title: Endogenous two-photon fluorescence imaging elucidates metabolic changes related to enhanced glycolysis and glutamine consumption in precancerous epithelial tissues.
abstract: Alterations in the balance between different metabolic pathways used to meet cellular bioenergetic and biosynthetic demands are considered hallmarks of cancer. Optical imaging relying on endogenous fluorescence has been used as a noninvasive approach to assess tissue metabolic changes during cancer development. However, quantitative correlations of optical assessments with variations in the concentration of relevant metabolites or in the specific metabolic pathways that are involved have been lacking. In this study, we use high-resolution, depth-resolved imaging, relying entirely on endogenous two-photon excited fluorescence in combination with invasive biochemical assays and mass spectrometry to demonstrate the sensitivity and quantitative nature of optical redox ratio tissue assessments. We identify significant differences in the optical redox ratio of live, engineered normal and precancerous squamous epithelial tissues. We establish that while decreases in the optical redox ratio are associated with enhanced levels of glycolysis relative to oxidative phosphorylation, increases in glutamine consumption to support energy production are associated with increased optical redox ratio values. Such mechanistic insights in the origins of optical metabolic assessments are critical for exploiting fully the potential of such noninvasive approaches to monitor and understand important metabolic changes that occur in live tissues at the onset of cancer or in response to treatment.
authors.affiliation: Authors' Affiliations: Departments of Biomedical Engineering and Chemical and Biological Engineering, Tufts University, Medford; and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Antonio
authors.initials: A
authors.lastname: Varone
authors.affiliation: Authors' Affiliations: Departments of Biomedical Engineering and Chemical and Biological Engineering, Tufts University, Medford; and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Joanna
authors.initials: J
authors.lastname: Xylas
authors.affiliation: Authors' Affiliations: Departments of Biomedical Engineering and Chemical and Biological Engineering, Tufts University, Medford; and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Kyle P
authors.initials: KP
authors.lastname: Quinn
authors.affiliation: Authors' Affiliations: Departments of Biomedical Engineering and Chemical and Biological Engineering, Tufts University, Medford; and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Pouli
authors.affiliation: Authors' Affiliations: Departments of Biomedical Engineering and Chemical and Biological Engineering, Tufts University, Medford; and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Gautham
authors.initials: G
authors.lastname: Sridharan
authors.affiliation: Authors' Affiliations: Departments of Biomedical Engineering and Chemical and Biological Engineering, Tufts University, Medford; and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: McLaughlin-Drubin
authors.affiliation: Authors' Affiliations: Departments of Biomedical Engineering and Chemical and Biological Engineering, Tufts University, Medford; and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Carlo
authors.initials: C
authors.lastname: Alonzo
authors.affiliation: Authors' Affiliations: Departments of Biomedical Engineering and Chemical and Biological Engineering, Tufts University, Medford; and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Kyongbum
authors.initials: K
authors.lastname: Lee
authors.affiliation: Authors' Affiliations: Departments of Biomedical Engineering and Chemical and Biological Engineering, Tufts University, Medford; and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Karl
authors.initials: K
authors.lastname: Münger
authors.affiliation: Authors' Affiliations: Departments of Biomedical Engineering and Chemical and Biological Engineering, Tufts University, Medford; and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts Irene.Georgakoudi@tufts.edu.
authors.forename: Irene
authors.initials: I
authors.lastname: Georgakoudi
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D003952:Diagnostic Imaging / Q000379:methods; D004734:Energy Metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology*; D005453:Fluorescence; D005973:Glutamine / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology*; D006801:Humans; D053858:Metabolic Networks and Pathways; D036641:Microscopy, Fluorescence, Multiphoton / Q000379:methods; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D011230:Precancerous Conditions / Q000378:metabolism* / Q000473:pathology; D023822:Tissue Engineering / Q000379:methods
chemical_list: D015415:Biomarkers; D005973:Glutamine