CXCR4 Is a Potential Target for Diagnostic PET/CT Imaging in Barrett's Dysplasia and Esophageal Adenocarcinoma

• Published in: Clinical cancer research 2018-03, Vol.24 (5), p.1048-1061
• Main Authors: Fang, Hsin-Yu, Münch, Natasha Stephens, Schottelius, Margret, Ingermann, Jonas, Liu, Haibo, Schauer, Michael, Stangl, Stefan, Multhoff, Gabriele, Steiger, Katja, Gerngroß, Carlos, Jesinghaus, Moritz, Weichert, Wilko, Kühl, Anja A, Sepulveda, Antonia R, Wester, Hans-Jürgen, Wang, Timothy C, Quante, Michael
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adenocarcinoma - diagnostic imaging; Adenocarcinoma - immunology; Adenocarcinoma - pathology; Aged; Aged, 80 and over; Animals; Autoradiography; Barrett Esophagus - diagnostic imaging; Barrett Esophagus - immunology; Barrett Esophagus - pathology; Barrett's esophagus; Biomarkers; Biomarkers, Tumor - immunology; Biomarkers, Tumor - metabolism; Biopsy; Cancer; Carcinogenesis; Carcinogenesis - pathology; Carcinogens; Computed tomography; Coordination Complexes - administration & dosage; CXCR4 protein; Diagnostic systems; Disease Models, Animal; Disease Progression; Dysplasia; Epithelial cells; Esophageal cancer; Esophageal Neoplasms - diagnostic imaging; Esophageal Neoplasms - immunology; Esophageal Neoplasms - pathology; Esophagus; Esophagus - immunology; Esophagus - pathology; Experimental design; Fluorescence; Health risk assessment; Humans; Imaging; Immune system; Interleukin 1; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Mice, Transgenic; Middle Aged; Molecular Imaging - methods; Peptides, Cyclic - administration & dosage; Positron emission; Positron Emission Tomography Computed Tomography - methods; Receptors, CXCR4 - immunology; Receptors, CXCR4 - metabolism; Target recognition; Tissue Array Analysis; Tomography; Transgenic mice; Tumor Microenvironment - immunology; Up-Regulation
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-17-1756

Barrett's esophagus represents an early stage in carcinogenesis leading to esophageal adenocarcinoma. Considerable evidence supports a major role for chronic inflammation and diverse chemokine pathways in the development of Barrett's esophagus and esophageal adenocarcinoma. Here we utilized an transgenic mouse model of Barrett's esophagus and esophageal adenocarcinoma and human patient imaging to analyze the importance of CXCR4-expressing cells during esophageal carcinogenesis. IL1β overexpression induces chronic esophageal inflammation and recapitulates the progression to Barrett's esophagus and esophageal adenocarcinoma. CXCR4 expression is increased in both epithelial and immune cells during disease progression in pL2-IL1β mice and also elevated in esophageal adenocarcinoma patient biopsy samples. Specific recruitment of CXCR4-positive (CXCR4 ) immune cells correlated with dysplasia progression, suggesting that this immune population may be a key contributor to esophageal carcinogenesis. Similarly, with progression to dysplasia, there were increased numbers of CXCR4 columnar epithelial cells at the squamocolumnar junction (SCJ). These findings were supported by stronger CXCR4-related signal intensity in fluorescence imaging and autoradiography with advanced dysplasia. Pilot CXCR4-directed PET/CT imaging studies in patients with esophageal cancer demonstrate the potential utility of CXCR4 imaging for the diagnosis and staging of esophageal cancer. In conclusion, the recruitment of CXCR4 immune cells and expansion of CXCR4 epithelial cells in esophageal dysplasia and cancer highlight the potential of CXCR4 as a biomarker and molecular target for diagnostic imaging of the tumor microenvironment in esophageal adenocarcinoma. .