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Noninvasive Multiparametric Imaging of Metastasis-Permissive Microenvironments in a Human Prostate Cancer Xenograft

¹ Johns Hopkins University In Vivo Cellular and Molecular Imaging Center Program, The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland and ² Laboratory Organic Synthesis and Molecular Imaging by Magnetic Resonance, Universidad Nacional de Educación a Distancia, Madrid, Spain

Requests for reprints: Zaver M. Bhujwalla, Department of Radiology, Johns Hopkins University School of Medicine, 208C Traylor Building, 720 Rutland Avenue, Baltimore, MD 21205. Phone: 410-955-9698; Fax: 410-614-1948; E-mail: zaver{at}mri.jhu.edu.

Metastasis continues to be one of the major causes of mortality from prostate cancer. Because human malignant cell lines metastasize more readily from orthotopic sites than from heterotopic sites, to identify metastasis-permissive tumor microenvironments, we used noninvasive imaging to compare the in vivo vascular, metabolic, and physiologic characteristics of a human prostate cancer xenograft implanted orthotopically in the prostate or s.c. in the flank. Hypoxia was detected in these xenografts by placing an enhanced green fluorescence protein optical reporter under the control of a hypoxia response element. A multiparametric analysis of hypoxia, extracellular pH, vascularization, and metabolism provided a characterization of environments that are permissive for metastasis to occur. We found that orthotopic tumors, which metastasized more easily, were characterized by higher vascular volume, permeability, and total choline and a more acidic extracellular pH. Interestingly, metastatic deposits in the lymph nodes as well as cancer cells in ascites fluid were found to be hypoxic, explaining, in part, the refractory nature of metastatic disease. These results also provide the basis for clinically translatable noninvasive imaging markers for predicting metastatic risk in prostate cancer. [Cancer Res 2009;69(22):8822–9]

Key Words: prostate cancer • hypoxia • vascularization • choline metabolism • pHe • magnetic resonance spectroscopy and imaging • metastasis