Metformin effects on head and neck squamous carcinoma microenvironment: Window of opportunity trial
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- Joseph Curry
- Department of Otolaryngology–Head and Neck Surgery Philadelphia Pennsylvania U.S.A.
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- Jennifer Johnson
- Department of Medical Oncology Philadelphia Pennsylvania U.S.A.
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- Patrick Tassone
- Department of Otolaryngology–Head and Neck Surgery Philadelphia Pennsylvania U.S.A.
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- Marina Domingo Vidal
- Department of Medical Oncology Philadelphia Pennsylvania U.S.A.
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- Diana Whitaker Menezes
- Department of Medical Oncology Philadelphia Pennsylvania U.S.A.
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- John Sprandio
- Department of Medical Oncology Philadelphia Pennsylvania U.S.A.
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- Mehri Mollaee
- Department of Pathology Anatomy, and Cell Biology Philadelphia Pennsylvania U.S.A.
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- Paolo Cotzia
- Department of Pathology Anatomy, and Cell Biology Philadelphia Pennsylvania U.S.A.
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- Ruth Birbe
- Department of Pathology Anatomy, and Cell Biology Philadelphia Pennsylvania U.S.A.
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- Zhao Lin
- Department of Medical Oncology Philadelphia Pennsylvania U.S.A.
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- Kurren Gill
- Department of Otolaryngology–Head and Neck Surgery Philadelphia Pennsylvania U.S.A.
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- Elizabeth Duddy
- Department of Otolaryngology–Head and Neck Surgery Philadelphia Pennsylvania U.S.A.
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- Tingting Zhan
- Department of Biostatistics Thomas Jefferson University Philadelphia Pennsylvania U.S.A.
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- Benjamin Leiby
- Department of Biostatistics Thomas Jefferson University Philadelphia Pennsylvania U.S.A.
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- Michelle Reyzer
- Department of Biochemistry‐National Research Resource for Imaging Mass Spectrometry Vanderbilt University Nashville Tennessee U.S.A.
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- David Cognetti
- Department of Otolaryngology–Head and Neck Surgery Philadelphia Pennsylvania U.S.A.
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- Adam Luginbuhl
- Department of Otolaryngology–Head and Neck Surgery Philadelphia Pennsylvania U.S.A.
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- Madalina Tuluc
- Department of Pathology Anatomy, and Cell Biology Philadelphia Pennsylvania U.S.A.
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- Ubaldo Martinez‐Outschoorn
- Department of Medical Oncology Philadelphia Pennsylvania U.S.A.
抄録
<jats:sec><jats:title>Objective</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Study Design</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Metformin was well tolerated. The average treatment course was 13.6 days. Posttreatment specimens showed a significant increase in stromal CAV1 (<jats:italic>P</jats:italic> < 0.001) and GALB (<jats:italic>P</jats:italic> < 0.005), as well as tumor cell apoptosis by TUNEL assay (<jats:italic>P</jats:italic> < 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 (<jats:italic>P</jats:italic> < 0.05), as measured by MSI.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Level of Evidence</jats:title><jats:p>4. <jats:italic>Laryngoscope</jats:italic>, 127:1808–1815, 2017</jats:p></jats:sec>
収録刊行物
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- The Laryngoscope
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The Laryngoscope 127 (8), 1808-1815, 2017-02-10
Wiley