Abstract
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.
Highlights
Colorectal cancer is the second most common cancer in women and the third most common in men [1]
Tumor uptake of indocyanine green (ICG) administered via enema to rats in a model of colon carcinogenesis In the four animals not administered an ICG enema, weak autofluorescence signals were detected in four adenomas and one adenocarcinoma and in the normal colon (Figure 3A)
This study demonstrated the ability of topical ICG application to reveal colon tumor tissues throughout the colon in a rat model of colon cancer
Summary
Colorectal cancer is the second most common cancer in women and the third most common in men [1]. Screening colonoscopy is widely used as the gold standard for the detection of colorectal cancer, as the early detection of polyps followed by their endoscopic removal has been shown to prevent the development of colorectal cancer and mortality due to the disease [2, 3] This strategy has several limitations with respect to the detection of small lesions and the microscopy-based identification of their pathological features. The advantages of fluorescence tumor imaging include its high specificity and sensitivity, real-time video frame-rate imaging, relatively low cost, portability, the absence of radiation exposure, and the option of simultaneous multiplexed imaging using fluorescent agents differing in their wavelengths [9, 10] It may be a valuable method in early cancer detection and in minimally invasive image-guided surgical procedures. Despite the variety of tumor imaging agents developed far, many of those intended for use in humans are still in pre-clinical or early-phase clinical trials [6]
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