title: Imaging of Secreted Extracellular Periostin, an Important Marker of Invasion in the Tumor Microenvironment in Esophageal Cancer.
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Pedram
authors.initials: P
authors.lastname: Heidari
authors.affiliation: Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Shadi A
authors.initials: SA
authors.lastname: Esfahani
authors.affiliation: Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Nazife S
authors.initials: NS
authors.lastname: Turker
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, New York; and.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Wong
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, New York; and.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
authors.affiliation: Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts umahmood@mgh.harvard.edu.
authors.forename: Umar
authors.initials: U
authors.lastname: Mahmood
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D003301:Copper Radioisotopes / Q000737:chemistry; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D005109:Extracellular Matrix / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000473:pathology; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D064847:Multimodal Imaging; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D049268:Positron-Emission Tomography; D011485:Protein Binding; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed; D059016:Tumor Microenvironment
chemical_list: D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; D003301:Copper Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; C512835:POSTN protein, human; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
keywords: esophageal cancer; extracellular matrix; immuno-PET imaging; periostin; tumor microenvironment