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PLoS One. 2015 Dec 7;10(12):e0141392. doi: 10.1371/journal.pone.0141392. eCollection 2015.

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

Author information

1
Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
2
Department of Internal Medicine, Hospital S. Joao, Porto, Portugal.
3
I3S, Institute for Innovation and Research in Heath, Metabolism, Nutrition and Endocrinology group, Biochemistry Department, Faculty of Medicine, Porto University, Porto, Portugal.
4
Department of Botany and Biotechnology, St. Xaviers College, Thumba, Trivandrum, Kerala, India.
5
Program of Biology and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, United States of America.
6
Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
7
Department of Zoology, Mar Ivanios College, Nalanchira, Trivandrum, Kerala, India.
8
School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, United States of America.
9
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.

Abstract

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.

PMID:
26641266
PMCID:
PMC4671732
DOI:
10.1371/journal.pone.0141392
[Indexed for MEDLINE]
Free PMC Article

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