Imaging of secreted extracellular periostin, an important marker of invasion in the tumor microenvironment in esophageal cancer

Abstract

Periostin, an extracellularmatrix protein, plays key role in cell adhesion and motility within the tumor microenvironment and is correlated with tumor invasion. We developed and characterized a PET tracer that specifically targets periostin and evaluated the probe in preclinical models of esophageal squamous cell carcinoma (ESCC). Methods: The Institutional Animal Care and Use Committee approved all animal studies. Antiperiostin-F(ab)2 was generated from a monoclonal antibody by enzymatic digestion, conjugated to DOTA, and labeled with 64Cu. Human ESCC cell lines, TE-11 with high and TT with minimal periostin expression, were implanted in nu/nu mice to generate the positive and control tumor models, respectively. PET/CT imaging was performed at 6, 12, and 24 h and organ-specific biodistribution at 24 h after probe injection. Additionally the probe was tested in a genetically engineered mouse model of periostinexpressing distal esophageal/forestomach ESCC. Tissue microarrays of esophageal neoplasms and ESCC as well as extracted tumor samples were stained for periostin. Results: We generated a 64Cu-DOTA-antiperiostin-F(ab)2 with a dissociation constant of 29.2 ± 3.0 nM. PET/CT images and biodistribution studies showed significantly higher tracer uptake in TE-11 than TT tumors (maximum standardized uptake value, 24 h: 0.67± 0.09 vs. 0.36 ± 0.03,P,0.0005; percentage injected dose per gram, 24 h: 3.24 ± 0.65 vs. 1.63 ± 0.49, P, 0.0001). In genetically engineered mouse models, ESCC high periostin tracer uptake anatomically correlated with the 18F-FDG uptake at the gastroesophageal junction. All of the ESCC cores and 96.2% of adenocarcinoma stained positive for periostin, with most stained strongly (67.3% and 69.3%, respectively). Conclusion: We demonstrated that specific imaging of extracellular matrix periostin in ESCC is feasible using a targeted PET tracer. Detection of periostin in the tumormicroenvironment may help with early detection, postsurgical follow-up, and in situ characterization of primary and metastatic lesions.