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4T1 Mammary Carcinoma Colonization of Metastatic Niches Is Accelerated by Obesity

Breast cancer (BC) remains the leading cause of cancer-related deaths among women, and the chances to develop it are duplicated by obesity. Still, the impact of obesity during BC progression remains less understood. We investigated the role of obesity in tumor progression using the murine model of 4...

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Autores principales: Evangelista, Gabriela Coeli Menezes, Salvador, Pollyanna Amaral, Soares, Sara Malaguti Andrade, Barros, Luciana Rodrigues Carvalho, Xavier, Felipe Henrique da Cunha, Abdo, Luiza Macedo, Gualberto, Ana Cristina Moura, Macedo, Gilson Costa, Clavijo-Salomon, Maria Alejandra, Gameiro, Jacy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764084/
https://www.ncbi.nlm.nih.gov/pubmed/31616626
http://dx.doi.org/10.3389/fonc.2019.00685
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author Evangelista, Gabriela Coeli Menezes
Salvador, Pollyanna Amaral
Soares, Sara Malaguti Andrade
Barros, Luciana Rodrigues Carvalho
Xavier, Felipe Henrique da Cunha
Abdo, Luiza Macedo
Gualberto, Ana Cristina Moura
Macedo, Gilson Costa
Clavijo-Salomon, Maria Alejandra
Gameiro, Jacy
author_facet Evangelista, Gabriela Coeli Menezes
Salvador, Pollyanna Amaral
Soares, Sara Malaguti Andrade
Barros, Luciana Rodrigues Carvalho
Xavier, Felipe Henrique da Cunha
Abdo, Luiza Macedo
Gualberto, Ana Cristina Moura
Macedo, Gilson Costa
Clavijo-Salomon, Maria Alejandra
Gameiro, Jacy
author_sort Evangelista, Gabriela Coeli Menezes
collection PubMed
description Breast cancer (BC) remains the leading cause of cancer-related deaths among women, and the chances to develop it are duplicated by obesity. Still, the impact of obesity during BC progression remains less understood. We investigated the role of obesity in tumor progression using the murine model of 4T1 mammary carcinoma in BALB/c female mice, previously high-fat-diet (HFD) fed. HFD induced obesity, metabolic impairment, and high serum and fat leptin levels. After injection of 4T1-cells, HFD-mice accelerated tumor progression and metastasis. 4T1-cells found within HFD-mice metastatic niches presented higher clonogenic potential. 4T1-cells treated in vitro with fat-conditioned medium derived from HFD-mice, increased migration capacity through CXCL12 and CCL25 gradients. In HFD-mice, the infiltration and activation of immune cells into tumor-sentinel lymph nodes was overall reduced, except for activated CD4(+) T cells expressing low CD25 levels. Within the bone marrow, the levels of haematopoiesis-related IL-6 and TNF-α decreased after 4T1-cells injection in HFD-mice whereas increased in the controls, suggesting that upregulation of both cytokines, regardless of the tumor, is disrupted by obesity. Finally, the expression of genes for leptin, CXCR4, and CCR9 (receptors of CXCL12 and CCL25, respectively) was negatively correlated with the infiltration of CD8 T cells in human triple-negative BC tumors from obese patients compared to non-obese. Together, our data present early evidence of systemic networks triggered by obesity that promote BC progression to the metastatic niches. Targeting these pathways might be useful to prevent the rapid BC progression observed among obese patients.
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spelling pubmed-67640842019-10-15 4T1 Mammary Carcinoma Colonization of Metastatic Niches Is Accelerated by Obesity Evangelista, Gabriela Coeli Menezes Salvador, Pollyanna Amaral Soares, Sara Malaguti Andrade Barros, Luciana Rodrigues Carvalho Xavier, Felipe Henrique da Cunha Abdo, Luiza Macedo Gualberto, Ana Cristina Moura Macedo, Gilson Costa Clavijo-Salomon, Maria Alejandra Gameiro, Jacy Front Oncol Oncology Breast cancer (BC) remains the leading cause of cancer-related deaths among women, and the chances to develop it are duplicated by obesity. Still, the impact of obesity during BC progression remains less understood. We investigated the role of obesity in tumor progression using the murine model of 4T1 mammary carcinoma in BALB/c female mice, previously high-fat-diet (HFD) fed. HFD induced obesity, metabolic impairment, and high serum and fat leptin levels. After injection of 4T1-cells, HFD-mice accelerated tumor progression and metastasis. 4T1-cells found within HFD-mice metastatic niches presented higher clonogenic potential. 4T1-cells treated in vitro with fat-conditioned medium derived from HFD-mice, increased migration capacity through CXCL12 and CCL25 gradients. In HFD-mice, the infiltration and activation of immune cells into tumor-sentinel lymph nodes was overall reduced, except for activated CD4(+) T cells expressing low CD25 levels. Within the bone marrow, the levels of haematopoiesis-related IL-6 and TNF-α decreased after 4T1-cells injection in HFD-mice whereas increased in the controls, suggesting that upregulation of both cytokines, regardless of the tumor, is disrupted by obesity. Finally, the expression of genes for leptin, CXCR4, and CCR9 (receptors of CXCL12 and CCL25, respectively) was negatively correlated with the infiltration of CD8 T cells in human triple-negative BC tumors from obese patients compared to non-obese. Together, our data present early evidence of systemic networks triggered by obesity that promote BC progression to the metastatic niches. Targeting these pathways might be useful to prevent the rapid BC progression observed among obese patients. Frontiers Media S.A. 2019-09-20 /pmc/articles/PMC6764084/ /pubmed/31616626 http://dx.doi.org/10.3389/fonc.2019.00685 Text en Copyright © 2019 Evangelista, Salvador, Soares, Barros, Xavier, Abdo, Gualberto, Macedo, Clavijo-Salomon and Gameiro. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Evangelista, Gabriela Coeli Menezes
Salvador, Pollyanna Amaral
Soares, Sara Malaguti Andrade
Barros, Luciana Rodrigues Carvalho
Xavier, Felipe Henrique da Cunha
Abdo, Luiza Macedo
Gualberto, Ana Cristina Moura
Macedo, Gilson Costa
Clavijo-Salomon, Maria Alejandra
Gameiro, Jacy
4T1 Mammary Carcinoma Colonization of Metastatic Niches Is Accelerated by Obesity
title 4T1 Mammary Carcinoma Colonization of Metastatic Niches Is Accelerated by Obesity
title_full 4T1 Mammary Carcinoma Colonization of Metastatic Niches Is Accelerated by Obesity
title_fullStr 4T1 Mammary Carcinoma Colonization of Metastatic Niches Is Accelerated by Obesity
title_full_unstemmed 4T1 Mammary Carcinoma Colonization of Metastatic Niches Is Accelerated by Obesity
title_short 4T1 Mammary Carcinoma Colonization of Metastatic Niches Is Accelerated by Obesity
title_sort 4t1 mammary carcinoma colonization of metastatic niches is accelerated by obesity
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764084/
https://www.ncbi.nlm.nih.gov/pubmed/31616626
http://dx.doi.org/10.3389/fonc.2019.00685
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