Expression of cholecystokinin 2 receptor (CCK2R) in rectal cancer: Clinical relevance and in vitro targeting with a fluorescent CCK2R-binding peptide

Abstract

The cholecystokinin type 2 receptor (CCK2R), which mediates the effects of gastrin and cholecystokinin (CCK), is known to promote colorectal cancer (CRC) proliferation in advanced stages. Though well-studied in gastric and pancreatic cancers, the role of CCK2R in colorectal, especially rectal cancer (RC), is still emerging. In this research, we initially evaluated CCK2R expression across rectal and colorectal cancer cell lines using qRT-PCR to establish baseline expression patterns. To explore the potential for near-infrared (NIR) fluorescence-based tumor targeting, we synthesized a CCK2R-binding peptide conjugate, Cy5@PP-F11, and demonstrated its receptor-specific uptake in vitro through live-cell imaging microscopy. While these results suggest promise for tumor targeting, further studies are needed to assess its in vivo performance and utility in fluorescence-guided surgery. In addition, a cohort of 495 Stage I-IV rectal cancer patients was analyzed using tissue microarrays (TMAs) and immunohistochemistry (IHC) to assess CCK2R expression in both tumor and normal tissues. Expression patterns and their prognostic significance were evaluated in relation to clinicopathological parameters. CCK2R localization and expression levels were quantified in both the epithelial and stromal tumor compartments, with cytoplasmic and nuclear staining specifically analyzed in the epithelial compartment. Scoring data were assessed to determine their clinical relevance. Our findings revealed significant overexpression of CCK2R in both epithelial and stromal compartments of rectal cancer tissues compared to normal tissues, showing its high suitability as target for tumor imaging. While epithelial CCK2R expression showed no significant link to clinical staging, stromal expression was notably involved, indicating a role in tumor-stroma interactions and the tumor microenvironment.