Abstract
We previously reported the utility of Low-Coherence Enhanced Backscattering (LEBS) Spectroscopy in detecting optical changes in uninvolved rectal mucosa, changes that are indicative of the presence of advanced colorectal adenomas elsewhere in the colon (field carcinogenesis). We hypothesized that the alterations in optical signatures are due to structural changes in colonocytes. To elucidate those colonocyte changes, we used LEBS and an early time point in an animal model of colorectal field carcinogenesis – rats treated with azoxymethane (AOM). Changes in LEBS markers in intact mucosa from AOM-treated rats could be at least partially attributed to changes in colonocytes. To investigate the molecular mechanisms underlying the colonocyte abnormalities in premalignant colon, we took a candidate approach. We compared expression profiles of genes implicated directly or indirectly in cytoskeletal dysregulation in colorectal tissues from saline-treated versus AOM-treated rats. Our data suggest that a number of genes known to affect colon tumorigenesis are up-regulated in colonocytes, and genes previously reported to be tumor suppressors in metastatic cancer are down-regulated in colonocytes, despite the colonocytes being histologically normal. To further understand the role of the cytoskeleton in generating changes in optical markers of cells, we used pharmacological disruption (using colchicine) of the cytoskeleton. We found that differences in optical markers (between AOM- and control-treated rats) were negated by the disruption, suggesting cytoskeletal involvement in the optical changes. These studies provide significant insights into the micro-architectural alterations in early colon carcinogenesis, and may enable optimization of both bio-photonic and molecular risk stratification techniques to personalize colorectal cancer screening.
Highlights
Field carcinogenesis [1] is the notion that the genetic/ environmental milieu that leads to a focal tumor exists at the tumor site, but can be diffusely present throughout the organ
We independently studied single cell preparations versus intact tissue structures to assess the biological origin of aberrant Low-Coherence Enhanced Backscattering (LEBS) signals
We did LEBS analysis on intact colon tissues as well as on a colonocyte pellet obtained from saline-treated and AOMtreated rats
Summary
Field carcinogenesis [1] is the notion that the genetic/ environmental milieu that leads to a focal tumor exists at the tumor site, but can be diffusely present throughout the organ. Previous biomarker studies of the rectum, such as the number of aberrant crypt foci [2], epithelial proliferation and/or apoptosis [3,4], and alterations in gene expression or in protein profiles [5,6,7] each suggest that there are subtle alterations in the rectum when neoplasia is present elsewhere in the colon This suggests the possibility of using the rectum as a surrogate site for probing the risk of CRC [8,9,10,11]
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