Endothelial induced EMT in breast epithelial cells with stem cell properties

Valgardur Sigurdsson; Bylgja Hilmarsdottir; Hekla Sigmundsdottir; Agla J R Fridriksdottir; Markus Ringnér; Rene Villadsen; Ake Borg; Bjarni A Agnarsson; Ole William Petersen; Magnus K Magnusson; Thorarinn Gudjonsson

doi:10.1371/journal.pone.0023833

Endothelial induced EMT in breast epithelial cells with stem cell properties

Valgardur Sigurdsson, Bylgja Hilmarsdottir, Hekla Sigmundsdottir, Agla J R Fridriksdottir, Markus Ringnér, Rene Villadsen, Ake Borg, Bjarni A Agnarsson, Ole William Petersen, Magnus K Magnusson, Thorarinn Gudjonsson

69 Citationer (Scopus)

Abstract

Epithelial to mesenchymal transition (EMT) is a critical event in cancer progression and is closely linked to the breast epithelial cancer stem cell phenotype. Given the close interaction between the vascular endothelium and cancer cells, especially at the invasive front, we asked whether endothelial cells might play a role in EMT. Using a 3D culture model we demonstrate that endothelial cells are potent inducers of EMT in D492 an immortalized breast epithelial cell line with stem cell properties. Endothelial induced mesenchymal-like cells (D492M) derived from D492, show reduced expression of keratins, a switch from E-Cadherin (E-Cad) to N-Cadherin (N-Cad) and enhanced migration. Acquisition of cancer stem cell associated characteristics like increased CD44(high)/CD24(low) ratio, resistance to apoptosis and anchorage independent growth was also seen in D492M cells. Endothelial induced EMT in D492 was partially blocked by inhibition of HGF signaling. Basal-like breast cancer, a vascular rich cancer with stem cell properties and adverse prognosis has been linked with EMT. We immunostained several basal-like breast cancer samples for endothelial and EMT markers. Cancer cells close to the vascular rich areas show no or decreased expression of E-Cad and increased N-Cad expression suggesting EMT. Collectively, we have shown in a 3D culture model that endothelial cells are potent inducers of EMT in breast epithelial cells with stem cell properties. Furthermore, we demonstrate that basal-like breast cancer contains cells with an EMT phenotype, most prominently close to vascular rich areas of these tumors. We conclude that endothelial cells are potent inducers of EMT and may play a role in progression of basal-like breast cancer.

Originalsprog	Engelsk
Tidsskrift	P L o S One
Vol/bind	6
Udgave nummer	9
Sider (fra-til)	e23833
ISSN	1932-6203
DOI	https://doi.org/10.1371/journal.pone.0023833
Status	Udgivet - 2011

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title = "Endothelial induced EMT in breast epithelial cells with stem cell properties",

abstract = "Epithelial to mesenchymal transition (EMT) is a critical event in cancer progression and is closely linked to the breast epithelial cancer stem cell phenotype. Given the close interaction between the vascular endothelium and cancer cells, especially at the invasive front, we asked whether endothelial cells might play a role in EMT. Using a 3D culture model we demonstrate that endothelial cells are potent inducers of EMT in D492 an immortalized breast epithelial cell line with stem cell properties. Endothelial induced mesenchymal-like cells (D492M) derived from D492, show reduced expression of keratins, a switch from E-Cadherin (E-Cad) to N-Cadherin (N-Cad) and enhanced migration. Acquisition of cancer stem cell associated characteristics like increased CD44(high)/CD24(low) ratio, resistance to apoptosis and anchorage independent growth was also seen in D492M cells. Endothelial induced EMT in D492 was partially blocked by inhibition of HGF signaling. Basal-like breast cancer, a vascular rich cancer with stem cell properties and adverse prognosis has been linked with EMT. We immunostained several basal-like breast cancer samples for endothelial and EMT markers. Cancer cells close to the vascular rich areas show no or decreased expression of E-Cad and increased N-Cad expression suggesting EMT. Collectively, we have shown in a 3D culture model that endothelial cells are potent inducers of EMT in breast epithelial cells with stem cell properties. Furthermore, we demonstrate that basal-like breast cancer contains cells with an EMT phenotype, most prominently close to vascular rich areas of these tumors. We conclude that endothelial cells are potent inducers of EMT and may play a role in progression of basal-like breast cancer.",

keywords = "Apoptosis, Blotting, Western, Cell Dedifferentiation, Cell Line, Cell Line, Tumor, Cells, Cultured, Epidermal Growth Factor, Epithelial Cells, Epithelial-Mesenchymal Transition, Female, Fibroblast Growth Factors, Flow Cytometry, Hepatocyte Growth Factor, Humans, Immunochemistry, Neoplastic Stem Cells, Transforming Growth Factor beta1",

author = "Valgardur Sigurdsson and Bylgja Hilmarsdottir and Hekla Sigmundsdottir and Fridriksdottir, {Agla J R} and Markus Ringn{\'e}r and Rene Villadsen and Ake Borg and Agnarsson, {Bjarni A} and Petersen, {Ole William} and Magnusson, {Magnus K} and Thorarinn Gudjonsson",

year = "2011",

doi = "10.1371/journal.pone.0023833",

language = "English",

volume = "6",

pages = "e23833",

journal = "PLoS Computational Biology",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "9",

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TY - JOUR

T1 - Endothelial induced EMT in breast epithelial cells with stem cell properties

AU - Sigurdsson, Valgardur

AU - Hilmarsdottir, Bylgja

AU - Sigmundsdottir, Hekla

AU - Fridriksdottir, Agla J R

AU - Ringnér, Markus

AU - Villadsen, Rene

AU - Borg, Ake

AU - Agnarsson, Bjarni A

AU - Petersen, Ole William

AU - Magnusson, Magnus K

AU - Gudjonsson, Thorarinn

PY - 2011

Y1 - 2011

N2 - Epithelial to mesenchymal transition (EMT) is a critical event in cancer progression and is closely linked to the breast epithelial cancer stem cell phenotype. Given the close interaction between the vascular endothelium and cancer cells, especially at the invasive front, we asked whether endothelial cells might play a role in EMT. Using a 3D culture model we demonstrate that endothelial cells are potent inducers of EMT in D492 an immortalized breast epithelial cell line with stem cell properties. Endothelial induced mesenchymal-like cells (D492M) derived from D492, show reduced expression of keratins, a switch from E-Cadherin (E-Cad) to N-Cadherin (N-Cad) and enhanced migration. Acquisition of cancer stem cell associated characteristics like increased CD44(high)/CD24(low) ratio, resistance to apoptosis and anchorage independent growth was also seen in D492M cells. Endothelial induced EMT in D492 was partially blocked by inhibition of HGF signaling. Basal-like breast cancer, a vascular rich cancer with stem cell properties and adverse prognosis has been linked with EMT. We immunostained several basal-like breast cancer samples for endothelial and EMT markers. Cancer cells close to the vascular rich areas show no or decreased expression of E-Cad and increased N-Cad expression suggesting EMT. Collectively, we have shown in a 3D culture model that endothelial cells are potent inducers of EMT in breast epithelial cells with stem cell properties. Furthermore, we demonstrate that basal-like breast cancer contains cells with an EMT phenotype, most prominently close to vascular rich areas of these tumors. We conclude that endothelial cells are potent inducers of EMT and may play a role in progression of basal-like breast cancer.

AB - Epithelial to mesenchymal transition (EMT) is a critical event in cancer progression and is closely linked to the breast epithelial cancer stem cell phenotype. Given the close interaction between the vascular endothelium and cancer cells, especially at the invasive front, we asked whether endothelial cells might play a role in EMT. Using a 3D culture model we demonstrate that endothelial cells are potent inducers of EMT in D492 an immortalized breast epithelial cell line with stem cell properties. Endothelial induced mesenchymal-like cells (D492M) derived from D492, show reduced expression of keratins, a switch from E-Cadherin (E-Cad) to N-Cadherin (N-Cad) and enhanced migration. Acquisition of cancer stem cell associated characteristics like increased CD44(high)/CD24(low) ratio, resistance to apoptosis and anchorage independent growth was also seen in D492M cells. Endothelial induced EMT in D492 was partially blocked by inhibition of HGF signaling. Basal-like breast cancer, a vascular rich cancer with stem cell properties and adverse prognosis has been linked with EMT. We immunostained several basal-like breast cancer samples for endothelial and EMT markers. Cancer cells close to the vascular rich areas show no or decreased expression of E-Cad and increased N-Cad expression suggesting EMT. Collectively, we have shown in a 3D culture model that endothelial cells are potent inducers of EMT in breast epithelial cells with stem cell properties. Furthermore, we demonstrate that basal-like breast cancer contains cells with an EMT phenotype, most prominently close to vascular rich areas of these tumors. We conclude that endothelial cells are potent inducers of EMT and may play a role in progression of basal-like breast cancer.

KW - Apoptosis

KW - Blotting, Western

KW - Cell Dedifferentiation

KW - Cell Line

KW - Cell Line, Tumor

KW - Cells, Cultured

KW - Epidermal Growth Factor

KW - Epithelial Cells

KW - Epithelial-Mesenchymal Transition

KW - Female

KW - Fibroblast Growth Factors

KW - Flow Cytometry

KW - Hepatocyte Growth Factor

KW - Humans

KW - Immunochemistry

KW - Neoplastic Stem Cells

KW - Transforming Growth Factor beta1

U2 - 10.1371/journal.pone.0023833

DO - 10.1371/journal.pone.0023833

M3 - Journal article

C2 - 21915264

SN - 1932-6203

VL - 6

SP - e23833

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 9

ER -

Endothelial induced EMT in breast epithelial cells with stem cell properties

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