ISMRM 24th Annual Meeting & Exhibition • 07-13 May 2016 • Singapore

Scientific Session: Cancer Metabolism & Metabolomics

Thursday Thursday, May 12, 2016
Room 331-332
10:30 - 12:30
Moderators: Tone Frost Bathen, Kristine Glunde

Metabolic profiling of the tumor interstitial fluid using NMR: contribution of breast cancer subtypes and VEGF overexpression
Santosh K Bharti1, Louis Dore-Savard1, Aleksander S Popel2, and Zaver M Bhujwalla1
1The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, School of Medicine, Division of Cancer Imaging Research, Baltimore, MD, United States, 2Department of Biomedical Engineering, Johns Hopkins University, School of Medicine, Systems Biology Laboratory, Baltimore, MD, United States
Interstitial fluid (IF) is a key component of the tumor microenvironment (TME) that encompasses the secretome and holds the key to several of the phenotypic traits of cancer.  Modern analytical methods like 1H MR spectroscopy (MRS) allow for comprehensive metabolic characterization of tissue, cell, and bio-fluids content to better understand the TME and cancer metabolism. Here, for the first time, we have metabolically characterized TIF from triple negative and estrogen receptor (ER)-positive human breast tumor xenografts with or without VEGF overexpression and detected significant differences between tumor types and with VEGF overexpression.    

NMR-based fecal metabolomics fingerprinting as predictors of earlier diagnosis in patients with colorectal cancer
Yan Lin1, Changchun Ma2, Zhening Wang1, Zhiwei Shen1, and Renhua Wu1
1Radiology Department, Second Affiliated Hospital, Shantou University Medical College, Shantou City, China, People's Republic of, 2Radiation Oncology, Cancer Hospital, Shantou University Medical College, Shantou City, China, People's Republic of
Colorectal cancer (CRC) is a growing cause of mortality in developing countries, warranting investigation into its earlier detection for optimal disease management.This study aimed to validate the ability of NMR-based fecal metabolomics fingerprinting as predictors of earlier diagnosis in CRC patients.Our findings revealed that the fecal metabolic profiles of healthy controls can be distinguished from CRC patients, even in the early stage (stage I/II), highlighting the potential utility of NMR-based fecal metabolomics fingerprinting as predictors of earlier diagnosis in CRC patients.

NMR metabolomics of biofluids for early diagnosis of brain metastasis
James R Larkin1, Alex M Dickens2, Timothy D W Claridge3, Daniel C Anthony2, and Nicola R Sibson1
1CRUK and MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom, 2Department of Pharmacology, University of Oxford, Oxford, United Kingdom,3Department of Chemistry, University of Oxford, Oxford, United Kingdom
Secondary tumours, or metastases, in the brain are currently detected at a late stage by gadolinium-enhanced MRI. We used mouse models of brain metastases, coupled with high resolution NMR of urine to identify characteristic patterns of metabolites in tumour-bearing animals. A model with a tumour cells implanted directly in the brain showed sensitive and specific detection at day 5 with increasing separation at later time points. Models injecting cells into the heart or venous circulation give rise to differing systemic and central nervous system (CNS) tumour burdens. Metabolite patterns allow identification of these animals with a heavy CNS tumour burden.

Hyperpolarized [1-13C]-Pyruvate Differentiates Distinctive Molecular Phenotypes in Diffuse Intrinsic Pontine Gliomas
Ilwoo Park1, Rintaro Hashizume2, Joanna Phillips3,4, Sabine Mueller3,5, and Sarah Nelson1,6
1Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United States, 2Neurological Surgery, Northwestern University, Chicago, IL, United States, 3Neurological Surgery, University of California San Francisco, San Francisco, CA, United States, 4Pathology, University of California San Francisco, San Francisco, CA, United States, 5Pediatrics, University of California San Francisco, San Francisco, CA, United States, 6Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, United States
Diffuse intrinsic pontine gliomas (DIPGs) are one of the most difficult pediatric cancers to treat. This study investigated the feasibility of 13C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized (HP) [1-13C]pyruvate for differentiating molecular characteristics of DIPGs. Differences in the lactate signal that were observed in two distinct biopsy-originated orthotopic DIPG tumors were associated with changes in the levels of LHDA and HIF-1α activity. This suggests that the non-invasive characterization of DIPGs using this new neuroimaging method may be helpful for assessing treatment response and tumor progression. 

Glutamatergic production of 2HG in IDH1-mutant tumor cells is retained by glutamate import in glutamine-free medium
Tom Peeters1, Vincent Breukels1, Krissie Lenting2, Sanne van Lith2, Arno van Rooij3, Remco Molenaar4, William Leenders2, and Arend Heerschap1
1Radiology and Nuclear Medicine, Radboud university medical center, Nijmegen, Netherlands, 2Pathology, Radboud university medical center, Nijmegen, Netherlands, 3Laboratory Medicine, Radboud university medical center, Nijmegen, Netherlands, 4Cell Biology and Histology, Academic Medical Center, Amsterdam, Netherlands
This study demonstrates that in IDH1-mutant tumor cells the pool of oncometabolite 2HG is predominantly replenished by αKG precursors glutamine and glutamate, and to a lesser extent by glucose-derived metabolites. Furthermore, we show that 2HG production is not significantly decreased when total the pool of glutamine and glutamate drops, which occurs upon substitution of glutamine by glutamate in the culture medium.

Differential Metabolism of Glucose and Acetate in Mitochondria of Early Stage Breast Cancer In Vivo - Permission Withheld
Elizabeth Maher1, Kumar Pichumani2, Venetia Sarode3, Tomoyuki Mashimo1, Manoj Cheriyan1, Vamsidhara Vemireddy1, Barbara Haley1, Dean Sherry2, Roshni Rao4, Craig Malloy2, and Robert Bachoo5
1Internal Medicine, UT Southwestern Medical Center, Dallas, TX, United States, 2Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX, United States, 3Pathology, UT Southwestern Medical Center, Dallas, TX, United States, 4Surgery, UT Southwestern Medical Center, Dallas, TX, United States, 5Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX, United States
Metabolic reprogramming of bioenergetic substrate utilization was shown in primary and metastatic brain tumors.  Whether the use of substrates other than glucose to fuel the citric acid cycle is a property of cancer cell growth in the brain or a fundamental property of a transformed cell is not known.  To address this question we studied early stage breast cancer patients using infusion of 13C-glucose or 13C-acetate during initial surgery.  13C-NMR spectra of resected tumors show that acetate but not glucose is oxidized in the citric acid cycle, suggesting that acetate may contribute to energy production in these early stage cancers.

Simultaneous imaging and 1H spectroscopy of small volume (1 µl) intracerebral microdialysate in healthy and glioblastoma-bearing rats using highly sensitive micro-coils
Silvia Rizzitelli1, Stefan Glöggler1, Noël Pinaud1, Gerard Raffard1, Veronique Bouchaud1, Vanessa Zhendre1, Stephane Sanchez1, Alan Wong2, and Yannick Cremillieux1
1Centre de Resonance Magnétique des Systemes Biologiques, University of Bordeaux, Bordeaux, France, 2NIMBE/LSDRM, CEA-Saclay, Gif-sur-Yvette, France
The challenge of this study was to investigate the ability of a custom-made 1H microsolenoidal coil operating at 7T, with an inner volume of 1 μL, of visualizing the on-line metabolism of brain metabolites through the use of a microdialysis catheter, carried out with the complementarity of MRI and MRS techniques. 1H-MR spectra of in vitro (human gliobastoma cells) and in vivo (healthy and glioblastoma-bearing rats) were acquired every 3.50 minutes to monitor the real-time variations of metabolites concentration, after injection of 13C labelled compunds. 

Molecular Effects of the Chemotherapeutic Drug Doxorubicin on Choline Phospholipid Metabolism of Breast Cancer Cells
Menglin Cheng1, Asif Rizwan1, Zaver M. Bhujwalla1,2, Lu Jiang1, and Kristine Glunde1,2
1The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, United States, 2The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
This study shows that the widely used chemotherapeutic drug doxorubicin increases the 1H or 31P MRS detectable glycerophosphocholine (GPC) concentration, while decreasing the phosphocholine (PC) concentration in human MCF-7 and MDA-MB-231 breast cancer cell lines. This GPC increase and PC decrease was caused by doxorubicin-induced decreases in the expression of the GPC-phosphodiesterase GDPD6, choline kinase α, and phospholipase D1. GDPD6 silencing was able to counteract the doxorubicin-induced promotion of breast cancer cell migration, which can occur at low doxorubicin concentrations. GPC, PC, and PC/GPC may serve as non-invasive surrogate makers of therapeutic response in breast cancer patients undergoing doxorubicin chemotherapy. 

Measurement of  Liver Fat Fraction and T2 Relaxation Times in an Experimental Rat Model of Hepatocarcinogenesis at 9.4T
Sami Alghamdi1,2, Gary Cowin1, Ian Brereton1, and Yasvir Tesiram1
1Centre for Advanced Imaging, University of Queensland, Brisbane, Australia, 2Dept. of Radiological sciences,King Saud University, Riyadh, Saudi Arabia
To investigate the correlation between fat fraction (FF) measured by in/out-phase (IP/OP) imaging, with transverse relaxation time (mono- and bi-exponential T2 values) and their relationship with nodular and tumour formation in the liver of rats maintained on a choline and amino acid modified diet (CDAA diet).

Evaluation of nearby lymph nodes in a tumor mouse model by longitudinal MRI imaging at 11.7 Tesla.
María Jiménez-González1, Sandra Plaza-García1, Géraldine Pastor1, and Torsten Reese1
1Molecular Imaging Unit, CIC biomaGUNE, San Sebastián, Spain
We developed a pancreatic tumor xenograft model in a nude mice to study characteristics of nearby lymph nodes. Using non invasive in vivo MR imaging at 11.7 Tesla, we monitored the tumor progression from 8 to 20 weeks. We observed enlarged lymph nodes in tumor bearing animals comparing to controls. Histological analysis  demonstrated the presence of significant histiocytosis but not metastasis. Our study suggests that lymph node histiocytosis, in absence of functional adaptative immune system, plays a significant role of the innate immuno defense against cancer cells spreading.

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