Abstract
Second Harmonic Generation (SHG) microscopy has been previously used to describe the morphology of collagen in the extracellular matrix (ECM) in different stages of invasion in breast cancer. Here this concept is extended by using SHG to provide quantitative discrimination of self-assembled collagen gels, consisting of mixtures of type I (Col I) and type V (Col V) isoforms which serve as models of changes in the ECM during invasion in vivo. To investigate if SHG is sensitive to changes due to Col V incorporation into Col I fibrils, gels were prepared with 0-20% Col V with the balance consisting of Col I. Using the metrics of SHG intensity, fiber length, emission directionality, and depth-dependent intensities, we found similar responses for gels comprised of 100% Col I, and 95% Col I/5% Col V, where these metrics were all significantly different from those of the 80% Col I/20% Col V gels. Specifically, the gels of lower Col V content produce brighter SHG, are characterized by longer fibers, and have a higher forward/backward emission ratio. These attributes are all consistent with more highly organized collagen fibrils/fibers and are in agreement with previous TEM characterization as well as predictions based on phase matching considerations. These results suggest that SHG can be developed to discriminate Col I/Col V composition in tissues to characterize and follow breast cancer invasion.
Highlights
For women in the US, death rates from breast cancer are the second highest among all cancers, and approximately 1 in 8 will develop the disease during their lifetime
We have explored the use of high resolution Second Harmonic Generation (SHG) imaging microscopy [9] to quantify differences in tissue structure using in vitro fibrillar models of the extracellular matrix (ECM) for breast cancer
1 August 2011 / Vol 2, No 8 / BIOMEDICAL OPTICS EXPRESS 2314 morphologies, the measured forward-backward intensity ratio (F/B) values are consistent in each case per the mathematical model we previously presented and discussed above [12]
Summary
For women in the US, death rates from breast cancer are the second highest among all cancers, and approximately 1 in 8 will develop the disease during their lifetime. Probing for alterations in the extracellular matrix (ECM) composition and structure may be a promising approach in this regard, as these changes are thought to be critical for tumor initiation and progression for several epithelial carcinomas [1,2,3]. Up-regulation of several proteases (e.g. MMP-1, MMP-9, and MMP-14) in breast cancer has been implicated in invasion/metastasis where these act by degrading the basement membrane and/or stroma [4,5]. Certain subtypes of breast cancer are thought to carry the necessary gene expression characteristics that promote very early metastasis at the time that they become invasive [8], such that routine screening modalities will fail to detect them early enough to impact survival. We propose that changes in the ECM may be a biomarker of invasion and these will provide insight into the factors that facilitate this process
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