ABSTRACT
PURPOSE: Colorectal cancer (CRC) is one of the major causes of cancer-related deaths in industrialized countries. The identification of small polyps and neoplasms with non-polypoid morphology remains to be a serious challenge, as about a quarter of them are missed during routine colonoscopy. The aim of this study was to evaluate the application of an integrin αvß3 optical probe in near-infrared fluorescence (NIRF) confocal laser endomicroscopy (CLE) for tumour detection in a rodent model. PROCEDURES: In a novel orthotopic CRC mouse model, tumour growth was monitored by bioluminescence imaging and by colonoscopy employing a rigid white-light endoscope, tumour development was scored by total number and size of tumours. Furthermore, NIRF CLE was established using a fibre probe attached to a confocal laser scanner operating at 660 nm and an antagonistic small-molecule integrin αvß3 NIRF contrast agent. RESULTS: Three CRC cell lines of different histological origin were successfully implanted in nude mice, proving the power of this new orthotopic model. Whole body NIRF images of tumour-bearing mice showed specific high accumulation of the integrin αvß3 probe in regions of tumour growth, colocalizing with the bioluminescent signal. Molecular imaging by means of a CLE fibre probe allowed distinguishing normal mucosa structures from tumour tissue, as confirmed by quantitation of fluorescence intensities and histology. CONCLUSIONS: Targeting integrin αvß3 in a molecular imaging approach was shown to be effective for CRC detection. Use of molecular guidance in near-infrared CLE represents a promising route to improving detection rates.
Subject(s)
Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Fluorescent Dyes/chemistry , Integrin alphaVbeta3/metabolism , Microscopy, Confocal/methods , Molecular Imaging/methods , Animals , Female , Fluorescent Dyes/metabolism , HCT116 Cells , Heterografts , Humans , Integrin alphaVbeta3/chemistry , Mice , Mice, Nude , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathologyABSTRACT
OBJECTIVE: Enzymatically oxygenated lipid products derived from omega-3 and omega-6 fatty acids play an important role in inflammation dampening. This study examined the anti-inflammatory effects of n-6 docosapentaenoic acid-derived (17S)-hydroxy-docosapentaenoic acid (17-HDPAn-6) and (10,17S)-dihydroxy-docosapentaenoic acid (10,17-HDPAn-6) as well as n-3 docosahexaenoic acid-derived 17(R/S)-hydroxy-docosahexaenoic acid (17-HDHA). MATERIALS AND METHODS: The effects of 17-HDPAn-6, 10,17-HDPAn-6 or 17-HDHA on activity and M1/M2 polarization of murine macrophage cell line RAW 264.7 were examined by phagocytosis assay and real-time PCR. To assess anti-inflammatory effects in vivo, dextran sodium sulfate (DSS) colitis was induced in mice treated with 17-HDPAn-6, 10,17-HDPAn-6, 17-HDHA or NaCl. RESULTS: Our results show that 17-HDPAn-6, 10,17-HDPAn-6 and 17-HDHA increase phagocytosis in macrophages in vitro and promote polarization towards the anti-inflammatory M2 phenotype with decreased gene expression of TNF-α and inducible Nitric oxide synthase and increased expression of the chemokine IL-1 receptor antagonist and the Scavenger receptor Type A. Intraperitoneal treatment with 17-HDPAn-6, 10,17-HDPAn-6, or 17-HDHA alleviated DSS-colitis and significantly improved body weight loss, colon epithelial damage, and macrophage infiltration. CONCLUSION: These results suggest that DPAn-6-derived 17-HDPAn-6 and 10,17-HDPAn-6 as well as the DHA-derived 17-HDHA have inflammation-dampening and resolution-promoting effects that could be used to treat inflammatory conditions such as inflammatory bowel disease.
