Colorectal cancer (CRC) is the second leading cause of cancer death in the United States with an estimated 50,000 deaths in 2016. Colonoscopy is the leading CRC screening strategy, and there is strong evidence that the removal of polyps detected by colonoscopy can prevent the development of CRC. However, colonoscopy screenings only provide partial protection due to the limitations of current polyp detection techniques and human factors such as the skill of the endoscopist. These contribute to diagnostic miss rates of up to 25%. In a new study published in Nature Medicine, an international team of researchers used the BioGenex automated molecular pathology staining system to develop a fluorescence colonoscopy technique that can accurately identify a polyp biomarker (i.e. c-Met) and thus improve polyp detection during colonoscopy screenings.
c-Met, also known as hepatocyte growth factor receptor (HGFR), is a single pass tyrosine kinase receptor essential for embryonic development, organogenesis and wound healing. Normally, only stem cells and progenitor cells express c-Met, which allows these cells to grow invasively in order to generate new tissues in an embryo or regenerate damaged tissues in an adult. Cancer stem cells are thought to hijack the ability of normal stem cells to express c-Met. The overexpression of c-Met has been shown to occur as an early event in the colorectal adenoma-carcinoma sequence, making it a suitable biomarker for colorectal neoplasia. In the new study, GE-137, a fluorescent probe with high affinity to c-Met was generated, and its biodistribution, pharmacokinetics and binding specificity were assessed in a xenograft mouse model using the human CRC cell line HT29. These preclinical studies showed that GE-137 accumulates specifically in human colorectal tumors and provides sufficient contrast to enable detection of c-Met-rich lesions. GE-137 was shown to be safe and well tolerated in humans. Fluorescence colonoscopy in patients receiving intravenous GE-137 detected all neoplastic polyps that were visible with white light, as well as an additional nine polyps that were missed by white light detection. To confirm that these polyps were indeed adenomas or hyperplastic polyps and expressed c-Met, all biopsies were evaluated by histology and immunohistochemistry (IHC) assays. The BioGenex EZ Retriever microwave was used for antigen retrieval, and the BioGenex i6000 automated staining system was used for staining with the c-Met specific antibody. Overall, fluorescence findings in vivo matched the histological findings. Whereas c-Met is expressed in normal colon tissue and is evenly expressed along the crypt axis on the epithelial cell membrane, it is significantly more highly expressed in both hyperplastic and adenomatous polyps, which corresponds to the binding of the fluorescent probe to the c-Met in vivo. This first-in-human pilot study shows that molecular imaging using an intravenous fluorescent agent specific for c-Met is feasible and safe, and that it may enable the detection of polyps missed by other techniques.
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