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Metformin Reduces Desmoplasia in Pancreatic Cancer by Reprogramming Stellate Cells and Tumor-Associated Macrophages

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic tumor with a dismal prognosis for most patients. Fibrosis and inflammation are hallmarks of tumor desmoplasia. We have previously demonstrated that preventing the activation of pancreatic stellate cells (PSCs) and alleviati...

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Autores principales: Incio, Joao, Suboj, Priya, Chin, Shan M., Vardam-Kaur, Trupti, Liu, Hao, Hato, Tai, Babykutty, Suboj, Chen, Ivy, Deshpande, Vikram, Jain, Rakesh K., Fukumura, Dai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671732/
https://www.ncbi.nlm.nih.gov/pubmed/26641266
http://dx.doi.org/10.1371/journal.pone.0141392
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author Incio, Joao
Suboj, Priya
Chin, Shan M.
Vardam-Kaur, Trupti
Liu, Hao
Hato, Tai
Babykutty, Suboj
Chen, Ivy
Deshpande, Vikram
Jain, Rakesh K.
Fukumura, Dai
author_facet Incio, Joao
Suboj, Priya
Chin, Shan M.
Vardam-Kaur, Trupti
Liu, Hao
Hato, Tai
Babykutty, Suboj
Chen, Ivy
Deshpande, Vikram
Jain, Rakesh K.
Fukumura, Dai
author_sort Incio, Joao
collection PubMed
description BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic tumor with a dismal prognosis for most patients. Fibrosis and inflammation are hallmarks of tumor desmoplasia. We have previously demonstrated that preventing the activation of pancreatic stellate cells (PSCs) and alleviating desmoplasia are beneficial strategies in treating PDAC. Metformin is a widely used glucose-lowering drug. It is also frequently prescribed to diabetic pancreatic cancer patients and has been shown to associate with a better outcome. However, the underlying mechanisms of this benefit remain unclear. Metformin has been found to modulate the activity of stellate cells in other disease settings. In this study, we examine the effect of metformin on PSC activity, fibrosis and inflammation in PDACs. METHODS/RESULTS: In overweight, diabetic PDAC patients and pre-clinical mouse models, treatment with metformin reduced levels of tumor extracellular matrix (ECM) components, in particular hyaluronan (HA). In vitro, we found that metformin reduced TGF-ß signaling and the production of HA and collagen-I in cultured PSCs. Furthermore, we found that metformin alleviates tumor inflammation by reducing the expression of inflammatory cytokines including IL-1β as well as infiltration and M2 polarization of tumor-associated macrophages (TAMs) in vitro and in vivo. These effects on macrophages in vitro appear to be associated with a modulation of the AMPK/STAT3 pathway by metformin. Finally, we found in our preclinical models that the alleviation of desmoplasia by metformin was associated with a reduction in ECM remodeling, epithelial-to-mesenchymal transition (EMT) and ultimately systemic metastasis. CONCLUSION: Metformin alleviates the fibro-inflammatory microenvironment in obese/diabetic individuals with pancreatic cancer by reprogramming PSCs and TAMs, which correlates with reduced disease progression. Metformin should be tested/explored as part of the treatment strategy in overweight diabetic PDAC patients.
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spelling pubmed-46717322015-12-10 Metformin Reduces Desmoplasia in Pancreatic Cancer by Reprogramming Stellate Cells and Tumor-Associated Macrophages Incio, Joao Suboj, Priya Chin, Shan M. Vardam-Kaur, Trupti Liu, Hao Hato, Tai Babykutty, Suboj Chen, Ivy Deshpande, Vikram Jain, Rakesh K. Fukumura, Dai PLoS One Research Article BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic tumor with a dismal prognosis for most patients. Fibrosis and inflammation are hallmarks of tumor desmoplasia. We have previously demonstrated that preventing the activation of pancreatic stellate cells (PSCs) and alleviating desmoplasia are beneficial strategies in treating PDAC. Metformin is a widely used glucose-lowering drug. It is also frequently prescribed to diabetic pancreatic cancer patients and has been shown to associate with a better outcome. However, the underlying mechanisms of this benefit remain unclear. Metformin has been found to modulate the activity of stellate cells in other disease settings. In this study, we examine the effect of metformin on PSC activity, fibrosis and inflammation in PDACs. METHODS/RESULTS: In overweight, diabetic PDAC patients and pre-clinical mouse models, treatment with metformin reduced levels of tumor extracellular matrix (ECM) components, in particular hyaluronan (HA). In vitro, we found that metformin reduced TGF-ß signaling and the production of HA and collagen-I in cultured PSCs. Furthermore, we found that metformin alleviates tumor inflammation by reducing the expression of inflammatory cytokines including IL-1β as well as infiltration and M2 polarization of tumor-associated macrophages (TAMs) in vitro and in vivo. These effects on macrophages in vitro appear to be associated with a modulation of the AMPK/STAT3 pathway by metformin. Finally, we found in our preclinical models that the alleviation of desmoplasia by metformin was associated with a reduction in ECM remodeling, epithelial-to-mesenchymal transition (EMT) and ultimately systemic metastasis. CONCLUSION: Metformin alleviates the fibro-inflammatory microenvironment in obese/diabetic individuals with pancreatic cancer by reprogramming PSCs and TAMs, which correlates with reduced disease progression. Metformin should be tested/explored as part of the treatment strategy in overweight diabetic PDAC patients. Public Library of Science 2015-12-07 /pmc/articles/PMC4671732/ /pubmed/26641266 http://dx.doi.org/10.1371/journal.pone.0141392 Text en © 2015 Incio et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Incio, Joao
Suboj, Priya
Chin, Shan M.
Vardam-Kaur, Trupti
Liu, Hao
Hato, Tai
Babykutty, Suboj
Chen, Ivy
Deshpande, Vikram
Jain, Rakesh K.
Fukumura, Dai
Metformin Reduces Desmoplasia in Pancreatic Cancer by Reprogramming Stellate Cells and Tumor-Associated Macrophages
title Metformin Reduces Desmoplasia in Pancreatic Cancer by Reprogramming Stellate Cells and Tumor-Associated Macrophages
title_full Metformin Reduces Desmoplasia in Pancreatic Cancer by Reprogramming Stellate Cells and Tumor-Associated Macrophages
title_fullStr Metformin Reduces Desmoplasia in Pancreatic Cancer by Reprogramming Stellate Cells and Tumor-Associated Macrophages
title_full_unstemmed Metformin Reduces Desmoplasia in Pancreatic Cancer by Reprogramming Stellate Cells and Tumor-Associated Macrophages
title_short Metformin Reduces Desmoplasia in Pancreatic Cancer by Reprogramming Stellate Cells and Tumor-Associated Macrophages
title_sort metformin reduces desmoplasia in pancreatic cancer by reprogramming stellate cells and tumor-associated macrophages
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671732/
https://www.ncbi.nlm.nih.gov/pubmed/26641266
http://dx.doi.org/10.1371/journal.pone.0141392
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