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' 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
Cancer Res. 2014 Jun 1;74(11):3067-75. doi: 10.1158/0008-5472.CAN-13-2713. Epub 2014 Mar 31.
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.
不同代谢途径之间的平衡变化被认为是癌症的特征，这些代谢途径用于满足细胞的生物能量和生物合成需求。依赖于内源性荧光的光学成像是一种非侵入性方法，用于评估癌症发展过程中组织代谢变化。然而，光学评估与相关代谢物浓度或涉及的特定代谢途径的变化之间的定量相关性一直缺乏。在这项研究中，我们使用高分辨率、深度分辨成像，完全依赖于内源性双光子激发荧光，结合侵入性生化分析和质谱分析，证明了光学氧化还原比组织评估的敏感性和定量性质。我们发现活的、工程化的正常和癌前鳞状上皮组织的光学氧化还原比存在显著差异。我们确定，虽然光学氧化还原比的降低与糖酵解相对于氧化磷酸化的增强水平相关，但谷氨酰胺消耗增加以支持能量产生与光学氧化还原比值的增加相关。这种对光学代谢评估起源的机制见解对于充分利用这种非侵入性方法来监测和理解癌症发生或治疗反应时活组织中发生的重要代谢变化至关重要。
