Cargando…

Transcriptional factor snail controls tumor neovascularization, growth and metastasis in mouse model of human ovarian carcinoma

BACKGROUND: Snail, a transcriptional factor and repressor of E-cadherin is well known for its role in cellular invasion. It can regulate epithelial to mesenchymal transition (EMT) during embryonic development and in epithelial cells. Snail also mediates tumor progression and metastases. Silencing of...

Descripción completa

Detalles Bibliográficos
Autores principales: Abdulkhalek, Samar, Geen, Olivia D, Brodhagen, Lacey, Haxho, Fiona, Alghamdi, Farah, Allison, Stephanie, Simmons, Duncan J, O'Shea, Leah K, Neufeld, Ronald J, Szewczuk, Myron R
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884043/
https://www.ncbi.nlm.nih.gov/pubmed/26932374
http://dx.doi.org/10.1186/s40169-014-0028-z
_version_ 1782434326986620928
author Abdulkhalek, Samar
Geen, Olivia D
Brodhagen, Lacey
Haxho, Fiona
Alghamdi, Farah
Allison, Stephanie
Simmons, Duncan J
O'Shea, Leah K
Neufeld, Ronald J
Szewczuk, Myron R
author_facet Abdulkhalek, Samar
Geen, Olivia D
Brodhagen, Lacey
Haxho, Fiona
Alghamdi, Farah
Allison, Stephanie
Simmons, Duncan J
O'Shea, Leah K
Neufeld, Ronald J
Szewczuk, Myron R
author_sort Abdulkhalek, Samar
collection PubMed
description BACKGROUND: Snail, a transcriptional factor and repressor of E-cadherin is well known for its role in cellular invasion. It can regulate epithelial to mesenchymal transition (EMT) during embryonic development and in epithelial cells. Snail also mediates tumor progression and metastases. Silencing of Snail and its associate member Slug in human A2780 ovarian epithelial carcinoma cell line was investigated to identify its role in tumor neovascularization. METHODS: Live cell sialidase, WST-1 cell viability and immunohistochemistry assays were used to evaluate sialidase activity, cell survival and the expression levels of tumor E-cadherin, N-cadherin, VE-cadherin, and host endothelial CD31+(PECAM-1) cells in archived paraffin-embedded ovarian A2780, A2780 Snail shRNA GIPZ lentiviral knockdown (KD) and A2780 Slug shRNA GIPZ lentiviral KD tumors grown in RAGxCγ double mutant mice. RESULTS: Oseltamivir phosphate (OP), anti-Neu1 antibodies and MMP-9 specific inhibitor blocked Neu1 activity associated with epidermal growth factor (EGF) stimulated A2780 ovarian epithelial carcinoma cells. Silencing Snail in A2780 cells abrogated the Neu1 activity following EGF stimulation of the cells compared to A2780 and A2780 Slug KD cells. OP treatment of A2780 and cisplatin-resistant A2780cis cells reproducibly and dose-dependently abated the cell viability with a LD(50) of 7 and 4 μm, respectively, after 48 h of incubation. Heterotopic xenografts of A2780 and A2780 Slug KD tumors developed robust and bloody tumor vascularization in RAG2xCγ double mutant mice. OP treatment at 50 mg/kg daily intraperitoneally did not significantly impede A2780 tumor growth rate but did cause a significant reduction of lung metastases compared with the untreated and OP 30mg/kg cohorts. Silencing Snail in A2780 tumor cells completely abrogated tumor vascularization, tumor growth and spread to the lungs in RAGxCγ double mutant mice. A2780 and A2780 Slug KD tumors expressed high levels of human N- and VE-cadherins, and host CD31+ endothelial cells, while A2780 Snail KD tumors expressed E-cadherin and reduced host CD31+ cells. OP 50mg/kg cohort tumors had reduced numbers of host CD31+ cells compared to a higher expression levels of CD31+ cells in tumors from the untreated control and OP 30mg/kg cohorts. CONCLUSION: Snail transcriptional factor is an important intermediate player in human ovarian tumor neovascularization. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40169-014-0028-z) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-4884043
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher Springer Berlin Heidelberg
record_format MEDLINE/PubMed
spelling pubmed-48840432016-06-21 Transcriptional factor snail controls tumor neovascularization, growth and metastasis in mouse model of human ovarian carcinoma Abdulkhalek, Samar Geen, Olivia D Brodhagen, Lacey Haxho, Fiona Alghamdi, Farah Allison, Stephanie Simmons, Duncan J O'Shea, Leah K Neufeld, Ronald J Szewczuk, Myron R Clin Transl Med Research BACKGROUND: Snail, a transcriptional factor and repressor of E-cadherin is well known for its role in cellular invasion. It can regulate epithelial to mesenchymal transition (EMT) during embryonic development and in epithelial cells. Snail also mediates tumor progression and metastases. Silencing of Snail and its associate member Slug in human A2780 ovarian epithelial carcinoma cell line was investigated to identify its role in tumor neovascularization. METHODS: Live cell sialidase, WST-1 cell viability and immunohistochemistry assays were used to evaluate sialidase activity, cell survival and the expression levels of tumor E-cadherin, N-cadherin, VE-cadherin, and host endothelial CD31+(PECAM-1) cells in archived paraffin-embedded ovarian A2780, A2780 Snail shRNA GIPZ lentiviral knockdown (KD) and A2780 Slug shRNA GIPZ lentiviral KD tumors grown in RAGxCγ double mutant mice. RESULTS: Oseltamivir phosphate (OP), anti-Neu1 antibodies and MMP-9 specific inhibitor blocked Neu1 activity associated with epidermal growth factor (EGF) stimulated A2780 ovarian epithelial carcinoma cells. Silencing Snail in A2780 cells abrogated the Neu1 activity following EGF stimulation of the cells compared to A2780 and A2780 Slug KD cells. OP treatment of A2780 and cisplatin-resistant A2780cis cells reproducibly and dose-dependently abated the cell viability with a LD(50) of 7 and 4 μm, respectively, after 48 h of incubation. Heterotopic xenografts of A2780 and A2780 Slug KD tumors developed robust and bloody tumor vascularization in RAG2xCγ double mutant mice. OP treatment at 50 mg/kg daily intraperitoneally did not significantly impede A2780 tumor growth rate but did cause a significant reduction of lung metastases compared with the untreated and OP 30mg/kg cohorts. Silencing Snail in A2780 tumor cells completely abrogated tumor vascularization, tumor growth and spread to the lungs in RAGxCγ double mutant mice. A2780 and A2780 Slug KD tumors expressed high levels of human N- and VE-cadherins, and host CD31+ endothelial cells, while A2780 Snail KD tumors expressed E-cadherin and reduced host CD31+ cells. OP 50mg/kg cohort tumors had reduced numbers of host CD31+ cells compared to a higher expression levels of CD31+ cells in tumors from the untreated control and OP 30mg/kg cohorts. CONCLUSION: Snail transcriptional factor is an important intermediate player in human ovarian tumor neovascularization. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40169-014-0028-z) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2014-09-23 /pmc/articles/PMC4884043/ /pubmed/26932374 http://dx.doi.org/10.1186/s40169-014-0028-z Text en © Abdulkhalek et al.; licensee Springer. 2014 This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.
spellingShingle Research
Abdulkhalek, Samar
Geen, Olivia D
Brodhagen, Lacey
Haxho, Fiona
Alghamdi, Farah
Allison, Stephanie
Simmons, Duncan J
O'Shea, Leah K
Neufeld, Ronald J
Szewczuk, Myron R
Transcriptional factor snail controls tumor neovascularization, growth and metastasis in mouse model of human ovarian carcinoma
title Transcriptional factor snail controls tumor neovascularization, growth and metastasis in mouse model of human ovarian carcinoma
title_full Transcriptional factor snail controls tumor neovascularization, growth and metastasis in mouse model of human ovarian carcinoma
title_fullStr Transcriptional factor snail controls tumor neovascularization, growth and metastasis in mouse model of human ovarian carcinoma
title_full_unstemmed Transcriptional factor snail controls tumor neovascularization, growth and metastasis in mouse model of human ovarian carcinoma
title_short Transcriptional factor snail controls tumor neovascularization, growth and metastasis in mouse model of human ovarian carcinoma
title_sort transcriptional factor snail controls tumor neovascularization, growth and metastasis in mouse model of human ovarian carcinoma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884043/
https://www.ncbi.nlm.nih.gov/pubmed/26932374
http://dx.doi.org/10.1186/s40169-014-0028-z
work_keys_str_mv AT abdulkhaleksamar transcriptionalfactorsnailcontrolstumorneovascularizationgrowthandmetastasisinmousemodelofhumanovariancarcinoma
AT geenoliviad transcriptionalfactorsnailcontrolstumorneovascularizationgrowthandmetastasisinmousemodelofhumanovariancarcinoma
AT brodhagenlacey transcriptionalfactorsnailcontrolstumorneovascularizationgrowthandmetastasisinmousemodelofhumanovariancarcinoma
AT haxhofiona transcriptionalfactorsnailcontrolstumorneovascularizationgrowthandmetastasisinmousemodelofhumanovariancarcinoma
AT alghamdifarah transcriptionalfactorsnailcontrolstumorneovascularizationgrowthandmetastasisinmousemodelofhumanovariancarcinoma
AT allisonstephanie transcriptionalfactorsnailcontrolstumorneovascularizationgrowthandmetastasisinmousemodelofhumanovariancarcinoma
AT simmonsduncanj transcriptionalfactorsnailcontrolstumorneovascularizationgrowthandmetastasisinmousemodelofhumanovariancarcinoma
AT oshealeahk transcriptionalfactorsnailcontrolstumorneovascularizationgrowthandmetastasisinmousemodelofhumanovariancarcinoma
AT neufeldronaldj transcriptionalfactorsnailcontrolstumorneovascularizationgrowthandmetastasisinmousemodelofhumanovariancarcinoma
AT szewczukmyronr transcriptionalfactorsnailcontrolstumorneovascularizationgrowthandmetastasisinmousemodelofhumanovariancarcinoma