Investigation of nanoscale structural alterations of cell nucleus as an early sign of cancer

Yang Liu,Sergey Alexandrov,Rajan K Bista,Shikhar Uttam

doi:10.1186/2046-1682-7-1

Abstract

BackgroundThe cell and tissue structural properties assessed with a conventional bright-field light microscope play a key role in cancer diagnosis, but they sometimes have limited accuracy in detecting early-stage cancers or predicting future risk of cancer progression for individual patients (i.e., prognosis) if no frank cancer is found. The recent development in optical microscopy techniques now permit the nanoscale structural imaging and quantitative structural analysis of tissue and cells, which offers a new opportunity to investigate the structural properties of cell and tissue below 200 – 250 nm as an early sign of carcinogenesis, prior to the presence of microscale morphological abnormalities. Identification of nanoscale structural signatures is significant for earlier and more accurate cancer detection and prognosis.ResultsOur group has recently developed two simple spectral-domain optical microscopy techniques for assessing 3D nanoscale structural alterations – spectral-encoding of spatial frequency microscopy and spatial-domain low-coherence quantitative phase microscopy. These two techniques use the scattered light from biological cells and tissue and share a common experimental approach of assessing the Fourier space by various wavelengths to quantify the 3D structural information of the scattering object at the nanoscale sensitivity with a simple reflectance-mode light microscopy setup without the need for high-NA optics. This review paper discusses the physical principles and validation of these two techniques to interrogate nanoscale structural properties, as well as the use of these methods to probe nanoscale nuclear architectural alterations during carcinogenesis in cancer cell lines and well-annotated human tissue during carcinogenesis.ConclusionsThe analysis of nanoscale structural characteristics has shown promise in detecting cancer before the microscopically visible changes become evident and proof-of-concept studies have shown its feasibility as an earlier or more sensitive marker for cancer detection or diagnosis. Further biophysical investigation of specific 3D nanoscale structural characteristics in carcinogenesis, especially with well-annotated human cells and tissue, is much needed in cancer research.

Highlights

The cell and tissue structural properties assessed with a conventional bright-field light microscope play a key role in cancer diagnosis, but they sometimes have limited accuracy in detecting early-stage cancers or predicting future risk of cancer progression for individual patients if no frank cancer is found
Results and discussion we will show some examples of using spectral-encoding of spatial frequency (SESF) and spatial-domain low-coherence quantitative phase microscopy (SL-QPM) based methods to detect nanoscale structural changes in a fundamental biological process important in cancer, as well as to demonstrate the ability to detect pre-cancerous changes in clinical samples beyond what conventional light microscopy can detect
The changes in DNA content or chromatin cluster are not visible in the bright-field images, but the SESF images show a significantly red-shifted color in the nucleus of G2/M, which suggests an increased spatial period corresponding to the presence of larger structures

Summary

Introduction

The cell and tissue structural properties assessed with a conventional bright-field light microscope play a key role in cancer diagnosis, but they sometimes have limited accuracy in detecting early-stage cancers or predicting future risk of cancer progression for individual patients (i.e., prognosis) if no frank cancer is found. We hypothesize that the complex genomic and epigenomic changes in carcinogenesis result in nanoscale structural alterations arising from the changes in the 3D spatial arrangement and the chromatin density variation in the cell nucleus. In other words, investigating the nanomorphology characteristics as the downstream structural manifestation of complex genetic and epigenetic events regardless of which molecular pathways are involved in carcinogenesis is an important effort. As such physical characteristics can be detected with low-cost, high throughput and high sensitivity, yet independent of molecular heterogeneity, they have the potential to become a new class of cancer markers to make a significant clinical impact. The analysis of cellular disorder strength has been reported to detect nano-architectural changes early in carcinogenesis that precede microscopically detectable cytological abnormalities [8] and show the ability to detect cancer from normal cells from a remote location in lung, colon and pancreas [9,10,11]

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