Comparison Of Tumor Angiogenesis In Subcutaneous And Orthotopic Lncap Mouse Models Using Contrast-Enhanced Ultrasound Imaging

Background: Understanding angiogenesis in prostate cancer is essential. LNCaP prostate xenograft tumors are androgen responsive and closely mimic clinical disease. Orthotopic animal models replicate aspects of the cancer microenvironment and are more clinically relevant than subcutaneous models. Comparative studies investigating angiogenesis using contrast-enhanced ultrasound (CEUS) imaging in subcutaneous and orthotopic mouse models of prostate cancer have not been performed. Methods: Tumor microcirculation and perfusion in subcutaneous and orthotopic LNCaP xenograft Balb/c athymic nude mice models were compared by investigating microbubble wash-in with CEUS. Results: The take rate of subcutaneous and orthotopic tumors were 58.3% and 68.2%, respectively. On CEUS, orthotopic prostate tumors enhanced more rapidly than subcutaneous tumors. Mean arrival time (Atm) for subcutaneous tumors, orthotopic prostate tumors, and kidney were 4.21 +/- 1.86, 1.72 +/- 0.79, and 0.73 +/- 0.12 s, respectively. Mean Atm was significantly longer for subcutaneous tumors compared to orthotopic prostate tumors or kidney (P<0.01). Mean time to peak enhancement (TtoPk) for subcutaneous tumors, orthotopic prostate tumors, and kidney were 38.56 +/- 13.23, 12.39 +/- 7.17, and 3.74 +/- 1.41 s, respectively. Mean TtoPk were significantly shorter for orthotopic prostate tumors and kidney compared to subcutaneous tumors (P<0.01). Mean wash-in area under the curve (WiAuC) for subcutaneous tumors, orthotopic prostate tumors, and kidney were 611.11 +/- 247.52, 1,800.57 +/- 623.11, and 1,887.51 +/- 103.68 dB, respectively. Mean AUC was significantly higher for orthotopic prostate tumors and kidney compared to subcutaneous tumors (P<0.01). Parametric imaging confirmed these findings. The density of CD31-positive vessels was significantly higher in orthotopic prostate tumors (43.98 +/- 6.14 vessels/field) compared to subcutaneous tumors (15.44 +/- 3.74 vessels/field, P<0.01). Conclusions: These findings demonstrate that orthotopic LNCaP xenografts better recreate a proangiogenic microenvironment than subcutaneous LNCaP xenografts.