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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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2020
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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. |
format | Online Article Text |
id | pubmed-7867573 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
record_format | MEDLINE/PubMed |
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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