Gene Expression Profiles, Histologic Analysis, and Imaging of Squamous Cell Carcinoma Model Treated with Focused Ultrasound Beams

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Abstract
OBJECTIVE. The purpose of our study was to evaluate the effect of short-pulse high-intensity focused ultrasound (HIFU) on inducing cell death in a head and neck cancer model (SCCVII [squamous cell carcinoma]) compared with continuous HIFU to get a better understanding of the biologic changes caused by HIFU therapy. MATERIALS AND METHODS. HIFU was applied to 12 SCCVII tumors in C3H/Km mice using a dual sonography system (imaging, 6 MHz; therapeutic, 1 MHz). A continuous HIFU mode (total time, 20 seconds; intensity, 6,730.6 W/cm2) and a short-pulse HIFU mode (frequency, 0.5Hz; pulse duration, 50 milliseconds; total time, 16.5 minutes; intensity, 134.4 W/cm2) was applied. Three hours later, MR images were obtained on a 1.5-T scanner. After imaging, the treated and untreated control tumor tissue samples were taken out for histology and oligonucleotide microarray analysis. RESULTS. Prominent changes were observed in the MR images in the continuous HIFU mode, whereas the short-pulse HIFU mode showed no discernible changes. Histology (H and E, TUNEL [terminal deoxynucleotidyl transferase-mediated dUTP {deoxyuridine triphosphate} nick-end labeling], and immunohistochemistry) of the tumors treated with the continuous HIFU mode revealed areas of significant necrosis. In the short-pulse HIFU mode, the H and E staining showed multifocal areas of coagulation necrosis. TUNEL staining showed a high apoptotic index in both modes. Gene expression analysis revealed profound differences. In the continuous HIFU mode, 23 genes were up-regulated (> twofold change) and five genes were down-regulated (< twofold change), and in the short-pulse HIFU mode, 32 different genes were up-regulated and 16 genes were down-regulated. CONCLUSION. Genomic analysis might be included when investigating tissue changes after interventional therapy because it offers the potential to find molecular targets for imaging and therapeutic applications.