Research Papers:

Fluorescence contrast-enhanced proliferative lesion imaging by enema administration of indocyanine green in a rat model of colon carcinogenesis

Nobuhiko Onda, Reiko Mizutani-Morita, Susumu Yamashita, Rei Nagahara, Shinya Matsumoto, Toshinori Yoshida and Makoto Shibutani _

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Oncotarget. 2017; 8:90278-90290. https://doi.org/10.18632/oncotarget.21744

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Nobuhiko Onda1,2, Reiko Mizutani-Morita2, Susumu Yamashita1, Rei Nagahara2, Shinya Matsumoto1, Toshinori Yoshida2 and Makoto Shibutani2,3

1Evaluation Technology Department 1, R&D Group, Olympus Corporation, Hachioji, Tokyo 192-8512, Japan

2Laboratory of Veterinary Pathology, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183-8509, Japan

3Institute of Global Innovation Research, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183-8509, Japan

Correspondence to:

Makoto Shibutani, email: [email protected]

Keywords: colon tumor, endoscopy, fluorescence imaging, indocyanine green, tight junction

Received: April 19, 2017    Accepted: August 08, 2017    Published: October 09, 2017


The fluorescent contrast agent indocyanine green (ICG) is approved by the Food and Drug Administration for clinical applications. We previously reported that cultured human colon tumor cells preferentially take up ICG by endocytic activity in association with disruption of their tight junctions. The present study explored ICG availability in fluorescence imaging of the colon to identify proliferative lesions during colonoscopy. The cellular uptake of ICG in cultured rat colon tumor cells was examined using live-cell imaging. Colon lesions in rats administered an ICG-containing enema were further assessed in rats with azoxymethane-induced colon carcinogenesis, using in vivo endoscopy, ex vivo microscopy, and immunofluorescence microscopy. The uptake of ICG by the cultured cells was temperature-dependent. The intracellular retention of the dye in the membrane trafficking system suggested endocytosis as the uptake mechanism. ICG administered via enema accumulated in colon proliferative lesions ranging from tiny aberrant crypt foci to adenomas and localized in proliferating cells. Fluorescence endoscopy detected these ICG-positive colonic proliferative lesions in vivo. The immunoreactivity of the tight-junction molecule occludin was altered in the proliferative lesions, suggesting the disruption of the integrity of tight junctions. These results suggest that fluorescence contrast-enhanced imaging following the administration of an ICG-containing enema can enhance the detection of mucosal proliferative lesions of the colon during colonoscopy. The tissue preference of ICG in the rat model evaluated in this study can be attributed to the disruption of tight junctions, which in turn promotes endocytosis by proliferative cells and the cellular uptake of ICG.

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