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

• Published in: PloS one Vol. 10; no. 12; p. e0141392
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07-12-2015; Public Library of Science (PLoS)
• Subjects: Adenocarcinoma; Adenocarcinoma - drug therapy; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Animal models; Animals; Antidiabetics; Autophagy; Biochemistry; Body weight; Cancer; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Care and treatment; Cell cycle; Cell Movement - drug effects; Cell Proliferation - drug effects; Collagen; Cytokines; Development and progression; Diabetes; Diabetes mellitus; Epithelial-Mesenchymal Transition - drug effects; Extracellular matrix; Fibroblasts; Fibrosis; Gene Expression Regulation, Neoplastic - drug effects; Hospitals; Hyaluronan; Hyaluronic acid; IL-1β; Infiltration; Inflammation; Insulin; Insulin-like growth factors; Interleukin-1beta - metabolism; Laboratory animals; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Male; Medical prognosis; Medical schools; Medicine; Mesenchyme; Metabolism; Metastases; Metastasis; Metformin; Metformin - pharmacology; Mice; Mice, Inbred C57BL; Obesity; Oncology; Overweight; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pancreatic Stellate Cells - drug effects; Pancreatic Stellate Cells - metabolism; Pancreatic Stellate Cells - pathology; Patient outcomes; Patients; Physiology; Prognosis; Rodents; Stat3 protein; STAT3 Transcription Factor - metabolism; Stellate cells; Stem cells; Transforming Growth Factor beta - metabolism; Transforming growth factors; Tumors; United States; United States > US; Portugal; Massachusetts; India
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0141392

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.
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.
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.