGNIFICANCE: Taken together, this data demonstrates that the antibody-mediated targeting of cathepsin S represents a novel method of inhibiting angiogenesis. Furthermore, when used in combination with anti-VEGF therapies, Fsn0503 has the potential to significantly enhance current treatments of tumour neovascularisation and may also be of use in the treatment of other conditions associated with inappropriate angiogenesis. |
| first_indexed | 2024-12-22T00:40:38Z |
| format | Article |
| id | doaj.art-3e20d26756f14f4193cfcc32518e6ad2 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-22T00:40:38Z |
| publishDate | 2010-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-3e20d26756f14f4193cfcc32518e6ad22022-12-21T18:44:42ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-01-0159e1248910.1371/journal.pone.0012543Antibody targeting of cathepsin S inhibits angiogenesis and synergistically enhances anti-VEGF.Claire WardDiana KuehnRoberta E BurdenJulie A GormleyThomas J JaquinMihaela GazdoiuDonna SmallRoy BicknellJames A JohnstonChristopher J ScottShane A OlwillBACKGROUND: Angiogenesis is a key hallmark of tumourigenesis and its inhibition is a proven strategy for the development of novel anti-cancer therapeutics. An important aspect of early angiogenesis is the co-ordinated migration and invasion of endothelial cells through the hypoxic tumour tissue. Cathepsin S has been shown to play an important role in angiogenesis as has vascular endothelial growth factor (VEGF). We sought to assess the anti-angiogenic effect of Fsn0503, a novel cathepsin S inhibitory antibody, when combined with anti-VEGF on vascular development. METHODOLOGY/PRINCIPAL FINDINGS: Cathepsin S expression and secretion from endothelial cells was characterised using RT-PCR and western blotting. We further show that cathepsin S promotes pericellular hydrolysis of extracellular matrix components in the tumour microenvironment and facilitates endothelial invasion. The cathepsin S inhibitory antibody, Fsn0503, blocks extracellular proteolysis, inhibiting endothelial invasion and tube formation in cell-based assays. The anti-angiogenic effects of Fsn0503 were also shown in vivo where it significantly retarded the development of vasculature in human xenograft models. Furthermore, when Fsn0503 was combined with an anti-VEGF antibody, a synergistic inhibition of microvascular development was observed. CONCLUSIONS/SIGNIFICANCE: Taken together, this data demonstrates that the antibody-mediated targeting of cathepsin S represents a novel method of inhibiting angiogenesis. Furthermore, when used in combination with anti-VEGF therapies, Fsn0503 has the potential to significantly enhance current treatments of tumour neovascularisation and may also be of use in the treatment of other conditions associated with inappropriate angiogenesis.http://europepmc.org/articles/PMC2932732?pdf=render |
| spellingShingle | Claire Ward Diana Kuehn Roberta E Burden Julie A Gormley Thomas J Jaquin Mihaela Gazdoiu Donna Small Roy Bicknell James A Johnston Christopher J Scott Shane A Olwill Antibody targeting of cathepsin S inhibits angiogenesis and synergistically enhances anti-VEGF. PLoS ONE |
| title | Antibody targeting of cathepsin S inhibits angiogenesis and synergistically enhances anti-VEGF. |
| title_full | Antibody targeting of cathepsin S inhibits angiogenesis and synergistically enhances anti-VEGF. |
| title_fullStr | Antibody targeting of cathepsin S inhibits angiogenesis and synergistically enhances anti-VEGF. |
| title_full_unstemmed | Antibody targeting of cathepsin S inhibits angiogenesis and synergistically enhances anti-VEGF. |
| title_short | Antibody targeting of cathepsin S inhibits angiogenesis and synergistically enhances anti-VEGF. |
| title_sort | antibody targeting of cathepsin s inhibits angiogenesis and synergistically enhances anti vegf |
| url | http://europepmc.org/articles/PMC2932732?pdf=render |
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