title: Optical metabolic imaging identifies glycolytic levels, subtypes, and early-treatment response in breast cancer.
abstract: Abnormal cellular metabolism is a hallmark of cancer, yet there is an absence of quantitative methods to dynamically image this powerful cellular function. Optical metabolic imaging (OMI) is a noninvasive, high-resolution, quantitative tool for monitoring cellular metabolism. OMI probes the fluorescence intensities and lifetimes of the autofluorescent metabolic coenzymes reduced NADH and flavin adenine dinucleotide. We confirm that OMI correlates with cellular glycolytic levels across a panel of human breast cell lines using standard assays of cellular rates of glucose uptake and lactate secretion (P < 0.05, r = 0.89). In addition, OMI resolves differences in the basal metabolic activity of untransformed from malignant breast cells (P < 0.05) and between breast cancer subtypes (P < 0.05), defined by estrogen receptor and/or HER2 expression or absence. In vivo OMI is sensitive to metabolic changes induced by inhibition of HER2 with the antibody trastuzumab (herceptin) in HER2-overexpressing human breast cancer xenografts in mice. This response was confirmed with tumor growth curves and stains for Ki67 and cleaved caspase-3. OMI resolved trastuzumab-induced changes in cellular metabolism in vivo as early as 48 hours posttreatment (P < 0.05), whereas fluorodeoxyglucose-positron emission tomography did not resolve any changes with trastuzumab up to 12 days posttreatment (P > 0.05). In addition, OMI resolved cellular subpopulations of differing response in vivo that are critical for investigating drug resistance mechanisms. Importantly, OMI endpoints remained unchanged with trastuzumab treatment in trastuzumab-resistant xenografts (P > 0.05). OMI has significant implications for rapid cellular-level assessment of metabolic response to molecular expression and drug action, which would greatly accelerate drug development studies.
authors.affiliation: Authors' Affiliations: Departments of Biomedical Engineering, Cancer Biology, Medicine, Vanderbilt University Institute of Imaging Science, and Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Nashville, Tennessee.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Walsh
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Cook
authors.forename: H Charles
authors.initials: HC
authors.lastname: Manning
authors.forename: Donna J
authors.initials: DJ
authors.lastname: Hicks
authors.forename: Alec
authors.initials: A
authors.lastname: Lafontant
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Skala
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009243:NAD / Q000378:metabolism; D061848:Optical Imaging / Q000379:methods*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D005182:Flavin-Adenine Dinucleotide; D009243:NAD; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab