Simon Walker-Samuel¹, Jake Burrell², Rajiv Ramasawmy¹, Peter Johnson³, Jack Wells¹, Bernard Siow¹, Simon P. Robinson², Barbara Pedley³, and Mark F. Lythgoe^1
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.

Moriel Vandsburger¹, Batya Cohen¹, Yoseph Addadi¹, Marina Radoul¹, and Michal Neeman^1
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.

Marie-France Penet¹, Samata Kakkad¹, Arvind P. Pathak¹, Venu Raman¹, Meiyappan Solaiyappan¹, and Zaver M. Bhujwalla^1
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.

Miguel R. Gonçalves^1,2, Simon Walker-Samuel¹, Sean P. Johnson², Rosamund B. Pedley², and Mark F. Lythgoe^1
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.

Eugene Kim¹, Jana Cebulla², B. Douglas Ward³, Kevin Rhie², Jiangyang Zhang², and Arvind P. Pathak^2,4
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.

Yunzhou Shi¹, David Finkle², Franklin Peale³, Jed Ross¹, Maj Hedehus¹, Nicholas Van Bruggen¹, Suzanna Clark², Rayna Venook², Sarajane Ross², and Richard Carano^1
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.

Xiaoyu Jiang¹, John A Engelbach², Jeremy Cates³, Dinesh K Thotala³, Robert E Drzymala³, Dennis E Hallahan³, Joseph JH Ackerman², and Joel R Garbow^2
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-3, 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-3, in this mouse model.

Giselle Alexandra Suero-Abreu^1,2, G. Praveen Raju³, Diane Pham³, Luis Barraza⁴, Kamila U. Szulc^1,2, Edward J. Houston², Alexandra Joyner⁴, and Daniel H. Turnbull^1,2
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.

Kim Brewer^1,2, Kerry Lake³, Nicole Pelot^3,4, Drew DeBay³, Andrea Penwell¹, Genevieve Weir¹, Marc Mansour¹, and Chris Bowen^2,3
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

DepoVax^TM 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 DepoVax^TM vaccine components, mice underwent a C3 (HPV16 model) challenge using SPIO conjugated to the TAA or associated with the lipid.

Nai-Wei Yao^1,2, Chiao-Chi V. Chen¹, Yi-Hua Hsu¹, Hsiu-Ting Lin¹, Jeou-Yuan Chen¹, and Chen Chang^1
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.