Walsh Alex, Cook Rebecca S, Rexer Brent, Arteaga Carlos L, Skala Melissa C
Department of Biomedical Engineering, Vanderbilt University, Station B, Box 1631, Nashville, Tennessee 37235, USA.
Biomed Opt Express. 2012 Jan 1;3(1):75-85. doi: 10.1364/BOE.3.000075. Epub 2011 Dec 9.
The optical redox ratio (fluorescence intensity of NADH divided by that of FAD), was acquired for a panel of breast cancer cell lines to investigate how overexpression of human epidermal growth factor receptor 2 (HER2) affects tumor cell metabolism, and how tumor metabolism may be altered in response to clinically used HER2-targeted therapies. Confocal fluorescence microscopy was used to acquire NADH and FAD auto-fluorescent images. The optical redox ratio was highest in cells overexpressing HER2 and lowest in triple negative breast cancer (TNBC) cells, which lack HER2, progesterone receptor, and estrogen receptor (ER). The redox ratio in ER-positive/HER2-negative cells was higher than what was seen in TNBC cells, but lower than that in HER2 overexpressing cells. Importantly, inhibition of HER2 using trastuzumab significantly reduced the redox ratio in HER2 overexpressing cells. Furthermore, the combinatorial inhibition of HER2 and ER decreased the redox ratio in ER+/HER2+ breast cancer cells to a greater extent than inhibition of either receptor alone. Interestingly, trastuzumab had little impact upon the redox ratio in a cell line selected for acquired resistance to trastuzumab. Taken together, these data indicate that the optical redox ratio measures changes in tumor metabolism that reflect the oncogenic effects of HER2 activity within the cell, as well as the response of the cell to therapeutic inhibition of HER2. Therefore, optical redox imaging holds the promise of measuring response and resistance to receptor-targeted breast cancer therapies in real time, which could potentially impact clinical decisions and improve patient outcome.
为了研究人类表皮生长因子受体2（HER2）的过表达如何影响肿瘤细胞代谢，以及肿瘤代谢如何因临床使用的HER2靶向治疗而改变，我们获取了一组乳腺癌细胞系的光学氧化还原比（NADH荧光强度除以FAD荧光强度）。共聚焦荧光显微镜用于获取NADH和FAD自发荧光图像。光学氧化还原比在HER2过表达的细胞中最高，在缺乏HER2、孕激素受体和雌激素受体（ER）的三阴性乳腺癌（TNBC）细胞中最低。ER阳性/HER2阴性细胞中的氧化还原比高于TNBC细胞，但低于HER2过表达细胞。重要的是，使用曲妥珠单抗抑制HER2可显著降低HER2过表达细胞中的氧化还原比。此外，HER2和ER的联合抑制比单独抑制任一受体更能降低ER+/HER2+乳腺癌细胞中的氧化还原比。有趣的是，曲妥珠单抗对选择获得性曲妥珠单抗耐药的细胞系中的氧化还原比几乎没有影响。综上所述，这些数据表明光学氧化还原比可测量肿瘤代谢的变化，这些变化反映了细胞内HER2活性的致癌作用以及细胞对HER2治疗性抑制的反应。因此，光学氧化还原成像有望实时测量对受体靶向乳腺癌治疗的反应和耐药性，这可能会影响临床决策并改善患者预后。
