Abstract 5174: Imaging of tissue factor expression in an orthotopic pancreatic tumor mouse model using small animal PET/CT and MRI
Authors: Nielsen Carsten H. , Jeppesen Troels E. , Kristensen Lotte K. , Larsen Laura H. , Madsen Jacob , Wiinberg Bo , Petersen Lars C. , Kjaer Andreas 
Published: August 2015

Abstract
Objectives: Tissue factor (TF) is up regulated in many solid tumors and its expression is linked to tumor angiogenesis, invasion, metastasis and prognosis. We have previously reported the use active site inhibited factor VII (FVIIai) labeled with 18F for specific in vivo imaging of TF expression. The aim of this study was to investigate the feasibility of non-invasive imaging of tumor TF expression in an orthotopic pancreatic tumor mouse model using 18F-FVIIai and small animal PET/CT and MR imaging.
Methods: Female NMRI nude mice (N = 24) were inoculated orthotopically with 5×105 human pancreatic adenocarcinoma cells (BxPC-3.luc2). Tumor development was monitored by bioluminescence imaging. Non-invasive TF imaging was performed 13 days after tumor inoculation. Each mouse (N = 18) underwent small animal PET/CT imaging 4 hours after intravenous administration of 2.9-8.3 MBq 18F-FVIIai. Anatomical T2-weighted MR imaging was performed the day after followed by surgical removal of the primary tumors. Bioluminescence imaging was applied to monitor tumor regrowth and metastatic development. The primary endpoint was overall survival using humane endpoints.
Results: The PET images showed high uptake of 18F-FVIIai in the orthotopic pancreatic tumors. A high tumor to normal tissue ratio clearly visualized the tumor margins on the combined PET/CT images. The pancreatic tumors had intense uptake in their outer margins and a low central uptake. This corresponded well with the findings on the T2-weigted MR images that showed central necrosis of the pancreatic tumors. Surgical removal of the primary orthotopic tumors reduced the bioluminescence signal more than 30-fold fold from 1.2×109 ±1.7×108 photons/s (mean ± SEM) to 3.4×107 ±1.7×107 photons/s. In comparison, the bioluminescence signal was 1.5×108 ±3.5×107 photons/s two days after inoculation of the BxPC-3.luc2 cells. All but one mouse had tumor re-growth and at autopsy, 5 animals had local disease, 5 animals had regional disease, and 7 animals had distant metastatic disease. Interestingly, 3 animals showed hematological spread with multiple metastatic foci found in the liver. The median overall survival was 30 days post surgery.
Conclusion: PET/CT imaging with 18F-FVIIai is able to clearly visualize TF positive orthotopic pancreatic tumors. High intensity uptake of 18F-FVIIai in tumor margins corresponded to viable tumor visualized by MRI. Further quantitative image analysis of 18F-FVIIai uptake in tumor regions will reveal if TF expression measured by non-invasive PET imaging is able to predict prognosis and metastatic disease.
Research Support: This work was supported by at grant from the Danish National Advanced Technology Foundation.
Citation Format: Carsten H. Nielsen, Troels E. Jeppesen, Lotte K. Kristensen, Laura H. Larsen, Jacob Madsen, Bo Wiinberg, Lars C. Petersen, Andreas Kjaer. Imaging of tissue factor expression in an orthotopic pancreatic tumor mouse model using small animal PET/CT and MRI. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5174. doi:10.1158/1538-7445.AM2015-5174