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BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

Nanoscale changes in chromatin organization represent the initial steps of tumorigenesis: a transmission electron microscopy study

Authors: Lusik Cherkezyan, Yolanda Stypula-Cyrus, Hariharan Subramanian, Craig White, Mart Dela Cruz, Ramesh K Wali, Michael J Goldberg, Laura K Bianchi, Hemant K Roy, Vadim Backman

Published in: BMC Cancer | Issue 1/2014

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Abstract

Background

Nuclear alterations are a well-known manifestation of cancer. However, little is known about the early, microscopically-undetectable stages of malignant transformation. Based on the phenomenon of field cancerization, the tissue in the field of a tumor can be used to identify and study the initiating events of carcinogenesis. Morphological changes in nuclear organization have been implicated in the field of colorectal cancer (CRC), and we hypothesize that characterization of chromatin alterations in the early stages of CRC will provide insight into cancer progression, as well as serve as a biomarker for early detection, risk stratification and prevention.

Methods

For this study we used transmission electron microscopy (TEM) images of nuclei harboring pre-neoplastic CRC alterations in two models: a carcinogen-treated animal model of early CRC, and microscopically normal-appearing tissue in the field of human CRC. We quantify the chromatin arrangement using approaches with two levels of complexity: 1) binary, where chromatin is separated into areas of dense heterochromatin and loose euchromatin, and 2) grey-scale, where the statistics of continuous mass-density distribution within the nucleus is quantified by its spatial correlation function.

Results

We established an increase in heterochromatin content and clump size, as well as a loss of its characteristic peripheral positioning in microscopically normal pre-neoplastic cell nuclei. Additionally, the analysis of chromatin density showed that its spatial distribution is altered from a fractal to a stretched exponential.

Conclusions

We characterize quantitatively and qualitatively the nanoscale structural alterations preceding cancer development, which may allow for the establishment of promising new biomarkers for cancer risk stratification and diagnosis. The findings of this study confirm that ultrastructural changes of chromatin in field carcinogenesis represent early neoplastic events leading to the development of well-documented, microscopically detectable hallmarks of cancer.
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Metadata
Title
Nanoscale changes in chromatin organization represent the initial steps of tumorigenesis: a transmission electron microscopy study
Authors
Lusik Cherkezyan
Yolanda Stypula-Cyrus
Hariharan Subramanian
Craig White
Mart Dela Cruz
Ramesh K Wali
Michael J Goldberg
Laura K Bianchi
Hemant K Roy
Vadim Backman
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-189

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