Detecting vascular changes in tumour xenografts using micro-ultrasound and micro-ct following treatment with VEGFR-2 blocking antibodies.
Blockade of vascular endothelial growth factor (VEGF) binding to its receptors on endothelial cells has been shown preclinically to induce tumour growth inhibition. Using ultrasound biomicroscopy (UBM) or micro-ultrasound imaging and micro-computed tomography (micro-CT) analysis, we have examined the effects of DC101, a highly specific vascular endothelial growth factor receptor-2 (VEGFR-2)-targeting antibody, in inducing growth inhibition and functional vascular changes in established melanoma (MeWo) xenografts in mice. Postprocessing of UBM imaging loops for speckle variance was introduced to estimate the level of functional blood flow in tumours. Perfused tumour area visualized by speckle variance revealed decreased blood flow within 48 h after DC101 injection (control versus DC101: 1.90 +/- 0.25% versus 1.01 +/- 0.11%, p < 0.01) and following a 3-wk DC101 therapy (control versus DC101: 0.76 +/- 0.14% versus 0.45 +/- 0.05%, p = 0.04), suggesting that VEGFR-2 blockade mediates both early and long-term effects on tumour blood flow. The growth of xenografts was significantly inhibited after treating with DC101 for 3 wk compared with controls. In addition to UBM, we examined the tumour vasculature in three-dimension (3D) using contrast-enhanced Micro-CT imaging, which displayed a reduction in the number of tumour vessels following extended VEGFR-2 blockade (vascular density of control versus DC101: 48.4 +/- 5.4% versus 20.6 +/- 1.8%). Lastly, decreased microvessel density (MVD) was noted in DC101-treated xenografts (3 wk) by performing immunohistochemical staining of endothelial marker CD34. Our study investigates tumour response to DC101 using complementing micro-ultrasound and micro-CT imaging tools.
Cheung
Alison M Y
AM
Imaging Research, Sunnybrook and Women's College Health Sciences Centre, Toronto, ON, Canada.
Brown
Allison S
AS
Cucevic
Viviene
V
Roy
Marcia
M
Needles
Andrew
A
Yang
Victor
V
Hicklin
Daniel J
DJ
Kerbel
Robert S
RS
Foster
F Stuart
FS
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D006801:Humans; D008545:Melanoma / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy; D051379:Mice; D008819:Mice, Nude; D033401:Microscopy, Acoustic / Q000379:methods; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging* / Q000628:therapy; D014057:Tomography, X-Ray Computed / Q000379:methods; D014183:Transplantation, Heterologous; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000276:immunology
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C511761:DC101 monoclonal antibody; D040301:Vascular Endothelial Growth Factor Receptor-2