Cancer - Animal Models & Physiology
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Monday 7 May 2012
Room 219-220  16:30 - 18:30 Moderators: Harish Poptani, Simon P. Robinson

16:30 0162.   
Imaging the relationship between tumour interstitial fluid velocity and microvascular perfusion with convection MRI
Simon Walker-Samuel1, Jake Burrell2, Rajiv Ramasawmy1, Peter Johnson3, Jack Wells1, Bernard Siow1, Simon P. Robinson2, Barbara Pedley3, and Mark F. Lythgoe1
1Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom, 2CR-UK & EPSRC Cancer Imaging Centre, The Institute of Cancer Research, United Kingdom, 3Cancer Institute, University College London, United Kingdom

High tumour interstitial fluid pressure (IFP) is hypothesised to be caused by raised vascular permeability and thus driven by microvascular pressure. We have developed a novel method for measuring tumour interstitial fluid velocity (IFV) named convectionMRI that can map the path of fluid transport through the tumour interstitium. By combining this technique with arterial spin labelling to evaluate vascular perfusion, we have shown a correspondence between IFV spatial distribution, vascular perfusion and spatial pressure gradients that are consistent with this microvascular pressure hypothesis. We discuss the potential for the non-invasive assessment of barriers to drug delivery.

16:42 0163.   
Mapping the systemic recruitment of ferritin expressing fibroblasts to the angiogenic rim of ovarian tumors
Moriel Vandsburger1, Batya Cohen1, Yoseph Addadi1, Marina Radoul1, and Michal Neeman1
1Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

Recruitment of fibroblasts by solid tumors plays a critical role in initiation, progression and metastatic dissemination. As such, cancer associated fibroblasts are attractive as potential avenues for novel anti-cancer therapies. MRI of fibroblast recruitment could enable assessment of drug efficacy on the cellular level, but is hindered by limitations of cell labeling techniques. We examined the potential of ferritin over-expression for quantitative MRI tracking of fibroblasts recruitment to human ovarian carcinoma both in vitro, and in vivo. Our results indicate even under conditions of sparse populations of tagged cells, over-expression of ferritin can be used for quantitative cell tracking.

16:54 0164.   Tumor location is a major determinant of macromolecular transport, collagen fiber morphology, and metastasis
Marie-France Penet1, Samata Kakkad1, Arvind P. Pathak1, Venu Raman1, Meiyappan Solaiyappan1, and Zaver M. Bhujwalla1
1JHU ICMIC Program, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, United States

Prostate cancers growing orthotopically in the prostate result in metastasis to lymph nodes, lungs and liver, and malignant ascites. In contrast, identical xenografts growing heterotopically in the flank rarely result in metastasis. Here we used noninvasive MRI and optical microscopy to characterize interstitial fluid transport and the extracellular matrix in metastasis-permissive or preventive environments using human prostate cancer cells engineered to fluoresce under hypoxia. We observed significant differences in macromolecular transport and collagen I fiber morphology between tumors implanted orthotopically and subcutaneously. These insights may lead to strategies to prevent prostate cancer metastasis.

17:06 0165.   
Investigating tumour vascular connectivity with resting state MRI and independent component analysis
Miguel R. Gonçalves1,2, Simon Walker-Samuel1, Sean P. Johnson2, Rosamund B. Pedley2, and Mark F. Lythgoe1
1UCL Centre for Advanced Biomedical Imaging, Division of Medicine and Institute of Child Health, University College London, London, United Kingdom, 2UCL Cancer Institute, London, United Kingdom

Solid tumours were found to exhibit oscillating patterns of hypoxia and reoxygenation due to microregional instabilities in blood flow and oxygen delivery. This phenomenon has been linked to a chemotherapy and radiotherapy resistance, and a correlation has been found between these fluctuating regions and measurements of tumour vascular functionality. Independent Component Analysis (ICA) is a computational technique previously used in the brain to identify patterns of activation during resting state. Given the similarity between oscillations in oxygenation in tumours and brain we investigated the utility of ICA to study and characterise these cyclical events in tumours.

17:18 0166.   
Assessing Breast Cancer Angiogenesis In Vivo: Which MRI Biomarkers are Relevant?
Eugene Kim1, Jana Cebulla2, B. Douglas Ward3, Kevin Rhie2, Jiangyang Zhang2, and Arvind P. Pathak2,4
1The Whitaker Biomedical Engineering Institute, Johns Hopkins University, Baltimore, MD, United States, 2The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, 3Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, United States, 4The Johns Hopkins University In Vivo Cellular and Molecular Imaging Center Program

There is a crucial need for noninvasive biomarkers of breast cancer angiogenesis to evaluate the efficacy of new anti-angiogenic therapies in vivo. Here, we validated in vivo steady-state susceptibility contrast (SSC)-MRI biomarkers of angiogenesis in an orthotopic human breast cancer model against the 3D vascular morphology obtained from high-resolution micro-computed tomography (µCT). Based on cross-validation analysis, the simple parameters that only require ΔR2and ΔR2* measurements were better predictors of their µCT analogs than were the complex parameters that require additional measurements. Thus, a stand-alone SSC-MRI experiment provides promising candidates for noninvasive, in vivo biomarkers of breast cancer angiogenesis.

17:30 0167.   Mapping in vivo Tumor Oxygenation within Viable Tumor using 19F MRI and Multispectral Analysis
Yunzhou Shi1, David Finkle2, Franklin Peale3, Jed Ross1, Maj Hedehus1, Nicholas Van Bruggen1, Suzanna Clark2, Rayna Venook2, Sarajane Ross2, and Richard Carano1
1Biomedical Imaging, Genentech Inc.(Roche group), South San Francisco, CA, United States, 2Translational Oncology, Genentech Inc.(Roche group), South San Francisco, CA, United States, 3Pathology, Genentech Inc.(Roche group), South San Francisco, CA, United States

A novel approach that combines 19F MRI oximetry with diffusion-based multispectral analysis was developed. The current study demonstrates that pO2measurements can be restricted to the viable tumor and that the necrotic tissue classes contribute erroneous data to whole-tumor estimates of the pO2response during a breathing gas challenge experiment on mice. This novel approach provides a means to measure pO2 within tissue of therapeutic interest and address the issue of tumor heterogeneity that complicates pO2 tumor imaging.

17:42 0168.   
MRI Describes Mitigation of Radiation Necrosis
Xiaoyu Jiang1, John A Engelbach2, Jeremy Cates3, Dinesh K Thotala3, Robert E Drzymala3, Dennis E Hallahan3, Joseph JH Ackerman2, and Joel R Garbow2
1Chemistry, Washington University in St. louis, St. louis, MO, United States, 2Radiology, Washington University in St. louis, St. louis, MO, United States,3Radiation Oncology, Washington University in St. louis, St. louis, MO, United States

Radiation necrosis is a severe, but late occurring, injury to normal tissue, within and surrounding a radiation treatment field. Increases in vascular permeability (“leakiness”) and acute vascular apoptosis have both been suggested as possible causes of radiation necrosis. Bevacizumab may help to repair “leaky” capillaries and thereby mitigate radiation necrosis. Specific inhibitors of GSK-3lower case Greek beta, a serine/threonine kinase, are known to ameliorate apoptosis. We have recently developed a novel mouse model of radiation necrosis using Gamma Knife irradiation. Here, we use small-animal MRI to measure the mitigation of radiation necrosis by bevacizumab and SB415286, an inhibitor of GSK-3lower case Greek beta, in this mouse model.

17:54 0169.   
MRI characterization of a novel mouse model of sporadic medulloblastoma
Giselle Alexandra Suero-Abreu1,2, G. Praveen Raju3, Diane Pham3, Luis Barraza4, Kamila U. Szulc1,2, Edward J. Houston2, Alexandra Joyner4, and Daniel H. Turnbull1,2
1Biomedical Imaging Department, NYU School of Medicine, New York, NY, United States, 2Skirball Institute of Biomolecular Medicine, NYU School of Medicine, New York, NY, United States, 3Department of Pediatrics, Weill Cornell Medical College, New York, NY, United States, 4Developmental Biology Program, Memorial Sloan Kettering Institute, New York, NY, United States

Preclinical brain tumors models have the ability to provide insights on the etiology and pathogenesis of the human disease. Since studies performed in end-stage tumors may not accurately reflect their critical genetic alterations, there is a need for sensitive imaging methods in order to analyze the early stages of tumorigenesis. In our study, we optimized an in vivo high resolution MEMRI protocol for the characterization of tumor progression in a novel mouse model of sporadic Medulloblastoma. We successfully detected early pre-neoplastic lesions, longitudinally assessed their progression and analyzed the molecular and imaging features of advanced-stage tumors.

18:06 0170.   
Biphasic clearance of depot vaccine antigen and substrate visualized using SPIO MRI
Kim Brewer1,2, Kerry Lake3, Nicole Pelot3,4, Drew DeBay3, Andrea Penwell1, Genevieve Weir1, Marc Mansour1, and Chris Bowen2,3
1Immunovaccine Inc., Halifax, NS, Canada, 2School of Biomedical Engineering, Dalhousie University, Halifax, NS, Canada, 3Institute for Biodiagnostics (Atlantic), National Research Council of Canada, Halifax, NS, Canada, 4Electrical Engineering, Dalhousie University, Halifax, NS, Canada

DepoVaxTM is a liposome-in-oil-based vaccine platform that uses tumor-associated antigens (TAA) encapsulated in liposomes and suspended in oil. The oil acts as an adjuvant that increases the potency of the vaccine. By attaching superparamagnetic iron oxide (SPIO) to the TAA and then encapsulating in liposomes, one can visualize the longitudinal biodistribution of the TAA and evaluate whether the TAA slowly clears from the depot site, resulting in a potentiated immune response. To evaluate the longitudinal clearance of the DepoVaxTM vaccine components, mice underwent a C3 (HPV16 model) challenge using SPIO conjugated to the TAA or associated with the lipid.

18:18 0171.   
Osteopontin is associated with tumor malignancy revealed by multi-parametric MRI assays
Nai-Wei Yao1,2, Chiao-Chi V. Chen1, Yi-Hua Hsu1, Hsiu-Ting Lin1, Jeou-Yuan Chen1, and Chen Chang1
1Institute of Biomedical Sciences, Academic Sinica, Taipei, Taiwan, 2Department of Zoology, National Taiwan University, Taipei, Taiwan

Gliomas are aggressive brain tumors with a poor prognosis and remain refractory to treatment. Osteopontin (OPN) is strongly expressed in high-grade and metastatic brain tumors and plays a major role in cancer progression. It is hypothesized in this study that OPN is associated with tumor malignancy. OPN knockdown of rat C6 glioblastoma cells was used as a tactic to investigate the roles of OPN in tumor malignancy. The present study demonstrates that the tumor with OPN-knockdown exhibited lower malignancy than control tumors, including decreased T2 signal intensity of tumor, lower vascular permeability, and the changes of tumor-related metabolites.