title: Metformin Reduces Desmoplasia in Pancreatic Cancer by Reprogramming Stellate Cells and Tumor-Associated Macrophages.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Internal Medicine, Hospital S. Joao, Porto, Portugal.|I3S, Institute for Innovation and Research in Heath, Metabolism, Nutrition and Endocrinology group, Biochemistry Department, Faculty of Medicine, Porto University, Porto, Portugal.
authors.forename: Joao
authors.initials: J
authors.lastname: Incio
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Botany and Biotechnology, St. Xaviers College, Thumba, Trivandrum, Kerala, India.
authors.forename: Priya
authors.initials: P
authors.lastname: Suboj
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Shan M
authors.initials: SM
authors.lastname: Chin
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Trupti
authors.initials: T
authors.lastname: Vardam-Kaur
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America.|Program of Biology and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Tai
authors.initials: T
authors.lastname: Hato
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Zoology, Mar Ivanios College, Nalanchira, Trivandrum, Kerala, India.
authors.forename: Suboj
authors.initials: S
authors.lastname: Babykutty
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America.|School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Ivy
authors.initials: I
authors.lastname: Chen
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Vikram
authors.initials: V
authors.lastname: Deshpande
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Dai
authors.initials: D
authors.lastname: Fukumura
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D058954:Pancreatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D050796:STAT3 Transcription Factor / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D050796:STAT3 Transcription Factor; D016212:Transforming Growth Factor beta; D008687:Metformin