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VEGF-C Mediates Tumor Growth and Metastasis Through Promoting EMT- Epithelial Breast Cancer cell Crosstalk

It is well established that a subset of cells within primary breast cancers can undergo an epithelial to mesenchymal transition (EMT), although the role of EMT in metastasis remains controversial. We previously demonstrated that breast cancer cells that had undergone an oncogenic EMT could increase...

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Autores principales: Kong, Deguang, Zhou, Hengbo, Neelakantan, Deepika, Hughes, Connor J., Hsu, Jessica Y., Srinivasan, Ramakrishnan Rajaram, Lewis, Michael T., Ford, Heide L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867573/
https://www.ncbi.nlm.nih.gov/pubmed/33299122
http://dx.doi.org/10.1038/s41388-020-01539-x
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author Kong, Deguang
Zhou, Hengbo
Neelakantan, Deepika
Hughes, Connor J.
Hsu, Jessica Y.
Srinivasan, Ramakrishnan Rajaram
Lewis, Michael T.
Ford, Heide L.
author_facet Kong, Deguang
Zhou, Hengbo
Neelakantan, Deepika
Hughes, Connor J.
Hsu, Jessica Y.
Srinivasan, Ramakrishnan Rajaram
Lewis, Michael T.
Ford, Heide L.
author_sort Kong, Deguang
collection PubMed
description It is well established that a subset of cells within primary breast cancers can undergo an epithelial to mesenchymal transition (EMT), although the role of EMT in metastasis remains controversial. We previously demonstrated that breast cancer cells that had undergone an oncogenic EMT could increase metastasis of neighboring cancer cells via non-canonical paracrine-mediated activation of GLI activity that is dependent on SIX1 expression in the EMT cancer cells. However, the mechanism by which these SIX1-expressing EMT cells activate GLI signaling remained unclear. In this study, we demonstrate a novel mechanism for activation of GLI-mediated signaling in epithelial breast tumor cells via EMT cell-induced production and secretion of VEGF-C. We show that VEGF-C, secreted by breast cancer cells that have undergone an EMT, promotes paracrine-mediated increases in proliferation, migration and invasion of epithelial breast cancer cells, via non-canonical activation of GLI-signaling. We further show that the aggressive phenotypes, including metastasis, imparted by EMT cells on adjacent epithelial cancer cells can be disrupted by either inhibiting VEGF-C in EMT cells or by knocking down NRP2, a receptor which interacts with VEGF-C, in neighboring epithelial cancer cells. Interrogation of TCGA and GEO public datasets supports the relevance of this pathway in human breast cancer, demonstrating that VEGF-C strongly correlates with activation of Hedgehog signaling and EMT in the human disease. Our study suggests that the VEGF-C/NRP2/GLI axis is a novel and conserved paracrine means by which EMT cells enhance metastasis, and provides potential targets for therapeutic intervention in this heterogeneous disease.
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spelling pubmed-78675732021-06-09 VEGF-C Mediates Tumor Growth and Metastasis Through Promoting EMT- Epithelial Breast Cancer cell Crosstalk Kong, Deguang Zhou, Hengbo Neelakantan, Deepika Hughes, Connor J. Hsu, Jessica Y. Srinivasan, Ramakrishnan Rajaram Lewis, Michael T. Ford, Heide L. Oncogene Article It is well established that a subset of cells within primary breast cancers can undergo an epithelial to mesenchymal transition (EMT), although the role of EMT in metastasis remains controversial. We previously demonstrated that breast cancer cells that had undergone an oncogenic EMT could increase metastasis of neighboring cancer cells via non-canonical paracrine-mediated activation of GLI activity that is dependent on SIX1 expression in the EMT cancer cells. However, the mechanism by which these SIX1-expressing EMT cells activate GLI signaling remained unclear. In this study, we demonstrate a novel mechanism for activation of GLI-mediated signaling in epithelial breast tumor cells via EMT cell-induced production and secretion of VEGF-C. We show that VEGF-C, secreted by breast cancer cells that have undergone an EMT, promotes paracrine-mediated increases in proliferation, migration and invasion of epithelial breast cancer cells, via non-canonical activation of GLI-signaling. We further show that the aggressive phenotypes, including metastasis, imparted by EMT cells on adjacent epithelial cancer cells can be disrupted by either inhibiting VEGF-C in EMT cells or by knocking down NRP2, a receptor which interacts with VEGF-C, in neighboring epithelial cancer cells. Interrogation of TCGA and GEO public datasets supports the relevance of this pathway in human breast cancer, demonstrating that VEGF-C strongly correlates with activation of Hedgehog signaling and EMT in the human disease. Our study suggests that the VEGF-C/NRP2/GLI axis is a novel and conserved paracrine means by which EMT cells enhance metastasis, and provides potential targets for therapeutic intervention in this heterogeneous disease. 2020-12-09 2021-02 /pmc/articles/PMC7867573/ /pubmed/33299122 http://dx.doi.org/10.1038/s41388-020-01539-x Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Kong, Deguang
Zhou, Hengbo
Neelakantan, Deepika
Hughes, Connor J.
Hsu, Jessica Y.
Srinivasan, Ramakrishnan Rajaram
Lewis, Michael T.
Ford, Heide L.
VEGF-C Mediates Tumor Growth and Metastasis Through Promoting EMT- Epithelial Breast Cancer cell Crosstalk
title VEGF-C Mediates Tumor Growth and Metastasis Through Promoting EMT- Epithelial Breast Cancer cell Crosstalk
title_full VEGF-C Mediates Tumor Growth and Metastasis Through Promoting EMT- Epithelial Breast Cancer cell Crosstalk
title_fullStr VEGF-C Mediates Tumor Growth and Metastasis Through Promoting EMT- Epithelial Breast Cancer cell Crosstalk
title_full_unstemmed VEGF-C Mediates Tumor Growth and Metastasis Through Promoting EMT- Epithelial Breast Cancer cell Crosstalk
title_short VEGF-C Mediates Tumor Growth and Metastasis Through Promoting EMT- Epithelial Breast Cancer cell Crosstalk
title_sort vegf-c mediates tumor growth and metastasis through promoting emt- epithelial breast cancer cell crosstalk
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867573/
https://www.ncbi.nlm.nih.gov/pubmed/33299122
http://dx.doi.org/10.1038/s41388-020-01539-x
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