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Phosphodiesterase 5 (PDE5) Is Highly Expressed in Cancer-Associated Fibroblasts and Enhances Breast Tumor Progression
The overexpression of phosphodiesterase (PDE) 5 is frequently found in various human cancers, such as those of the breast. However, PDE5’s role in the tumor microenvironment is still unknown. As PDE5 represents a high-value therapeutic target, we investigated whether the expression and function of P...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895904/ https://www.ncbi.nlm.nih.gov/pubmed/31698786 http://dx.doi.org/10.3390/cancers11111740 |
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author | Catalano, Stefania Panza, Salvatore Augimeri, Giuseppina Giordano, Cinzia Malivindi, Rocco Gelsomino, Luca Marsico, Stefania Giordano, Francesca Győrffy, Balázs Bonofiglio, Daniela Andò, Sebastiano Barone, Ines |
author_facet | Catalano, Stefania Panza, Salvatore Augimeri, Giuseppina Giordano, Cinzia Malivindi, Rocco Gelsomino, Luca Marsico, Stefania Giordano, Francesca Győrffy, Balázs Bonofiglio, Daniela Andò, Sebastiano Barone, Ines |
author_sort | Catalano, Stefania |
collection | PubMed |
description | The overexpression of phosphodiesterase (PDE) 5 is frequently found in various human cancers, such as those of the breast. However, PDE5’s role in the tumor microenvironment is still unknown. As PDE5 represents a high-value therapeutic target, we investigated whether the expression and function of PDE5 in breast cancer-associated fibroblasts (CAFs) may be clinically relevant to malignant progression. PDE5 expression was increased in human breast cancer stroma compared with normal stroma and was correlated to a shorter overall survival. Treatment of CAFs, isolated from breast tumor biopsies, with selective PDE5 inhibitors inhibited their proliferation, motility, and invasiveness, and negatively controlled tumor–stroma interactions in both ‘in vitro’ and ‘in vivo’ models. PDE5 stable overexpression transformed immortalized mouse embryonic fibroblasts (MEFs) towards an activated fibroblast phenotype, impacting their intrinsic characteristics and paracrine effects on breast cancer cell growth and migration through an enhanced production of the C-X-C motif chemokine 16 (CXCL16). On the other hand, CAF exposure to PDE5 inhibitors was associated with reduced CXCL16 expression and secretion. Importantly, CXCL16 levels in breast cancer stroma showed a strong correlation with PDE5 levels and poor patient outcomes. In conclusion, PDE5 is overexpressed in breast cancer stroma, enhances the tumor-stimulatory activities of fibroblasts, and impacts clinical outcomes; thus, we propose this enzyme as an attractive candidate for prognosis and a potential target for treatments in breast cancer patients. |
format | Online Article Text |
id | pubmed-6895904 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-68959042019-12-24 Phosphodiesterase 5 (PDE5) Is Highly Expressed in Cancer-Associated Fibroblasts and Enhances Breast Tumor Progression Catalano, Stefania Panza, Salvatore Augimeri, Giuseppina Giordano, Cinzia Malivindi, Rocco Gelsomino, Luca Marsico, Stefania Giordano, Francesca Győrffy, Balázs Bonofiglio, Daniela Andò, Sebastiano Barone, Ines Cancers (Basel) Article The overexpression of phosphodiesterase (PDE) 5 is frequently found in various human cancers, such as those of the breast. However, PDE5’s role in the tumor microenvironment is still unknown. As PDE5 represents a high-value therapeutic target, we investigated whether the expression and function of PDE5 in breast cancer-associated fibroblasts (CAFs) may be clinically relevant to malignant progression. PDE5 expression was increased in human breast cancer stroma compared with normal stroma and was correlated to a shorter overall survival. Treatment of CAFs, isolated from breast tumor biopsies, with selective PDE5 inhibitors inhibited their proliferation, motility, and invasiveness, and negatively controlled tumor–stroma interactions in both ‘in vitro’ and ‘in vivo’ models. PDE5 stable overexpression transformed immortalized mouse embryonic fibroblasts (MEFs) towards an activated fibroblast phenotype, impacting their intrinsic characteristics and paracrine effects on breast cancer cell growth and migration through an enhanced production of the C-X-C motif chemokine 16 (CXCL16). On the other hand, CAF exposure to PDE5 inhibitors was associated with reduced CXCL16 expression and secretion. Importantly, CXCL16 levels in breast cancer stroma showed a strong correlation with PDE5 levels and poor patient outcomes. In conclusion, PDE5 is overexpressed in breast cancer stroma, enhances the tumor-stimulatory activities of fibroblasts, and impacts clinical outcomes; thus, we propose this enzyme as an attractive candidate for prognosis and a potential target for treatments in breast cancer patients. MDPI 2019-11-06 /pmc/articles/PMC6895904/ /pubmed/31698786 http://dx.doi.org/10.3390/cancers11111740 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Catalano, Stefania Panza, Salvatore Augimeri, Giuseppina Giordano, Cinzia Malivindi, Rocco Gelsomino, Luca Marsico, Stefania Giordano, Francesca Győrffy, Balázs Bonofiglio, Daniela Andò, Sebastiano Barone, Ines Phosphodiesterase 5 (PDE5) Is Highly Expressed in Cancer-Associated Fibroblasts and Enhances Breast Tumor Progression |
title | Phosphodiesterase 5 (PDE5) Is Highly Expressed in Cancer-Associated Fibroblasts and Enhances Breast Tumor Progression |
title_full | Phosphodiesterase 5 (PDE5) Is Highly Expressed in Cancer-Associated Fibroblasts and Enhances Breast Tumor Progression |
title_fullStr | Phosphodiesterase 5 (PDE5) Is Highly Expressed in Cancer-Associated Fibroblasts and Enhances Breast Tumor Progression |
title_full_unstemmed | Phosphodiesterase 5 (PDE5) Is Highly Expressed in Cancer-Associated Fibroblasts and Enhances Breast Tumor Progression |
title_short | Phosphodiesterase 5 (PDE5) Is Highly Expressed in Cancer-Associated Fibroblasts and Enhances Breast Tumor Progression |
title_sort | phosphodiesterase 5 (pde5) is highly expressed in cancer-associated fibroblasts and enhances breast tumor progression |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895904/ https://www.ncbi.nlm.nih.gov/pubmed/31698786 http://dx.doi.org/10.3390/cancers11111740 |
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