Imaging of Secreted ECM Periostin, a Marker of Invasion in the Tumor Microenvironment

Journal of Nuclear Medicine August 2015, 56 (8) 1246-1251.

Background: Periostin, an extracellular matrix 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 (64)Cu. 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 periostin-expressing 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 (64)Cu-DOTA-anti-periostin-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 (18)F-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 tumor microenvironment may help with early detection, postsurgical follow-up, and in situ characterization of primary and metastatic lesions.