Gastrin and cholecystokinin 2 receptor, and gastrin-releasing peptide receptor in cancer: From pathogenesis to precision medicine.

Gastrin regulates gastric acid secretion and mucosal homeostasis via the cholecystokinin-2 receptor (CCK2R). Aberrant signaling via CCK2R (cholecystokinin family) and the distinct class A GPCR, gastrin-releasing peptide receptor (GRPR; bombesin family), drives oncogenesis across diverse GI and non-GI malignancies through calcium mobilization, MAPK/PI3K activation, EGFR transactivation, and constitutive splice variants like CCK2Ri4sv. Furthermore, precursor forms such as progastrin remodel the tumor microenvironment by interacting with non-CCK binding sites (p78, Annexin A2), converting fibroblasts into pro-invasive CAFs and sustaining cancer stem cells. Chronic hypergastrinemia, induced by Helicobacter pylori infection, autoimmune gastritis, or long-term proton pump inhibitor (PPI) therapy, drives enterochromaffin-like (ECL) cell hyperplasia, promoting gastric neuroendocrine tumors and diffuse-type carcinomas. Beyond gastroenteropancreatic physiology, selective expression of CCK2R on ECL and thyroid C-cells, combined with widespread ectopic GRPR overexpression in solid tumors, establishes versatile platforms for molecular imaging and radiotheranostics. Radiolabeled peptide antagonists and stabilized minigastrin/bombesin analogs conjugated to diagnostic (68Ga, 64Cu) or therapeutic radionuclides (177Lu,225Ac, 212Pb) enable high-resolution PET imaging and targeted radionuclide therapy (PRRT/TAT). These strategies demonstrate high diagnostic accuracy and localized cytotoxicity in medullary thyroid carcinoma, small cell lung cancer, prostate neoplasms, and ER+ breast cancers. Concurrently, novel circulating biomarkers, including multi-genomic liquid biopsies (NETest®) and ProGRP, significantly improve non-invasive disease tracking. Unraveling these receptor pathways bridges tumor biology with translational medicine, offering transformative potential for personalized diagnosis, risk stratification, and targeted radionuclide therapy.