Four-Dimensional Elastic Light-Scattering Fingerprints as Preneoplastic Markers in the Rat Model of Colon Carcinogenesis

Background & Aims: Identification of preneoplastic changes in histologically normal epithelium (the "field effect") could provide a powerful screening tool for colorectal cancer. However, to date, reliable detection has not been possible. We have recently developed a new generation of optical technology, 4-dimensional elastic light-scattering fingerprinting (4D-ELF), which enables us to probe the nanoscale/microscale architecture of living cells. We therefore investigated whether 4D-ELF would be able to identify preneoplastic changes in the colonocytes of the azoxymethane (AOM)-treated rat model of colon carcinogenesis. Methods: Forty-eight Fisher 344 rats were randomized to either 2 weekly injections of AOM or saline. Animals were killed 2-20 weeks after the second injection of AOM. Colons were removed and subjected to 4D-ELF analysis, with a subset undergoing assessment of aberrant crypt foci (ACF). All AOM-treated animals were compared with age-matched saline-treated controls. Results: AOM-induced ACF became apparent at approximately 4-6 weeks and continued to increase over time. ACF were predominantly located in the distal colon. At 2 weeks (before development of ACF), there were marked changes in a number of 4D-ELF signatures. The relevance to carcinogenesis of these 4D-ELF-detected microarchitectural abnormalities is supported by their spatial and temporal correlation with subsequent development of ACF. All changes reported were highly statistically significant. Conclusions: We show that probing the nanoscale cellular architecture with 4D-ELF provided an unprecedented tool for detecting the earliest stages of colon carcinogenesis. Future studies are necessary to explore the clinical applicability of this technology and elucidate the biological determinants of these microarchitectural changes.