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Abstract. The activity of the Na + /H + exchanger NHE1 is required for human melanoma cell adhesion and migration. The goal of the present study was to suppress mouse melanoma (B16V) cell invasion in vivo by inhibiting NHE1. Intravital observations in mobilized left liver lobes of laparotomized male Sprague-Dawley rats disclosed that five minutes after intra-arterial administration of the B16V cell suspension, cells adhered to the endothelia of liver sinusoidal capillaries and started to migrate into the surrounding liver tissue. In the presence of the NHE1-specific inhibitor cariporide, migration/invasion was reduced by about 50% while adhesion was not lowered. Time-lapse video microscopy and adhesion/invasion assays revealed that in vitro, blockade of NHE1 by cariporide i) significantly decreased the migratory speed of the cells and ii) completely inhibited the invasive behavior of both an artificial, basement membrane-like and a dermis-like matrix. Cells were more motile on the basement membrane and more invasive on the dermis-like matrix. Small-animal PET (positron-emission tomography) analyses of B16V metastasis in female C57BL/6 mice showed that, although NHE1 inhibition hardly affected the percentage of animals developing metastases or relapses, metastases seem to get directed to the lungs in cariporide-treated animals while animals feeding on the standard diet show metastases spread all over the body. We conclude that i) B16V cells prefer to invade a dermis-like rather than a basement membranelike matrix; ii) the extracellular matrix (ECM) composition strongly impacts on NHE1-dependent in vitro cell motility and invasion; and iii) the lungs are metastasis-prone and impair the efficiency of cariporide due to their ECM composition and the pulmonary interstitial (extravascular) pH.

The murine model mimics the characteristics of head and neck cancer in humans and offers excellent opportunities to investigate immunomodulatory anticancer drugs. The CD137 antibody showed antitumor effects in some therapy-responsive mice.

Purpose Dynamic FDG imaging for prostate cancer characterization is limited by generally small size and low uptake in prostate tumors. Our aim in this pilot study is to explore feasibility of simultaneous PET/MRI to guide localization of prostate lesions for dynamic FDG analysis using a graphical approach. Methods Three patients with biopsy-proven prostate cancer underwent simultaneous FDG PET/MRI, incorporating dynamic prostate imaging. Histology and multi-parametric MRI findings were used to localize tumors, which in turn guided identification of tumors on FDG images. Regions-of-interest (ROIs) were manually placed on tumor and benign prostate tissue. Blood activity was extracted from an ROI placed on the femoral artery on PET images. FDG data was analyzed by graphical analysis using the influx constant Ki (Patlak analysis) when FDG binding appeared irreversible, and distribution volume VT [(reversible graphical analysis (RGA)] when FDG binding appeared reversible given presence of washout. Results Given inherent coregistration, simultaneous acquisition facilitated use of MRI data to localize small lesions on PET and subsequent graphical analysis in all cases. In two cases with irreversible binding, tumor had higher Ki than benign using Patlak analysis (0.023 vs. 0.006 and 0.019 vs. 0.008 mL/cm3/min). In one case appearing reversible, tumor had higher VT than benign using RGA (0.68 vs. 0.52 mL/cm3). Conclusion Simultaneous PET/MRI allows localization of small prostate tumors for dynamic PET analysis. By taking of advantage of inclusion of the femoral arteries in the field-of-view, we applied advanced PET data analysis methods beyond conventional static measures and without blood sampling.