title: Metformin effects on head and neck squamous carcinoma microenvironment: Window of opportunity trial.
abstract: The tumor microenvironment frequently displays abnormal cellular metabolism, which contributes to aggressive behavior. Metformin inhibits mitochondrial oxidative phosphorylation, altering metabolism. Though the mechanism is unclear, epidemiologic studies show an association between metformin use and improved outcomes in head and neck squamous cell carcinoma (HNSCC). We sought to determine if metformin alters metabolism and apoptosis in HNSCC tumors.
  
  
  
  Window of opportunity trial of metformin between diagnostic biopsy and resection. Participants were patients with newly diagnosed HNSCC. Fifty patients were enrolled, and 39 completed a full-treatment course. Metformin was titrated to standard diabetic dose (2,000 mg/day) for a course of 9 or more days prior to surgery.
  
  
  
  Immunohistochemistry (IHC) for the metabolic markers caveolin-1 (CAV1), B-galactosidase (GALB), and monocarboxylate transporter 4 (MCT4), as well as the Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) apoptosis assay and Ki-67 IHC, were performed in pre- and postmetformin specimens. Exploratory mass spectroscopy imaging (MSI) to assess lactate levels also was performed in three subjects.
  
  
  
  Metformin was well tolerated. The average treatment course was 13.6 days. Posttreatment specimens showed a significant increase in stromal CAV1 (P < 0.001) and GALB (P < 0.005), as well as tumor cell apoptosis by TUNEL assay (P < 0.001). There was no significant change in stromal MCT4 expression or proliferation measured by Ki67. Lactate levels in carcinoma cells were increased 2.4-fold postmetformin (P < 0.05), as measured by MSI.
  
  
  
  Metformin increases markers of reduced catabolism and increases senescence in stromal cells as well as carcinoma cell apoptosis. This study demonstrates that metformin modulates metabolism in the HNSCC microenvironment.
  
  
  
  4. Laryngoscope, 127:1808-1815, 2017.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Philadelphia, Pennsylvania, U.S.A.
authors.forename: Joseph
authors.initials: J
authors.lastname: Curry
authors.affiliation: Department of Medical Oncology, Philadelphia, Pennsylvania, U.S.A.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Johnson
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Philadelphia, Pennsylvania, U.S.A.
authors.forename: Patrick
authors.identifier: 0000-0001-8633-2126
authors.initials: P
authors.lastname: Tassone
authors.affiliation: Department of Medical Oncology, Philadelphia, Pennsylvania, U.S.A.
authors.forename: Marina Domingo
authors.initials: MD
authors.lastname: Vidal
authors.affiliation: Department of Medical Oncology, Philadelphia, Pennsylvania, U.S.A.
authors.forename: Diana Whitaker
authors.initials: DW
authors.lastname: Menezes
authors.affiliation: Department of Medical Oncology, Philadelphia, Pennsylvania, U.S.A.
authors.forename: John
authors.initials: J
authors.lastname: Sprandio
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Philadelphia, Pennsylvania, U.S.A.
authors.forename: Mehri
authors.initials: M
authors.lastname: Mollaee
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Philadelphia, Pennsylvania, U.S.A.
authors.forename: Paolo
authors.initials: P
authors.lastname: Cotzia
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Philadelphia, Pennsylvania, U.S.A.
authors.forename: Ruth
authors.initials: R
authors.lastname: Birbe
authors.affiliation: Department of Medical Oncology, Philadelphia, Pennsylvania, U.S.A.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Philadelphia, Pennsylvania, U.S.A.
authors.forename: Kurren
authors.identifier: 0000-0003-4370-6110
authors.initials: K
authors.lastname: Gill
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Philadelphia, Pennsylvania, U.S.A.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Duddy
authors.affiliation: Department of Biostatistics, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhan
authors.affiliation: Department of Biostatistics, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Leiby
authors.affiliation: Department of Biochemistry-National Research Resource for Imaging Mass Spectrometry, Vanderbilt University, Nashville, Tennessee, U.S.A.
authors.forename: Michelle
authors.initials: M
authors.lastname: Reyzer
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Philadelphia, Pennsylvania, U.S.A.
authors.forename: David
authors.initials: D
authors.lastname: Cognetti
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Philadelphia, Pennsylvania, U.S.A.
authors.forename: Adam
authors.initials: A
authors.lastname: Luginbuhl
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Philadelphia, Pennsylvania, U.S.A.
authors.forename: Madalina
authors.initials: M
authors.lastname: Tuluc
authors.affiliation: Department of Medical Oncology, Philadelphia, Pennsylvania, U.S.A.
authors.forename: Ubaldo
authors.initials: U
authors.lastname: Martinez-Outschoorn
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D000077195:Squamous Cell Carcinoma of Head and Neck; D059016:Tumor Microenvironment
chemical_list: D008687:Metformin
keywords: Head and neck cancer; metformin; squamous cell carcinoma; tumor metabolism