Cancer - Cells, Animals & Metabolism
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Tuesday 8 May 2012
Plenary Hall  10:00 - 12:00 Moderators: E. Jim Delikatny, Arvind P. Pathak

10:00 0175.   31P Magnetic Resonance Spectroscopy study on the effects of stably silencing the glycerophosphocholine phosphodiesterase GDPD5 in a breast cancer model in vivo
Jannie P. Wijnen1,2, Lu Jiang1, Tiffany R. Greenwood1, Maria D. Cao3, Balaji Krishnamachary1, Dennis W.J. Klomp2, and Kristine Glunde1
1Johns Hopkins University In Vivo Cellular and Molecular Imaging Center,Russell H. Morgan Department, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States, 2Department of Radiology, University Medical Centre Utrecht, Utrecht, Netherlands, 3Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trontheim, Norway

In the present study, we stably silenced glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5) using short hairpin RNA (shRNA) against GDPD5 and investigated the effects of this stable GDPD5 silencing in a breast tumour xenograft model with 31P Magnetic Resonance Spectroscopy (MRS). Stable silencing of the GDPD5 gene caused an increase in glycerophosphocholine (GPC) and a decrease in free choline in the tumour. This can be explained by the reduction GDPD5 expression in the GDPD5-silenced tumours, which leads to less degradation of GPC into free choline and glycerol-3-phosphate as GDPD5 confers GPC-PDE activity. We also observed an increase in phosphoethanolamine, which could be caused by phosphorylation of ethanolamine by choline and/or ethanolamine kinase as a compensatory mechanism to maintain high levels of phosphomonoesters in the cells.

10:12 0176.   
Treatment with the MEK inhibitor U0126 induces a decrease in hyperpolarized pyruvate to lactate conversion in breast but not in prostate cancer cells
Alessia Lodi1, Sarah M Woods1, and Sabrina M Ronen1
1University of California San Francisco, San Francisco, California, United States

To date, response to anti-neoplastic treatment has been associated with a drop in 13C MRS-detectable hyperpolarized pyruvate to lactate conversion. Here we assessed the effect of treatment with the MEK inhibitor U0126 in prostate and breast cancer cells. Drug action resulted in a drop in the pyruvate to lactate conversion in breast cancer cells, but an increase in prostate cancer cells. This effect is likely mediated by an increase in intracellular lactate and LDH expression and activity in both cancer models and a concurrent drop in MCT1 expression in breast, but not in prostate cancer cells.

10:24 0177.   
Assessment of Glutamine Metabolism in Mammary Tumor Recurrence Using 13C MRS
Dania Daye1,2, Suzanne Wehrli3, George Belka4,5, Anthony Mancuso6, Chris Sterner4,5, Mitchell Schnall6, and Lewis Chodosh4,5
1Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States,2Bioengineering Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania, United States, 3Children's Hospital of Philadelphia, 4Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, 5Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, 6Department of Radiology, Perelman School of Medicine at the University of Pennsylvania

Tumor recurrence represents the principal cause of death from breast cancer. Despite being a critical clinical problem, little is known about the cellular and molecular mechanisms underlying tumor recurrence. Our laboratory has developed an inducible transgenic mouse model that accurately reproduces key features of the natural history of human breast cancer progression including tumor recurrence. Dysregulated metabolism has been shown to be key feature of tumorigenesis. To date, very little is know about the association between changes in metabolism and cancer recurrence. In this study, we investigate the role of 13C-glutamine as a potential breast cancer progression marker using MRS.

10:36 0178.   
Mining Lipid Signatures in a Breast Tumor Model by Combining Magnetic Resonance Spectroscopic Imaging and Mass Spectrometric Imaging
Lu Jiang1, Kamila Chughtai2, Tiffany Greenwood1, Gert Eijkel2, Ron Heeren2, and Kristine Glunde1
1JHU ICMIC Program, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institute, Baltimore, Maryland, United States, 2FOM-Institute AMOLF, Netherlands

The intensity of the total choline (tCho) signal in magnetic resonance spectroscopic imaging (MRSI) of tumors is spatially heterogeneous. In vivo H1 MRSI with the spectral resolution to resolve the components of the tCho signal and its membrane precursors is currently unavailable. Mass spectrometry imaging (MSI) of histologic tumor sections is able to detect thousands of molecules from the tissue surface. We have investigated the correlations between tCho, lipid metabolites, and membrane phospholipids in a human breast cancer model by combining in vivo MRSI with ex vivo MSI, which identified specific membrane phosphatidylcholine species that are decreased in high tCho regions.

10:48 0179.   Molecular Correlates to in vivo Hyperpolarized [1-13C] Dehydroascorbate Reduction
Victor Sai1, Kayvan R. Keshari1, Romelyn Delos Santos1, John Kurhanewicz1, and David M. Wilson1
1Radiology and Biomedical Imaging, University of California, San Francisco (UCSF), San Francisco, CA, United States

In vivo MRSI studies using HP [1-13C] dehydroascorbate (DHA) in a transgenic model of prostate cancer (TRAMP) show rapid uptake of DHA and reduction to Vitamin C. We hypothesized that this is secondary to increased uptake via GLUT-type transporters and elevated intracellular glutathione levels. Gene expression analysis demonstrated elevated GLUT3 but decreased GLUT1 expression. Thioredoxin reductase was also found to be elevated. Intracellular glutathione levels were increased in TRAMP tumor relative to normal prostate, and mercury orange staining for non-protein thiols was also increased in TRAMP tumor compared to normal control.

11:00 0180.   
Quantitative Biomarkers of Cancer from Metabolic Activity Decomposition using Stimulated-Echoes and Hyperpolarized Carbon-13 MR
Christine M Leon1,2, Peder EZ Larson1, Adam B Kerr3, Robert Bok1, John M Pauly3, John Kurhanewicz1, and Daniel B Vigneron1
1Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States, 2UC Berkeley | UCSF Graduate Group in Bioengineering, University of California, Berkeley and University of California, San Francisco, San Francisco, CA, United States,3Department of Electrical Engineering, Stanford University, Stanford, CA, United States

We propose a new and robust method for quantification of dynamic data. Using Metabolic Activity Decomposition, we investigated real-time conversion parameters as biomarkers of cancer. Ex vivo enzyme experiments validated the technique, allowing for direct observation of real-time conversion, which can only be due to the LDH enzyme. Conventional modeling yields four unknowns but only two equations, an underdetermined system of equations. Using Metabolic Activity Decomposition, twice the amount of information can be obtained from a same acquisition providing a well-conditioned system. Moreover, fitting in vivo data with MAD-STEAM yielded KPyrright arrowLac values that robustly distinguished tumor versus normal (p-value=0.009)

11:12 0181.   
Imaging of Prostate Cancer Metabolic Heterogeneity with CEST and MT MRI
Kejia Cai1, He N Xu2, Anup Singh1, Mohammad Haris1, Ravinder Reddy1, and Lin Z Li2
1CMROI, Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States, 2Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States

Here we report the preliminary data on chemical exchange saturation transfer (CEST) & magnetization transfer (MT) magnetic resonance imaging (MRI) and redox scanning of two aggressive human prostate tumor lines (PC-3 and DU-145) xenografted in athymic nude mice. The results obtained by these methods appeared to be consistent with all showing higher level of heterogeneity in DU-145 tumors than in PC-3 tumors at this stage of tumor progression. MT and CEST MRI method could serve as a surrogate metabolic imaging biomarkers for redox imaging of tumor metastatic potential.

11:24 0182.   
Quantitative imaging of tumour glucose uptake using glucoseCEST: comparison with 18F-FDG autoradiography
Simon Walker-Samuel1, Rajiv Ramasawmy1, Francisco Torrealdea2, Marilena Rega2, Peter Johnson3, Vineeth Rajkumar3, Simon Richardson1, Dave Thomas2, Barbara Pedley3, Mark F. Lythgoe1, and Xavier Golay2
1Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom, 2Institute of Neurology, University College London, United Kingdom, 3Cancer Institute, University College London, United Kingdom

We have recently developed a technique named glucoseCEST that enables the accumulation of exogeneously administered, unlabelled glucose to be detected in tumours. Here we present a technique that allows glucoseCEST measurements to be converted to an absolute glucose concentration. This approach is evaluated in two colorectal tumour xenograft models (SW1222 and LS174T) and compared with 18F-FDG autoradiography. Significant differences in uptake were observed between tumour cell lines in both FDG and glucose measurements. Median tumour glucose and FDG concentrations were also significant correlated. These results suggest that glucoseCEST and 18F-FDG autoradiogaphy (and therefore FDG-PET) may provide corresponding information.

11:36 0183.   DCE-MRI and ICP-MS evaluation of biodistribution of contrast agents and chemotherapeutic agents to gliomas with a new pharmacological approach in F98 glioma cells implanted Fischer rats
Jerome Cote1, Luc Tremblay2, David Fortin3, Fernand Gobeil4, and Martin Lepage2
1CIMS, Université de Sherbrooke, Sherbrooke, Quebec, Canada, 2CIMS, Université de Sherbrooke, Sherbrooke, Québec, Canada, 3Chirurgie, Université de Sherbrooke, Sherbrooke, Québec, Canada, 4Pharmacologie, Université de Sherbrooke, Sherbrooke, Québec, Canada

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with intravenous Gd-DTPA or Gadomer was used to monitor the selective increase of blood-brain barrier permeability at the tumor of glioma-bearing rats, induced by a novel pharmacological approach. Our results indicate that the biodistribution of both contrast agents within rat gliomas and surrounding brain tissues was doubled. This was confirmed by a two-fold increase (versus vehicle) of concentrations of Gd-DTPA and Carboplatin in tumor and peripheral tissues measured by inductively coupled plasma mass spectrometry (ICP-MS).

11:48 0184.   Tumor drug resistance and sodium-diffusion MRI in rat glioma model
Victor D. Schepkin1, Thomas Morgan2, Fabian Calixto-Bejarano3, Petr L. Gor'kov3, William Brey3, Chunqi Qian4, Shannon Gower-Winter5, Manuel Ozambela2, and Cathy Levenson2
1CIMAR/MRI, NHMFL/FSU, Tallahassee, FL, United States, 2College of Medicine, FSU, Tallahassee, FL, United States, 3CIMAR/NMR, NHMFL/FSU, Tallahassee, FL, United States, 4NINDS, NIH, Bethesda, MD, United States, 5College of Medicine, FSU, Tallahassee, United States

During cancer progression, tumors develop mechanisms permitting them to obstruct chemotherapeutic interventions. To formulate individualized treatments it is important to provide a prompt and noninvasive assessment of tumor resistance. Mitochondria play a central role in ATP production, apoptosis and are associated with changes in tumor resistance. We hypothesize that the energy metabolism shift due to increased tumor resistance can affect sodium homeostasis, and MRI has the potential to reflect changes in tumor resistance. The results demonstrate that alterations in tumor resistance can be detected prior to treatment by sodium and diffusion MRI, allowing individualized adjustments to prevent ineffective treatments.