Cancer Animal Models
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Thursday May 12th
Room 518-A-C  10:30 - 12:30 Moderators: Yuen-Li Chung and Robert J. Gillies

10:30 551.   Imaging of glucose uptake in breast tumors using non-labeled D-glucose 
Kannie Wai Yan Chan1, Michael C McMahon2,3, Guanshu Liu4,5, Yoshinori Kato4, Zaver Bhujwalla4, Dmitri Artemov4, and Peter Christiaan van Zijl1,5
1Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States, 2Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, 3F.M. Kirby Research Center, Kennedy Krieger Research Insitute, Baltimore, MD, United States, 4Johns Hopkins University School of Medicine, 5kennedy Krieger Research Insitute

PET studies of 18-fluorodeoxyglucose (18FDG) uptake can detect abnormal glucose uptake in tumors, which is an important biomarker for staging of cancer and assessing the efficacy of therapies. Using xenografts of a highly aggressive and metastatic human breast cancer cell line (MDA-MB-231) in mice, we show that glucose uptake can be imaged using non-labeled D-glucose intra-venous infusion through detection with chemical exchange saturation transfer (CEST). Magnetization transfer ratio asymmetry spectra showed a typical glucose line shape appearance. Glucose uptake reflects the combined effects of perfusion, leakage into extravascular extracellular space (EES), and metabolism.

10:42 552.   HGF/SF-Induced Ca+2 Intake to Breast Tumor Cells ľ a Manganese Enhanced MRI Study 
Galia Tsarfaty1, Ilan Tsarfaty2, Sari Natan2, Eli Konen1, and Tammar Kushnir1
1Dept. of Diagnostic Imaging, MRI Unit, The Chaim Sheba Medical Center, Tel Hashomer, Israel, 2Department of Human Microbiology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Met tyrosine kinase receptor and its ligand hepatocyte growth factor/scatter factor (HGF/SF) play an important role in a variety of human cancers. HGF/SF induce diverse metabolic alteration including increase in calcium intake to the tumor cells. MEMRI enables monitoring functional cellular Ca+2 intake, via in-vivo mapping of Mn+2 ions that enter the cells due to the permeability of voltage-gated calcium channels. Using MEMRI we demonstrate that HGF/SF enhances intake of Mn+2 to Met-dependent murine mammary tumors that is inhibited by the Ca+2 blocker Verapamil. Thus HGF/SF MEMRI may serve as a Met functional molecular imaging modality for monitoring anti-Met treatment.

10:54 553.   Mapping of Oxygen By Imaging Lipids relaxation Enhancement (MOBILE): Application to Changes in Tumor Oxygenation of Mammary Cancer Models 
Julie Magat1, Elif Ozel1, ValÚrie Marchand1, Caroline Bouzin2, Olivier Feron2, Benedicte F Jordan1, and Bernard Gallez1
1Louvain Drug Research Institute, Biomedical Magnetic Resonance Research Group, University of Louvain, Brussels, B, Belgium, 2Pole of Pharmacotherapy, University of Louvain, Brussels, Belgium

Dissolved oxygen acts as a T1-shortening paramagnetic contrast agent. We suggest here to monitor the changes in R1 of the lipid peak instead of water to exploit the higher solubility property of oxygen in lipids. For this purpose, we developed a method to map variations in oxygenation based on the changes in the relaxation properties of the tissue lipids. The method was applied in vitro for calibration and in vivo lipids in vivo in mammary cancer models during breathing challenges. The measurement of R1 in lipids offer an increased sensitivity compared to previously described techniques that measure the variations of R1 in the water component

11:06 554.   Histological Verification of Oxygen-Enhanced MRI for Detection of Hypoxia 
Inna V Linnik1,2, Marietta Scott3, Neil Woodhouse3, John C Waterton1,3, Helen Young3, Carsten Liess3, HervÚ Barjat3, Jose Ulloa3, Cassandra L Hodgkinson4, Timothy Ward4, Caroline Dive4, Darren Roberts4, Josephine H Naish1,2, and Geoffrey J M Parker1,2
1Imaging Science and Biomedical Engineering, School of Cancer and Enabling Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom,2Biomedical Imaging Institute, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom, 3Imaging, Translational Sciences, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom, 4Paterson Institute for Cancer Research, Manchester, United Kingdom

Dynamic oxygen-enhanced (OE) MRI monitors the tissue change in longitudinal relaxation rate (R1) when switching from breathing air to 100 % O2. It was shown using dynamic OE-MRI that some tumour regions demonstrate an R1 increase under O2 inhalation consistent with the delivery of paramagnetic molecular oxygen via the blood plasma. However, our recent studies have demonstrated that tumours also exhibit regions that paradoxically reduce R1 with the switch to O2. Here we provide a theoretical explanation of this difference in response between regions and demonstrate that OE-MRI may provide a new non-invasive method for quantifying hypoxic extent in tumours.

11:18 555.   In vivo dynamic contrast enhanced MRI and histopathological assessment of tumor angiogenesis in luminal-like and basal-like breast cancer xenografts 
Else Marie Huuse1, Siver Andre Moestue1, Tone Frost Bathen 1, Anna Bofin2, Gunhild Mari MŠlandsmo3, Lars A Akslen4, Olav Engebraaten3,5, and Ingrid S Gribbestad1
1Department of Circulation and Medical Imaging, Norwegian University of Science and Tehcnology (NTNU), Trondheim, Norway, 2Department of Laboratory Medicine, Children's and Women's Health, NTNU, Trondheim, Norway, 3Department of Oncology and Department of Tumor Biology, Oslo University Hospital, Oslo, Norway, 4The Gade Institute, Section for Pathology, University of Bergen, Bergen, Norway, 5Institute for Clinical Medicine, University of Oslo, Oslo, Norway

Two new breast cancer xenograft models, reflecting luminal-like (MAS98.06, ER+, low growth rate) and basal-like (MAS98.12, ER-, high growth rate) subgroups, have recently been established by direct transplantation of primary tumor tissue. The differences in tumor vasculature and angiogenesis, and the effect of tumor volume were investigated using DCE-MRI and histopathological measures. The results showed a significantly higher Ktrans, vp and vascular proliferation index in the aggressive basal-like tumors compared to the luminal-like tumors. Additionally, the results showed a positive correlation between vp and micro vessel density and a negative correlation between vp and hypoxia and between Ktrans and hypoxia.

11:30 556.   Dual PI3K/mTOR Inhibition Induces Structural Changes in Tumor Vasculature Assessed by Vessel Size Imaging 
Shelby Katherine Wyatt1, Sharon E Ungersma1, Jason R Oeh2, Calvin Ho1, Tim C Cao1, Hartmut Koeppen3, Lori S Friedman2, Deepak Sampath2, and Richard A. D. Carano1
1Biomedical Imaging, Genentech, Inc, South San Francisco, CA, United States, 2Translational Oncology, Genentech, Inc, South San Francisco, CA, United States,3Pathology, Genentech, Inc, South San Francisco, CA, United States

This study aims to elucidate the role of PI3K and mTOR inhibition on vascular structure using an in-vivo multispectral vessel size index (VSI) MRI approach and ex-vivo micro-computed tomography (micro-CT) angiography. In-vivo multispectral VSI MRI demonstrated significant tumor growth suppression, reduced Q, increased VSI and decreased blood volume, while ex-vivo micro-CT angiography demonstrated decreased vascular density following PI3K/mTOR inhibition. These results are consistent with the loss of small vessels and help elucidate the effects of inhibiting the PI3K and mTOR pathways on vascular structure.

11:42 557.   Genetic manipulation of proton transport mechanisms generates modulations of intra and extracellular pH and growth characteristics in tumors  -permission withheld
Norbert W. Lutz1, Johanna Chiche2, Yann LeFur1, Frederic Frassineti3, Laurent Daniel3, Jacques Pouyssegur2, and Patrick J. Cozzone1
1Dept. of Medicine La Timone, Marseille, France, 2Institute of Developmental Biology and Cancer, University of Nice, Nice, France, 3Dept. of Pathology La Timone, Marseille, France

The excessive production of lactic acid through glycolysis in tumors can in principle be exploited for cancer treatment by using drugs to decrease intracellular pH (pHi), thus inducing cell death. We now present results obtained for fibroblasts genetically manipulated to modulate two proton transport mechanisms, the sodium/proton exchanger, NHE1, and the monocarboxylate transporter, MCT4. pHi and extracellular pH (pHe) were determined simultaneously in vivo in a nude mouse model, in conjunction with tumor morphology, tumor growth and necrosis, and were complemented with histological data. Our results validate the suggested treatment concept based on manipulating pH regulation via MCT4 and NHE1.

11:54 558.   Metabolic Profiling of Primary and Recurrent Mammary Gland Tumors in an Inducible Her2/neu Breast Cancer Mouse Model Using 1H MRS 
Dania Daye1, James Alvarez2,3, Suzanne Wehrli4, Mitchell Schnall5, and Lewis Chodosh2,3
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States, 2Department of Cancer Biology, University of Pennsylvania, 3Abramson Family Cancer Research Institute, University of Pennsylvania, 4Nuclear Magnetic Resonance Core Facility, Children's Hospital of Philadelphia, 5Department of Radiology, University of Pennsylvania

Breast cancer is the most commonly diagnosed malignancy in women and is the second leading cause of cancer-related death in the female population worldwide. Cancer recurrence represents the principal cause of death from this disease. To dissect the mechanisms implicated in recurrence, our lab has developed an inducible transgenic mouse model that accurately reproduces key features of the natural history of human breast cancer progression: primary tumor development, tumor dormancy and recurrence. The goal of this study was to investigate the role of 1H MRS metabolic profiling as a potential breast cancer progression marker using this model.

Rossella Canese1, Giorgia Nardo2, Marika Crescenzi2, Egidio Iorio1, and Stefano Indraccolo2
1Istituto Superiore di SanitÓ, Rome, RM, Italy, 2Istituto Oncologico Veneto -IRCCS, Padova, Italy

We investigate by in vitro and in vivo 1H MRS two experimental models of ovarian cancer with different glycolytic phenotypes based on measurements of glucose consumption and lactate production rates in vitro as well as assessment of expression levels of glycolysis-associated genes. Metabolic differences have been detected between the two cell lines as well as the two in vivo models, notably in the lactate content. These differences were associated with tumour morphology and internal composition detected by MRI and ADC. These results could highlight a link between the Warburg effect and the response to anti angiogenic therapy in ovarian cancer.

12:18 560.   Magnetic Resonance Spectroscopic Imaging of Orthotopic Ovarian Cancer 
Marie-France Penet1, Kristine Glunde1, Dmitri Artemov1, Franca Podo2, and 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,2Department of Cell Biology and Neurosciences, Section of Molecular and Cellular Imaging, Istituto Superiore di SanitÓ, Rome, Italy

Epithelial ovarian cancer remains the leading cause of death from gynecologic malignancy among women in developed countries. New therapeutic strategies evaluated with relevant preclinical models are urgently needed to improve survival rates. Here we have characterized orthotopically implanted ovarian tumors with in vivo MRI and MR spectroscopic imaging (MRSI), with the ultimate purpose of determining the effects of choline kinase targeting on tumor growth, metastasis occurrence, and ascites formation. Total choline and phosphocholine were significantly higher in orthotopic compared to subcutaneous tumors, demonstrating the importance of the inoculation site in the metabolic phenotype.