Visualizing the effects of metformin on tumor growth, vascularity, and metabolism in head and neck cancer.

Abstract

BACKGROUND:

The antidiabetic drug metformin (Met) is believed to inhibit tumor proliferation by altering the metabolism of cancer cells. In this study, we examined the effects of Met on tumor oxygenation, metabolism, and growth in head and neck squamous cell carcinoma (HNSCC) using non-invasive multimodal imaging.

MATERIALS AND METHODS:

Severe combined immunodeficient (SCID) mice bearing orthotopic FaDu HNSCC xenografts were treated with Met (200 mg/kg, ip) once daily for 5 days. Tumor oxygen saturation (%sO2 ) and hemoglobin concentration (HbT) were measured using photoacoustic imaging (PAI). Fluorescence imaging was employed to measure intratumoral uptake of 2-deoxyglucosone (2-DG) following Met treatment while magnetic resonance imaging (MRI) was utilized to measure tumor volume. Correlative immunostaining of tumor sections for markers of proliferation (Ki67) and vascularity (CD31) was also performed.

RESULTS:

At 5 days post-Met treatment, PAI revealed a significant increase (P < .05) in %sO2 and HbT levels in treated tumors compared to untreated controls. Fluorescence imaging at this time point revealed a 46% decrease in mean 2-DG uptake compared to controls. No changes in hemodynamic parameters were observed in mouse salivary gland tissue. A significant decrease in Ki-67 staining (P < .001) and MR-based tumor volume was also observed in Met-treated tumors compared to controls with no change in CD31 + vessel count following Met therapy.

CONCLUSION:

Our results provide, for the first time, direct in vivo evidence of Met-induced changes in tumor microenvironmental parameters in HNSCC xenografts. Our findings highlight the utility of multimodal functional imaging for non-invasive mapping of the effects of Met in HNSCC.

• Authors: Aparajita Verma, Laurie J Rich, Vui King Vincent-Chong, Mukund Seshadri
• Journal: Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology (J Oral Pathol Med) Vol. 47 Issue 5 Pg. 484-491 (May 2018) ISSN: 1600-0714 [Electronic] Denmark
• PMID: 29573032 (Publication Type: Journal Article)
• Copyright: © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• Hemoglobins
• Hypoglycemic Agents
• Ki-67 Antigen
• MKI67 protein, human
• Platelet Endothelial Cell Adhesion Molecule-1
• Metformin
• Oxygen

Topics

• Animals
• Carcinoma, Squamous Cell (blood supply, diagnostic imaging, metabolism, pathology)
• Cell Proliferation
• Female
• Head and Neck Neoplasms (blood supply, diagnostic imaging, metabolism, pathology)
• Hemoglobins (metabolism)
• Hypoglycemic Agents (pharmacology)
• Ki-67 Antigen (metabolism)
• Metformin (administration & dosage, pharmacology)
• Mice, SCID
• Multimodal Imaging
• Neoplasm Transplantation
• Oxygen (metabolism)
• Platelet Endothelial Cell Adhesion Molecule-1 (metabolism)
• Squamous Cell Carcinoma of Head and Neck
• Tumor Microenvironment (drug effects)