期刊
MOLECULAR IMAGING
卷 15, 期 -, 页码 1-11出版社
SAGE PUBLICATIONS INC
DOI: 10.1177/1536012116644881
关键词
indoleamine 2,3-dioxygenase; tryptophan 2,3-dioxygenase; alpha-[C-11]-methyl-L-tryptophan; patient-derived xenograft; orthotopic mouse model
资金
- National Cancer Institute [R01 CA123451]
- Fund for Medical Research and Education, Wayne State University School of Medicine
- Strategic Research Initiative Grant from the Karmanos Cancer Institute
- Dean's Diversity Fellowship awarded by Wayne State University
- Animal Model and Therapeutics Evaluation Core
- Microscopy, Imaging and Cytometry Resources Core
- Bio-banking and Correlative Sciences Core
- NIH Center Grant [P30 CA022453]
Increasing evidence demonstrates the immunosuppressive kynurenine pathway's (KP) role in the pathophysiology of human gliomas. To study the KP in vivo, we used the noninvasive molecular imaging tracer alpha-[C-11]-methyl-L-tryptophan (AMT). The AMT-positron emission tomography (PET) has shown high uptake in high-grade gliomas and predicted survival in patients with recurrent glioblastoma (GBM). We generated patient-derived xenograft (PDX) models from dissociated cells, or tumor fragments, from 5 patients with GBM. Mice bearing subcutaneous tumors were imaged with AMT-PET, and tumors were analyzed to detect the KP enzymes indoleamine 2,3-dioxygenase (IDO) 1, IDO2, tryptophan 2,3-dioxygenase, kynureninase, and kynurenine 3-monooxygenase. Overall, PET imaging showed robust tumoral AMT uptake in PDX mice with prolonged tracer accumulation over 60 minutes, consistent with AMT trapping seen in humans. Immunostained tumor tissues demonstrated positive detection of multiple KP enzymes. Furthermore, intracranial implantation of GBM cells was performed with imaging at both 9 and 14 days postimplant, with a marked increase in AMT uptake at 14 days and a corresponding high level of tissue immunostaining for KP enzymes. These results indicate that our PDX mouse models recapitulate human GBM, including aberrant tryptophan metabolism, and offer an in vivo system for development of targeted therapeutics for patients with GBM.
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