Bioluminescent Approaches for Measuring Tumor Growth in a Mouse Model of Neurofibromatosis

Mouse Cancer Genetics Program, National Cancer Institute, Frederick, Maryland 21702, USA.
Toxicologic Pathology (Impact Factor: 2.14). 02/2010; 38(1):123-30. DOI: 10.1177/0192623309357075
Source: PubMed


Neurofibomatosis (NF1) patients are susceptible to multiple tumors of the nervous system including neurofibromas, optic glioma, malignant peripheral nerve sheath tumors (MPNSTs), and astrocytoma. The Nf1+/-;Trp53+/- (NPcis) mouse model of NF1 spontaneously develops astrocytoma and MPNSTs that are very similar to human NF1 tumors. To use this model for testing potential therapeutics, we have developed systems that take advantage of bioluminescent reporters of tumor growth. We have generated E2F1 promoter-driving luciferase (ELUX) reporter mice to detect proliferating tumors in NPcis mice in vivo using bioluminescence. The power of this system is that it enables looking at tumor evolution and detecting spontaneous tumors at early stages of development as they evolve within their natural haploinsufficient microenvironment. This system can be used to identify tumors at different stages of tumorigenesis and to examine where spontaneous NF1 tumors initiate. The ability to rapidly screen multiple animals at a time increases the potential for use of this model in preclinical trials. This model will be valuable for the characterization of spontaneous NF1 tumors and will be important for studying the treatment and prevention of NF1 tumors in vivo.

Download full-text


Available from: Karlyne M Reilly, Sep 30, 2015
18 Reads
  • Source
    • "The maximum backgroundcorrected value for that tumor during the 30-minute imaging session was used as the maximum bioluminescent value. The bioluminescence of tumors was tracked over time using a measure termed fold, which was defined as follows: [current max BLI signal]/[initial pretreatment max BLI signal] [7] [8]. IVIS imaging was repeated at least weekly to measure tumor size. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Preclinical studies of cranial radiation therapy (RT) using animal brain tumor models have been hampered by technical limitations in the delivery of clinically relevant RT. We established a bioimageable mouse model of glioblastoma multiforme (GBM) and an image-guided radiation delivery system that facilitated precise tumor localization and treatment and which closely resembled clinical RT. Our novel radiation system makes use of magnetic resonance imaging (MRI) and bioluminescent imaging (BLI) to define tumor volumes, computed tomographic (CT) imaging for accurate treatment planning, a novel mouse immobilization system, and precise treatments delivered with the Small Animal Radiation Research Platform. We demonstrated that, in vivo, BLI correlated well with MRI for defining tumor volumes. Our novel restraint system enhanced setup reproducibility and precision, was atraumatic, and minimized artifacts on CT imaging used for treatment planning. We confirmed precise radiation delivery through immunofluorescent analysis of the phosphorylation of histone H2AX in irradiated brains and brain tumors. Assays with an intravenous near-infrared fluorescent probe confirmed that radiation of orthografts increased disruption of the tumor blood-brain barrier (BBB). This integrated model system, which facilitated delivery of precise, reproducible, stereotactic cranial RT in mice and confirmed RT's resultant histologic and BBB changes, may aid future brain tumor research.
    Translational oncology 08/2012; 5(4):230-7. DOI:10.1593/tlo.12136 · 2.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Bioluminescent imaging (BLI) has been widely applicable in the imaging of process envisioned in life sciences. As the most conventional technique for BLI, the firefly luciferin-luciferase system is exceptionally functional in vitro and in vivo. The state-of-the-art strategy in such a system is to cage the luciferin, in which free luciferin is conjugated with distinctive functional groups, thus accommodating an impressive toolkit for exploring various biological processes, such as monitoring enzymes activity, detecting bioactive small molecules, evaluating the properties of molecular transporters, etc. This review article summarizes the rational design of caged luciferins towards diverse biotargets, as well as their applications in bioluminescent imaging. It should be emphasized that these caged luciferins can stretch out the applications of bioluminescence imaging and shed light upon understanding the pathogenesis of various diseases.
    Chemical Society Reviews 10/2012; 42(2). DOI:10.1039/c2cs35249d · 33.38 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Glioblastoma multiforme (GBM) is a common, usually lethal disease with a median survival of only ~15 months. It has proven resistant in clinical trials to chemotherapeutic agents such as paclitaxel that are highly effective in vitro, presumably because of impaired drug delivery across the tumor's blood-brain barrier (BBB). In an effort to increase paclitaxel delivery across the tumor BBB, we linked the drug to a novel filomicelle nanocarrier made with biodegradable poly(ethylene-glycol)-block-poly(ε-caprolactone-r-D,L-lactide) and used precisely collimated radiation therapy (RT) to disrupt the tumor BBB's permeability in an orthotopic mouse model of GBM. Using a non-invasive bioluminescent imaging technique to assess tumor burden and response to therapy in our model, we demonstrated that the drug-loaded nanocarrier (DLN) alone was ineffective against stereotactically implanted intracranial tumors yet was highly effective against GBM cells in culture and in tumors implanted into the flanks of mice. When targeted cranial RT was used to modulate the tumor BBB, the paclitaxel-loaded nanocarriers became effective against the intracranial tumors. Focused cranial RT improved DLN delivery into the intracranial tumors, significantly improving therapeutic outcomes. Tumor growth was delayed or halted, and survival was extended by >50% (p less than 0.05) compared to the results obtained with either RT or the DLN alone. Combinations of RT and chemotherapeutic agents linked to nanocarriers would appear to be an area for future investigations that could enhance outcomes in the treatment of human GBM.
    Oncotarget 12/2012; 4(1). DOI:10.18632/oncotarget.777 · 6.36 Impact Factor
Show more