Abstract
Early detection of colorectal cancer (CRC) is crucial for effective treatment. Among CRC screening techniques, optical colonoscopy is widely considered the gold standard. However, it is a costly and invasive procedure with a low rate of compliance. Our long-term goal is to develop molecular imaging agents for the non-invasive detection of CRC by molecular imaging-based colonoscopy using CT, MRI or fluorescence. To achieve this, cell surface targets must be identified and validated. Here, we report the discovery of cell-surface markers that distinguish CRC from surrounding tissues that could be used as molecular imaging targets. Profiling of mRNA expression microarray data from patient tissues including adenoma, adenocarcinoma, and normal gastrointestinal tissues was used to identify potential CRC specific cell-surface markers. Of the identified markers, six were selected for further validation (CLDN1, GPR56, GRM8, LY6G6D/F, SLCO1B3 and TLR4). Protein expression was confirmed by immunohistochemistry of patient tissues. Except for SLCO1B3, diffuse and low expression was observed for each marker in normal colon tissues. The three markers with the greatest protein overexpression were CLDN1, LY6G6D/F and TLR4, where at least one of these markers was overexpressed in 97% of the CRC samples. GPR56, LY6G6D/F and SLCO1B3 protein expression was significantly correlated with the proximal tumor location and with expression of mismatch repair genes. Marker expression was further validated in CRC cell lines. Hence, three cell-surface markers were discovered that distinguish CRC from surrounding normal tissues. These markers can be used to develop imaging or therapeutic agents targeted to the luminal surface of CRC.
Highlights
Colorectal cancer (CRC) is the third leading cause of cancer related deaths for both men and women in welldeveloped and industrialized countries [1]
Through profiling of mRNA expression microarray data and immunohistochemistry (IHC) of patient tissue samples, we report the discovery of cell surface markers that are highly expressed in colon adenomas and adenocarcinomas relative to normal tissues
Based on known biology relevant to cancer, the availability of known ligands, known structure activity relationships, or the level and breadth of expression in adenomas and adenocarcinomas relative to normal colon, six of the putative cell surface markers were selected for further validation by confirmation of protein expression in patient samples: CLDN1, G-protein-coupled receptor 56 (GPR56), GRM8, LY6G6D/F, SLCO1B1/3/7 and tolllike receptor 4 (TLR4)
Summary
Colorectal cancer (CRC) is the third leading cause of cancer related deaths for both men and women in welldeveloped and industrialized countries [1]. Most CRCs arise from benign colorectal adenomas that can be removed by endoscopic polypectomy, preventing the development of malignancy. These small, pre-malignant www.impactjournals.com/oncotarget polyps are typically asymptomatic, increasing the need for an effective early detection-screening program to identify patients requiring therapeutic intervention. Effective screening can detect CRC at earlier stages leading to improved overall survival, i.e. 90% 5 year survival [Colorectal Cancer Facts & Figures 2014-2016, American Cancer Society (ACS)]. Patients diagnosed with metastatic CRC have a poor (13%) five-year survival rate (ACS)
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