Cancer Animal Models
Wednesday 5 May 2010
Room A7 10:30-12:30 Moderators: Hagit Dafni and Simon P. Robinson

10:30 392.  

An MRI Investigation of the Effect of Active Site Mutant DDAH1 in C6 Glioma Xenografts in Vivo
Jessica Katherine Rowena Boult1, Simon Walker-Samuel1, Yann Jamin1, James M. Leiper2, Guy St.John Whitley3, Simon P. Robinson1
1CRUK and EPSRC Cancer Imaging Centre, The Institute of Cancer Research and Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom; 2MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, United Kingdom; 3Department of Basic Medical Sciences, St. Georges, University of London, London, United Kingdom

Dimethylarginine dimethylaminohydrolase (DDAH) metabolizes the endogenous inhibitor of nitric oxide synthesis, asymmetric dimethylarginine (ADMA), indirectly leading to an increase in nitric oxide. Diffusion-weighted and dynamic contract enhanced MRI were used to evaluate the vascular phenotypes of C6 glioma xenografts overexpressing either wildtype DDAH1 or an active site mutant DDAH1 incapable of metabolizing ADMA. Tumours expressing mDDAH1 demonstrated an intermediate phenotype between control and wtDDAH1 expressing tumours. Differences in ADC and native T1 and T2 times were consistent with higher cellularity/lower necrosis in the DDAH1 expressing tumours. Despite differences in VEGF expression and perfusion, no significant alterations in Ktrans or ve were observed between the 3 tumour groups.

     
10:42 393.  

Microscopic Morphology of Brain and Bone Metastases in a Rat Breast Cancer Model by Diffusion MRI
Matthew D. Budde1, Molly Resnick1, Eric Gold1, E Kay Jordan1, Joseph A. Frank1

1Radiology and Imaging Sciences, National Institutes of Health, Bethesda, MD, United States

The apparent diffusion coefficient (ADC) measured with diffusion MRI has shown promise as an early marker of therapeutic response in malignant gliomas.  However, metastatic tumors are the primary cause of intracranial tumors, and it is unknown whether brain metastases exhibit similar diffusion characteristics as the preclinical implanted brain tumor model.  A rat model of metastatic breast cancer was used to examine the diffusion properties of brain and bone metastases.  The results demonstrate that ADC is sensitive to the microscopic growth patterns of brain and bone metastases that result from their differing microenvironments.

     
10:54 394

Vessel Size Index (VSI) MRI in Solid Tumours - Validation with Microvascular Corrosion Casts
Jake Samuel Burrell1, Jane Halliday2, Simon Walker-Samuel3, John C. Waterton2, Philip J. Withers4, Robert S. Bradley4, Jessica Boult1, Yann Jamin1, Lauren C. Baker1, Simon P. Robinson1
1
The Institute of Cancer Research, Sutton, Surrey, United Kingdom; 2AstraZeneca, Manchester, United Kingdom; 3UCL, London, United Kingdom; 4School of Materials, University of Manchester, Manchester, United Kingdom

Susceptibility contrast MRI vessel size index (VSI) derived vessel diameters were compared with vessel diameters measured from vascular corrosion casts of the same SW1222 colorectal tumours. Good agreement was found between the MRI and vascular corrosion cast derived vessel sizes, reported as 38 ▒ 6Ám and 39 ▒ 2Ám respectively. This work helps to qualify non-invasive MRI vessel size measurements with appropriate histology.

     
11:06 395.  

Gas Challenge-Blood Oxygen Level Dependent (BOLD) MRI in Monitoring Tumor Angiogenesis of a Rodent Novikoff Hepatoma Model
Yang Guo1, Ning Jin1,2, Rachel Klein1, Guang-Yu Yang3, Reed Omary1,2, Andrew Larson1,2
1
Department of Radiology, Northwestern University, Chicago, IL, United States; 2Department of Biomedical Engineering , Northwestern University, Chicago, IL, United States; 3Department of Pathology, Northwestern University, Chicago, IL, United States

Angiogenesis is fundamental for tumor growth, invasion and metastasis. Non-invasive methods to monitor tumor neo-vascular changes during tumor progression and/or in response to anti-angiogenic therapy may be critical. The purpose of our study was to investigate the relationship between gas-challenge (GC)-BOLD response and degree of tumor angiogenesis during tumor progression in rodent hepatoma model. A positive correlation was found between GC-BOLD response and tumor microvessel density and a negative correlation was between GC-BOLD response and tumor size. GC-BOLD MRI may offer the potential to serve as a non-invasive method for evaluating angiogenesis and monitoring anti-angiogenic therapy response in hepatic tumors.

     
11:18 396.

Hypoxia Detected with Phase Contrast MRI Is an Early Event in Micrometastatic Breast Cancer Development in the Rat Brain
Matthew D. Budde1, Eric Gold1, E Kay Jordan1, Melissa Smith-Brown1, Joseph A. Frank1
1Radiology and Imaging Sciences, National Institutes of Health, Bethesda, MD, United States

Hypoxia is an important prognostic factor in tumor growth and therapeutic response and is a driving force in the angiogenic cascade. Blood oxygen level dependent (BOLD) MRI contrast is related to the oxygenation status of tumors, but brain tumors can have significant edema that can complicate measurements of magnetic field inhomogeneities caused by deoxygenated hemoglobin.  The purpose of this study was to determine if phase contrast MRI was more sensitive to vascular abnormalities than BOLD MRI in a rat model of breast cancer metastases to the brain and whether these changes were indicative of hypoxic changes that precede angiogenesis.

     
11:30 397

Hypoxic Environments Disrupt Collagen I Fibers and Macromolecular Transport
Samata Kakkad1, Marie-France Penet1, Meiyappan Solaiyappan1, Arvind Pathak1, Venu Raman1, Kristine Glunde1, Zaver M. Bhujwalla1
1
JHU ICMIC Program, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, United States

Solid tumors are characterized by hypoxic environments.  Hypoxia stimulates the gene expression of a cluster of hydroxylases used for collagen fiber formation.  Hypoxic environments in tumors may lead to abnormal collagen deposits either by cancer cells or by fibroblasts within the tumor stroma.  In normal tissue collagen fibers direct interstitial fluid into lymphatic channels.  In tumors these fibers may not be structured for efficient flow of fluid, especially in hypoxic areas.  Our purpose was to understand the role of hypoxia in modifying macromolecular fluid transport using MRI, and collagen fiber distribution using second harmonic generation microscopy.

     
11:42 398

High-Resolution Imaging of Non-Small Cell Lung Cancer in a Mouse Model of Brain Metastasis
Hye-Won Kang1, Geun-Ho Im2, Jung Hee Lee2, Alexei A. Bogdanov1
1
Radiology, University of Massachusetts Medical School, Worcester, MA, United States; 2Radiology, Samsung Medical Center, Seoul, Korea, Republic of

A combination of anti-human EGFR antibody-enzyme conjugates and a paramagnetic substrate has been designed for EGFR MR imaging for detecting NSCLC in vivo. The specificity of conjugate to the tumors and the sensitivity to EGFR expression in vivo were examined. The experimental group of mice after the injection of pretargeting conjugates followed by the injection of the paramagnetic substrate showed a strong enhancement of the tumor. The increase of MR signal was higher and the peak of enhancement was reached earlier than in the control group. The higher signal around the tumor periphery was retained for up to 24 h.

     
11:54 399

Theranostic Imaging of Metastatic Disease
Zhihang Chen1, Marie-France Penet1, Sridhar Nimmagadda1, Cong Li1, Sangeeta Ray1, Paul Winnard1, Dmitri Artemov1, Kristine Glunde1, Martin G. Pomper1, Zaver M. Bhujwalla1
1JHU ICMIC Program, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, United States

There is a compelling need to find effective treatments for metastatic disease, as it typically becomes refractory to treatment.  We are developing targeted nanoplexes carrying multimodality imaging reporters together with small interfering RNA (siRNA) and a prodrug enzyme for theranostic imaging of metastatic prostate cancer.  Down-regulation of specific pathways using siRNA provides unique opportunities to target cancer cells selectively while sparing normal tissue.  The targeted nanoplexes we develop will allow us to deliver siRNA together with a prodrug enzyme, under image guidance for developing theranostic imaging of metastatic prostate cancer.

     
12:06 400.

In Vivo Detection of PI3K Pathway Inhibition by Hyperpolarized 13C MRSI at 14 Tesla
Myriam Marianne Chaumeil1, Subramanian Sukumar1, Humsa Venkatesh1, Christopher Ward1, Kristen R. Scott1, Tomoko Ozawa2, C David James2, John Kurhanewicz1, Daniel B. Vigneron1, Sarah J. Nelson1, Sabrina M. Ronen1

1Radiology, UCSF, San Francisco, CA, United States; 2Brain Tumor Research Center, UCSF, San Francisco, CA, United States

In vivo  inhibition of the PI3K pathway by Everolimus was evaluated using hyperpolarized (HP) 13C MRSI in subcutaneous tumors in mice at 14 Tesla. Whereas lactate-to-pyruvate ratio was increased in control animals, this ratio was decreased by 78% and 35% in treated animals relative to controls after 2 and 7 days, respectively. The drop in lactate-to-pyruvate ratio following Everolimus treatment is in line with the findings in treated cells and likely indicates a decrease in LDH activity in treated tumors.  This preliminary in vivo  study demonstrates the likely value of HP 13C studies of pyruvate for noninvasive monitoring PI3K inhibition.

     
12:18 401

In Vivo P31 NMR Demonstrates Reduced ATP Synthesis Rate in Skeletal Muscle in a Murine Cancer Cachexia Model
Dionyssios Mintzopoulos1,2, Cibely Cristine Fontes de Oliveira3, Jianxin He4, Caterina Constantinou4, Michael N. Mindrinos5, Laurence G. Rahme4, Josep M. Argiles3, A. Aria Tzika1,2

1NMR Surgical Laboratory, Department of Surgery, Massachusetts General Hospital and Shriners Burns Institute, Harvard Medical School, Boston, MA, United States; 2Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Athinoula A. Martinos Center for Biomedical Imaging, Boston, MA, United States; 3Cancer Research Group, Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain; 4Molecular Surgery Laboratory, Department of Surgery, Massachusetts General Hospital and Shriners Burns Institute, Harvard Medical School, Boston, MA, United States; 5Stanford Genome Technology Center, Department of Biochemistry, Stanford University School of Medicine, Palo Alto, CA, United States

We employed in vivo P31 NMR on intact mice, in a mouse cancer (Lewis lung carcinoma) cachexia model. We examined ATP synthesis rate and the gene expression of key regulatory genes, involved in regulation of skeletal muscle metabolism. Our in vivo NMR results that showed significantly reduced rate of ATP synthesis rate were cross-validated with genomic analysis, showing aberrant expression levels in key regulatory genes. Our findings implicate that reduction in ATP synthesis rate is linked to mitochondrial dysfunction leading to wasting of skeletal muscle in cancer cachexia.

     

 

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