Epithelial ovarian cancer-induced angiogenic phenotype of human omental microvascular endothelial cells may occur independently of VEGF signaling.

2.50
Hdl Handle:
http://hdl.handle.net/11287/609607
Title:
Epithelial ovarian cancer-induced angiogenic phenotype of human omental microvascular endothelial cells may occur independently of VEGF signaling.
Authors:
Winiarski, B. K.; Wolanska, K. I.; Rai, S.; Ahmed, T.; Acheson, Nigel; Gutowski, Nicholas J.; Whatmore, Jacqueline L.
Abstract:
Epithelial ovarian cancer (EOC) metastasizes transcoelomically to the peritoneum and omentum, and despite surgery and chemotherapy, recurrent disease is likely. Metastasis requires the induction of proangiogenic changes in the omental microenvironment and EOC-induced omental angiogenesis is currently a key therapeutic target. In particular, antiangiogenic therapies targeting the vascular endothelial growth factor A (VEGFA) pathway are commonly used, although, with limited effects. Here, using human omental microvascular endothelial cells (HOMECs) and ovarian cancer cell lines as an in vitro model, we show that factors secreted from EOC cells increased proliferation, migration, and tube-like structure formation in HOMECs. However, EOC-induced angiogenic tube-like formation and migration were unaffected by inhibition of tyrosine kinase activity of VEGF receptors 1 and 2 (Semaxanib; SU5416) or neutralization of VEGFA (neutralizing anti-VEGFA antibody), although VEGFA165-induced HOMEC migration and tube-like structure formation were abolished. Proteomic investigation of the EOC secretome identified several alternative angiogenesis-related proteins. We screened these for their ability to induce an angiogenic phenotype in HOMECs, i.e., proliferation, migration, and tube-like structure formation. Hepatocyte growth factor (HGF) and insulin-like growth factor binding protein 7 (IGFBP-7) increased all three parameters, and cathepsin L (CL) increased migration and tubule formation. Further investigation confirmed expression of the HGF receptor c-Met in HOMECs. HGF- and EOC-induced proliferation and angiogenic tube structure formation were blocked by the c-Met inhibitor PF04217903. Our results highlight key alternative angiogenic mediators for metastatic EOC, namely, HGF, CL, and IGFBP-7, suggesting that effective antiangiogenic therapeutic strategies for this disease require inhibition of multiple angiogenic pathways.
Citation:
Epithelial ovarian cancer-induced angiogenic phenotype of human omental microvascular endothelial cells may occur independently of VEGF signaling. 2013, 6 (6):703-14 Transl Oncol
Publisher:
Elsevier
Journal:
Translational oncology
Issue Date:
1-Dec-2013
URI:
http://hdl.handle.net/11287/609607
PubMed ID:
24466373
Additional Links:
http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24466373/
Note:
This article is freely available via Open Access. Click on the 'Additional Link' above to access the full-text via the publisher's site.
Type:
Journal Article
Language:
en
ISSN:
1936-5233
Appears in Collections:
Neurology; pre-2014 RD&E publications; Honorary contracts publications

Full metadata record

DC FieldValue Language
dc.contributor.authorWiniarski, B. K.en
dc.contributor.authorWolanska, K. I.en
dc.contributor.authorRai, S.en
dc.contributor.authorAhmed, T.en
dc.contributor.authorAcheson, Nigelen
dc.contributor.authorGutowski, Nicholas J.en
dc.contributor.authorWhatmore, Jacqueline L.en
dc.date.accessioned2016-05-18T14:43:51Zen
dc.date.available2016-05-18T14:43:51Zen
dc.date.issued2013-12-01en
dc.identifier.citationEpithelial ovarian cancer-induced angiogenic phenotype of human omental microvascular endothelial cells may occur independently of VEGF signaling. 2013, 6 (6):703-14 Transl Oncolen
dc.identifier.issn1936-5233en
dc.identifier.pmid24466373en
dc.identifier.urihttp://hdl.handle.net/11287/609607en
dc.description.abstractEpithelial ovarian cancer (EOC) metastasizes transcoelomically to the peritoneum and omentum, and despite surgery and chemotherapy, recurrent disease is likely. Metastasis requires the induction of proangiogenic changes in the omental microenvironment and EOC-induced omental angiogenesis is currently a key therapeutic target. In particular, antiangiogenic therapies targeting the vascular endothelial growth factor A (VEGFA) pathway are commonly used, although, with limited effects. Here, using human omental microvascular endothelial cells (HOMECs) and ovarian cancer cell lines as an in vitro model, we show that factors secreted from EOC cells increased proliferation, migration, and tube-like structure formation in HOMECs. However, EOC-induced angiogenic tube-like formation and migration were unaffected by inhibition of tyrosine kinase activity of VEGF receptors 1 and 2 (Semaxanib; SU5416) or neutralization of VEGFA (neutralizing anti-VEGFA antibody), although VEGFA165-induced HOMEC migration and tube-like structure formation were abolished. Proteomic investigation of the EOC secretome identified several alternative angiogenesis-related proteins. We screened these for their ability to induce an angiogenic phenotype in HOMECs, i.e., proliferation, migration, and tube-like structure formation. Hepatocyte growth factor (HGF) and insulin-like growth factor binding protein 7 (IGFBP-7) increased all three parameters, and cathepsin L (CL) increased migration and tubule formation. Further investigation confirmed expression of the HGF receptor c-Met in HOMECs. HGF- and EOC-induced proliferation and angiogenic tube structure formation were blocked by the c-Met inhibitor PF04217903. Our results highlight key alternative angiogenic mediators for metastatic EOC, namely, HGF, CL, and IGFBP-7, suggesting that effective antiangiogenic therapeutic strategies for this disease require inhibition of multiple angiogenic pathways.en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24466373/en
dc.rightsArchived with thanks to Translational oncologyen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.en
dc.subjectWessex Classification Subject Headings::Gynaecologyen
dc.titleEpithelial ovarian cancer-induced angiogenic phenotype of human omental microvascular endothelial cells may occur independently of VEGF signaling.en
dc.typeJournal Articleen
dc.identifier.journalTranslational oncologyen
dc.description.noteThis article is freely available via Open Access. Click on the 'Additional Link' above to access the full-text via the publisher's site.en
dc.type.versionPublisheden
All Items in RD&E Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.