Magnetic resonance imaging defines cervicovaginal anatomy, cancer, and VEGF trap antiangiogenic efficacy in estrogen-treated K14-HPV16 transgenic mice.
Noninvasive detection of dysplasia provides a potential platform for monitoring the efficacy of chemopreventive therapy of premalignancy, imaging the tissue compartments comprising dysplasia: epithelium, microvasculature, and stromal inflammatory cells. Here, using respiratory-gated magnetic resonance imaging (MRI), the anatomy of premalignant and malignant stages of cervical carcinogenesis in estrogen-treated K14-HPV16 transgenic mice was noninvasively defined. Dynamic contrast enhanced (DCE)-MRI was used to quantify leakage across premalignant dysplastic microvasculature. Vascular permeability as measured by DCE-MRI, K(trans), was similar in transgenic (0.053 +/- 0.020 min(-1); n = 32 mice) and nontransgenic (0.056 +/- 0.029 min(-1); n = 17 mice) animals despite a 2-fold increase in microvascular area in the former compared with the latter. DCE-MRI did detect a significant decrease in vascular permeability accompanying diminution of dysplastic microvasculature by the antiangiogenic agent, vascular endothelial growth factor Trap (K(trans) = 0.052 +/- 0.013 min(-1) pretreatment; n = 6 mice versus K(trans) = 0.019 +/- 0.008 min(-1) post-treatment; n = 5 mice). Thus, we determined that the threshold of microvessel leakage associated with cervical dysplasia was <17 kDa and highlighted the potential of DCE-MRI to noninvasively monitor the efficacy of antiangiogenic drugs or chemoprevention regimens targeting the vasculature in premalignant cervical dysplasia.
Department of Radiology, Alvin J Siteman Cancer Center, Washington University in St Louis, Missouri 63110, USA. garbow@wustl.edu
Joel R
JR
Garbow
Andrea C
AC
Santeford
Jeff R
JR
Anderson
John A
JA
Engelbach
Jeffrey M
JM
Arbeit
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D002199:Capillary Permeability; D002294:Carcinoma, Squamous Cell / Q000098:blood supply* / Q000188:drug therapy / Q000821:virology; D003287:Contrast Media; D004967:Estrogens / Q000627:therapeutic use*; D005260:Female; D005836:Genitalia, Female / Q000473:pathology*; D006801:Humans; D053547:Keratin-14 / Q000235:genetics; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000175:diagnosis* / Q000188:drug therapy; D009856:Oncogene Proteins, Viral / Q000235:genetics; D050725:Papillomavirus E7 Proteins; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000821:virology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
D020533:Angiogenesis Inhibitors; D003287:Contrast Media; D004967:Estrogens; D053547:Keratin-14; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; C059731:oncogene protein E7, Human papillomavirus type 16; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor