title: Magnetic resonance imaging and characterization of spontaneous lesions in a transgenic mouse model of tuberous sclerosis as a model for endothelial cell-based transgene delivery.
abstract: Tuberous sclerosis (TSC) is an autosomal dominant genetic disorder characterized by abnormalities in cellular migration, proliferation, and differentiation in many tissues. Benign hamartomas develop in multiple organs, believed to be caused by somatic mutation in addition to germ line mutation to cause loss of both alleles of either the TSC1 or TSC2 tumor suppressor gene, with resultant dysregulated growth due to loss of hamartin or tuberin function, respectively. This study focuses on detecting spontaneous lesions in a knockout mouse model of TSC2 by magnetic resonance imaging (MRI) and exploring the efficiency of introducing gene products into lesions, using transduced endothelial cells as gene vehicles. MRI was shown to be effective in detecting spontaneous lesions in multiple tissues as a means of assessing the prevalence of tumors. Tsc(2+/) heterozygous mice were screened at 12-24 months of age. MRI detected 100% of the renal lesions (cystadenomas, renal cell carcinomas) and 75% of the hepatic lesions (hemangiosarcomas), later identified by histology. Cell-mediated gene delivery was evaluated by immunohistochemical analysis of renal, hepatic, and lung lesions after intravenous delivery of MS1 mouse endothelial cells, transduced to express an enhanced form of green fluorescent protein (EGFP). Preliminary immunohistochemical analysis, using a polyclonal antibody to EGFP and a horseradish peroxidase-diaminobenzidine detection system, revealed these cells throughout liver, kidney, and lung sections from injected animals, organs that are frequently affected in TSC2 patients, as well as within the lesions themselves.
authors.affiliation: Brain Tumor Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. abrown2@caregroup.harvard.edu
authors.forename: Alice B
authors.initials: AB
authors.lastname: Brown
authors.forename: Umar
authors.initials: U
authors.lastname: Mahmood
authors.forename: Maria L
authors.initials: ML
authors.lastname: Cortes
authors.forename: Yi
authors.initials: Y
authors.lastname: Tang
authors.forename: George
authors.initials: G
authors.lastname: Dai
authors.forename: Anat
authors.initials: A
authors.lastname: Stemmer-Rachamimov
authors.forename: Shilpa
authors.initials: S
authors.lastname: Prabhakar
authors.forename: Kimberlee
authors.initials: K
authors.lastname: Leishear
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Onda
authors.forename: David
authors.initials: D
authors.lastname: Kwiatkowski
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Xandra
authors.initials: X
authors.lastname: Breakefield
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D002460:Cell Line; D004195:Disease Models, Animal; D042783:Endothelial Cells; D018014:Gene Transfer Techniques; D016147:Genes, Tumor Suppressor; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007680:Kidney Neoplasms / Q000473:pathology; D008168:Lung / Q000473:pathology; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D014161:Transduction, Genetic; D019076:Transgenes; D014402:Tuberous Sclerosis / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D049452:Green Fluorescent Proteins