The high angiogenic activity in very early breast cancer enables reliable imaging with VEGFR2-targeted microbubbles (BR55)

• Published in: European radiology Vol. 23; no. 2; pp. 468 - 475
• Main Authors: Bzyl, Jessica, Palmowski, Moritz, Rix, Anne, Arns, Susanne, Hyvelin, Jean-Marc, Pochon, Sibylle, Ehling, Josef, Schrading, Simone, Kiessling, Fabian, Lederle, Wiltrud
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.02.2013; Springer Nature B.V
• Subjects: Angiogenesis; Animals; Automation; Blood; Breast cancer; Contrast Media; Diagnostic Radiology; Disease Models, Animal; Early Detection of Cancer - methods; Female; Imaging; Internal Medicine; Interventional Radiology; Mammary Glands, Animal - blood supply; Mammary Neoplasms, Experimental - blood supply; Mammary Neoplasms, Experimental - diagnostic imaging; Mammary Neoplasms, Experimental - pathology; Medicine; Medicine & Public Health; Mice; Microbubbles; Molecular Biology; Molecular Imaging; Neovascularization, Pathologic - diagnostic imaging; Neovascularization, Pathologic - metabolism; Neuroradiology; Predictive Value of Tests; Radiology; Random Allocation; Sensitivity and Specificity; Transplantation, Heterologous; Tumors; Ultrasonic imaging; Ultrasonography, Doppler, Color - methods; Ultrasound; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Aachen Germany; Germany; VEGFR2; Angiogenesis; Breast cancer; 3D molecular ultrasound; Small tumours
• ISSN: 0938-7994; 1432-1084
• DOI: 10.1007/s00330-012-2594-z

Objectives Tumour xenografts of well-discernible sizes can be examined well by molecular ultrasound. Here, we investigated whether very early breast carcinomas express sufficient levels of VEGFR2 for reliable molecular ultrasound imaging with targeted microbubbles. Methods MCF-7 breast cancer xenografts were orthotopically implanted in nude mice ( n  = 26). Tumours measuring from 4 mm 3 (2 mm diameter) up to 65 mm 3 (5 mm diameter) were examined with automated 3D molecular ultrasound using clinically translatable VEGFR2-targeted microbubbles (BR55). Additionally, the relative tumour blood volume was assessed with non-targeted microbubbles (BR38). In vivo ultrasound data were validated by quantitative immunohistochemistry. Results Very small lesions 2 mm in diameter showed the highest binding of VEGFR2-specific microbubbles. In larger tumours significantly less BR55 accumulated ( p  = 0.023). Nonetheless, binding of VEGFR2-targeted microbubbles was still high enough for imaging. The relative blood volume was comparable at all tumour sizes. Both findings were confirmed by immunohistochemistry. Additionally, a significantly enhanced number of large and mature vessels were detected with increasing tumour size ( p  < 0.01), explaining the decrease in VEGFR2 expression during tumour growth. Conclusions 3D molecular ultrasound using BR55 is very well suited to depicting the angiogenic activity in very small breast lesions, suggesting its potential for detecting and characterising these lesions. Key Points • Xenografts implanted into nude mice offer new insights into breast cancer. • Small MCF-7 breast xenografts (2 mm) exhibit greater VEGFR2 expression than larger tumours. • 3D molecular ultrasound with BR55 microbubbles accurately depicts the high angiogenic activity. • Detecting and characterising small cancers with molecular ultrasound may become possible.