title: Longitudinal Assessment of Lung Cancer Progression in Mice Using the Sodium Iodide Symporter Reporter Gene and SPECT/CT Imaging.
abstract: Lung cancer has the highest mortality rate of any tissue-specific cancer in both men and women. Research continues to investigate novel drugs and therapies to mitigate poor treatment efficacy, but the lack of a good descriptive lung cancer animal model for preclinical drug evaluation remains an obstacle. Here we describe the development of an orthotopic lung cancer animal model which utilizes the human sodium iodide symporter gene (hNIS; SLC5A5) as an imaging reporter gene for the purpose of non-invasive, longitudinal tumor quantification. hNIS is a glycoprotein that naturally transports iodide (I-) into thyroid cells and has the ability to symport the radiotracer 99mTc-pertechnetate (99mTcO4-). A549 lung adenocarcinoma cells were genetically modified with plasmid or lentiviral vectors to express hNIS. Modified cells were implanted into athymic nude mice to develop two tumor models: a subcutaneous and an orthotopic xenograft tumor model. Tumor progression was longitudinally imaged using SPECT/CT and quantified by SPECT voxel analysis. hNIS expression in lung tumors was analyzed by quantitative real-time PCR. Additionally, hematoxylin and eosin staining and visual inspection of pulmonary tumors was performed. We observed that lentiviral transduction provided enhanced and stable hNIS expression in A549 cells. Furthermore, 99mTcO4- uptake and accumulation was observed within lung tumors allowing for imaging and quantification of tumor mass at two-time points. This study illustrates the development of an orthotopic lung cancer model that can be longitudinally imaged throughout the experimental timeline thus avoiding inter-animal variability and leading to a reduction in total animal numbers. Furthermore, our orthotopic lung cancer animal model is clinically relevant and the genetic modification of cells for SPECT/CT imaging can be translated to other tissue-specific tumor animal models.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.
authors.forename: Dominique N
authors.initials: DN
authors.lastname: Price
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.|Sandia National Laboratory, Albuquerque, New Mexico, United States of America.
authors.forename: Amber A
authors.initials: AA
authors.lastname: McBride
authors.affiliation: Institute of Molecular Immunology/Experimental Oncology and Therapy Research, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Anton
authors.affiliation: Department of Pathology, University of New Mexico School of Medicine, Albuquerque, New Mexico, United States of America.
authors.forename: Donna F
authors.initials: DF
authors.lastname: Kusewitt
authors.affiliation: New Mexico Center for Isotopes in Medicine, Albuquerque, New Mexico, United States of America.|University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico, United States of America.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Norenberg
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.
authors.forename: Debra A
authors.initials: DA
authors.lastname: MacKenzie
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.|University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico, United States of America.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Thompson
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.|University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico, United States of America.
authors.forename: Pavan
authors.initials: P
authors.lastname: Muttil
mesh_terms: D000072283:A549 Cells; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D007454:Iodides / Q000378:metabolism; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000000981:diagnostic imaging* / Q000235:genetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013670:Sodium Pertechnetate Tc 99m / Q000378:metabolism; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*; D014057:Tomography, X-Ray Computed / Q000379:methods*; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics; D000099209:Sodium-Iodide Symporters
chemical_list: D007454:Iodides; D013670:Sodium Pertechnetate Tc 99m; D027981:Symporters; D000099209:Sodium-Iodide Symporters