Magnetic resonance imaging defines cervicovaginal anatomy, cancer, and VEGF trap antiangiogenic efficacy in estrogen-treated K14-HPV16 transgenic mice

Cancer Res. 2009 Oct 15;69(20):7945-52. doi: 10.1158/0008-5472.CAN-09-1271. Epub 2009 Sep 29.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / therapeutic use
  • Animals
  • Capillary Permeability
  • Carcinoma, Squamous Cell / blood supply*
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / virology
  • Contrast Media
  • Estrogens / therapeutic use*
  • Female
  • Genitalia, Female / pathology*
  • Humans
  • Keratin-14 / genetics
  • Magnetic Resonance Imaging*
  • Mice
  • Mice, Transgenic
  • Neovascularization, Pathologic / diagnosis*
  • Neovascularization, Pathologic / drug therapy
  • Oncogene Proteins, Viral / genetics
  • Papillomavirus E7 Proteins
  • Receptors, Vascular Endothelial Growth Factor
  • Recombinant Fusion Proteins / therapeutic use*
  • Tumor Cells, Cultured
  • Uterine Cervical Neoplasms / blood supply*
  • Uterine Cervical Neoplasms / drug therapy
  • Uterine Cervical Neoplasms / virology
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors

Substances

  • Angiogenesis Inhibitors
  • Contrast Media
  • Estrogens
  • Keratin-14
  • Oncogene Proteins, Viral
  • Papillomavirus E7 Proteins
  • Recombinant Fusion Proteins
  • Vascular Endothelial Growth Factor A
  • oncogene protein E7, Human papillomavirus type 16
  • aflibercept
  • Receptors, Vascular Endothelial Growth Factor