Normal cell function is dependent on the proper maintenance of chromatin structure. Regulation of chromatin structure is controlled by histone modifications that directly influence chromatin architecture and genome function. Specifically, the histone deacetylase (HDAC) family of proteins modulate chromatin compaction and are commonly dysregulated in many tumors, including colorectal cancer (CRC). However, the role of HDAC proteins in early colorectal carcinogenesis has not been previously reported. We found HDAC1, HDAC2, HDAC3, HDAC5, and HDAC7 all to be up-regulated in the field of human CRC. Furthermore, we observed that HDAC2 up-regulation is one of the earliest events in CRC carcinogenesis and observed this in human field carcinogenesis, the azoxymethane-treated rat model, and in more aggressive colon cancer cell lines. The universality of HDAC2 up-regulation suggests that HDAC2 up-regulation is a novel and important early event in CRC, which may serve as a biomarker. HDAC inhibitors (HDACIs) interfere with tumorigenic HDAC activity; however, the precise mechanisms involved in this process remain to be elucidated. We confirmed that HDAC inhibition by valproic acid (VPA) targeted the more aggressive cell line. Using nuclease digestion assays and transmission electron microscopy imaging, we observed that VPA treatment induced greater changes in chromatin structure in the more aggressive cell line. Furthermore, we used the novel imaging technique partial wave spectroscopy (PWS) to quantify nanoscale alterations in chromatin. We noted that the PWS results are consistent with the biological assays, indicating a greater effect of VPA treatment in the more aggressive cell type. Together, these results demonstrate the importance of HDAC activity in early carcinogenic events and the unique role of higher-order chromatin structure in determining cell tumorigenicity.
To investigate the transition from non-cancerous to metastatic from a physical sciences perspective, the Physical Sciences–Oncology Centers (PS-OC) Network performed molecular and biophysical comparative studies of the non-tumorigenic MCF-10A and metastatic MDA-MB-231 breast epithelial cell lines, commonly used as models of cancer metastasis. Experiments were performed in 20 laboratories from 12 PS-OCs. Each laboratory was supplied with identical aliquots and common reagents and culture protocols. Analyses of these measurements revealed dramatic differences in their mechanics, migration, adhesion, oxygen response, and proteomic profiles. Model-based multi-omics approaches identified key differences between these cells' regulatory networks involved in morphology and survival. These results provide a multifaceted description of cellular parameters of two widely used cell lines and demonstrate the value of the PS-OC Network approach for integration of diverse experimental observations to elucidate the phenotypes associated with cancer metastasis.
Despite major importance in physics, biology, and other sciences, optical sensing of nanoscale structures in the far-zone remains an open problem due to the fundamental diffraction limit of resolution. We establish that the expected value of spectral variance (Σ̃2) of a far-field, diffraction-limited microscope image can quantify the refractive-index fluctuations of a label-free, weakly scattering sample at subdiffraction length scales. We report the general expression of Σ̃ for an arbitrary refractive-index distribution. For an exponential refractive-index spatial correlation, we obtain a closed-form solution of Σ̃ which is in excellent agreement with three-dimensional finite-difference time-domain solutions of Maxwell's equations. Sensing complex inhomogeneous media at the nanoscale can benefit fields from material science to medical diagnostics.
We report a study of the nanoscale mass-density fluctuations of heterogeneous optical dielectric media, including nanomaterials and biological cells, by quantifying their nanoscale light-localization properties. Transmission electron microscope images of the media are used to construct corresponding effective disordered optical lattices. Light-localization properties are studied by the statistical analysis of the inverse participation ratio ͑IPR͒ of the localized eigenfunctions of these optical lattices at the nanoscale. We validated IPR analysis using nanomaterials as models of disordered systems fabricated from dielectric nanoparticles. As an example, we then applied such analysis to distinguish between cells with different degrees of aggressive malignancy. © 2010 American Institute of Physics. ͓doi:10.1063/1.3524523͔Quantifying the degree of nanoscale disorder is a major research interest in characterizing the optical ͑electronic͒ properties of disordered condensed-matter systems. 1 Statistical properties, such as the mean and standard deviation ͑std͒, of the inverse participation ratio ͑IPR͒ of the spatially localized optical eigenfunctions of these optical systems are important quantitative measures of the degree of disorder of these lattices, where IPR of an eigenfunction E is defined as IPR= ͉͐E͑r͉͒ 4 dr ជ ͓in units of inverse area in two dimension ͑2D͔͒. 2,3 The average value of the IPR of a uniform lattice is a fixed universal number ͑ϳ2.5 in 2D͒, but the value increases with an increasing degree of disorder ͑or degree of localization͒. IPR has been well-studied in condensed-matter physics for characterizing the degree of disorder of homogeneous and heterogeneous media in a single parameter. [4][5][6] In this paper, we report the study of light-localization properties of biological cells by first constructing optical lattices of these cells via transmission electron microscopy ͑TEM͒ imaging 7 and then studying the statistical properties of IPR of the eigenfunctions of these lattices. In our most recent optical experiments, we show that the degree of nanoscale disorder increases with the degree of carcinogenesis for both control and precancerous cells ͑in cell lines, mouse model, and different organs in human studies, such as pancreas, colon, and lung͒. [8][9][10] These nanoscale changes may result from the rearrangements of DNA, RNA, lipids, or proteins. We want to verify and quantify these nanoscale changes as observed in optical studies by TEM.It has been shown that the optical refractive index ͑n͒ is linearly proportional to the local density ͑ ͒ of intracellular macromolecules for a majority of the scattering substances found in living cells, such as proteins, lipids, DNA, or RNA, i.e., n = n 0 + ⌬n = n 0 + ␣ , where n 0 is the refractive index of the medium, is the local concentration of solids, with ␣ ϳ 0.18. 11 Furthermore, we consider that the absorption of the contrast agent by the cell is linearly proportional to the total mass present in the thin cell voxel. Therefore, if TEM imaging is perfo...
Cytoskeleton is ubiquitous throughout the cell and is involved in important cellular processes such as cellular transport, signal transduction, gene transcription, cell-division, etc. Partial wave spectroscopic microscopy is a novel optical technique that measures the statistical properties of cell nanoscale organization in terms of the disorder strength. It has been found previously that the increase in the disorder strength of cell nanoarchitecture is one of the earliest events in carcinogenesis. In this study, we investigate the cellular components responsible for the differential disorder strength between two morphologically (and hence microscopically) similar but genetically altered human colon cancer cell lines, HT29 cells and Csk shRNA-transfected HT29 cells that exhibit different degrees of neoplastic aggressiveness. To understand the role of cytoskeleton in nanoarchitectural alterations, we performed selective drug treatment on the specific cytoskeletal components of these cell types and studied the effects of cytoskeletal organization on disorder strength differences. We report that altering the cell nanoarchitecture by disrupting cytoskeletal organization leads to the attenuation of the disorder strength differences between microscopically indistinguishable HT29 and CSK constructs. We therefore demonstrate that cytoskeleton plays a role in the control of cellular nanoscale disorder.
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