Paidi Santosh Kumar, Rizwan Asif, Zheng Chao, Cheng Menglin, Glunde Kristine, Barman Ishan
Department of Mechanical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Cancer Res. 2017 Jan 15;77(2):247-256. doi: 10.1158/0008-5472.CAN-16-1862. Epub 2016 Nov 15.
Recent advances in animal modeling, imaging technology, and functional genomics have permitted precise molecular observations of the metastatic process. However, a comprehensive understanding of the premetastatic niche remains elusive, owing to the limited tools that can map subtle differences in molecular mediators in organ-specific microenvironments. Here, we report the ability to detect premetastatic changes in the lung microenvironment, in response to primary breast tumors, using a combination of metastatic mouse models, Raman spectroscopy, and multivariate analysis of consistent patterns in molecular expression. We used tdTomato fluorescent protein expressing MDA-MB-231 and MCF-7 cells of high and low metastatic potential, respectively, to grow orthotopic xenografts in athymic nude mice and allow spontaneous dissemination from the primary mammary fat pad tumor. Label-free Raman spectroscopic mapping was used to record the molecular content of premetastatic lungs. These measurements show reliable distinctions in vibrational features, characteristic of the collageneous stroma and its cross-linkers as well as proteoglycans, which uniquely identify the metastatic potential of the primary tumor by recapitulating the compositional changes in the lungs. Consistent with histological assessment and gene expression analysis, our study suggests that remodeling of the extracellular matrix components may present promising markers for objective recognition of the premetastatic niche, independent of conventional clinical information. Cancer Res; 77(2); 247-56. ©2016 AACR.
动物建模、成像技术和功能基因组学的最新进展使得对转移过程进行精确的分子观察成为可能。然而，由于能够绘制器官特异性微环境中分子介质细微差异的工具有限，对转移前生态位的全面理解仍然难以捉摸。在这里，我们报告了使用转移小鼠模型、拉曼光谱和分子表达一致模式的多变量分析相结合的方法，检测肺部微环境中对原发性乳腺肿瘤的转移前变化的能力。我们分别使用表达tdTomato荧光蛋白的具有高转移潜力和低转移潜力的MDA-MB-231和MCF-7细胞，在无胸腺裸鼠中生长原位异种移植物，并允许从原发性乳腺脂肪垫肿瘤自发扩散。使用无标记拉曼光谱映射来记录转移前肺部的分子含量。这些测量结果显示了在振动特征方面的可靠差异，这些差异是胶原质基质及其交联剂以及蛋白聚糖的特征，通过概括肺部的成分变化来独特地识别原发性肿瘤的转移潜力。与组织学评估和基因表达分析一致，我们的研究表明，细胞外基质成分的重塑可能为独立于传统临床信息的转移前生态位的客观识别提供有前景的标志物。《癌症研究》；77(2)；247 - 56。©2016美国癌症研究协会。
