title: In vivo MRI and histopathological assessment of tumor microenvironment in luminal-like and basal-like breast cancer xenografts.
abstract: OBJECTIVE
  To explore tumor pathophysiology with special attention to the microenvironment in two molecular subtypes of human breast cancer using in vivo magnetic resonance imaging (MRI) and histopathology. The impact of tumor growth, size, and the influence of estradiol were also investigated.
  
  
  METHODS
  Two orthotopic and directly transplanted human breast cancer models representing luminal-like and basal-like molecular subtypes were characterized by dynamic contrast-enhanced MRI and diffusion-weighted MRI. Ex vivo measurements of vascularization, hypoxia, mitoses, and the level of VEGF activations were associated with the calculated in vivo MRI parameters of the tumors.
  
  
  RESULTS
  The vascular permeability and perfusion (K(trans) ) was significantly higher in basal-like compared to luminal-like tumors. These findings were confirmed by a 4-fold higher proliferating microvessel density (pMVD) in basal-like tumors, reflecting the difference in aggressiveness between the subtypes. No effect of tumor growth was observed during 6 days of growth in any of the models; however, large tumors had lower K(trans) , higher extracellular extravascular volume fraction (v(e) ), and more hypoxia than medium-sized tumors. Estradiol withdrawal induced increased K(trans) , v(e) , and tumor water diffusion (ADC) in luminal-like tumors, corresponding to increased VEGFR2 activation, which is likely to cause increased tumor vessel permeability.
  
  
  CONCLUSIONS
  These novel data confirm the potential of functional MRI methods to map histopathologically proven changes in breast tumor vasculature and microenvironment in vivo.
authors.affiliation: MI Lab and Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway. else.m.huuse@ntnu.no
authors.forename: Else M
authors.initials: EM
authors.lastname: Huuse
authors.forename: Siver A
authors.initials: SA
authors.lastname: Moestue
authors.forename: Evita M
authors.initials: EM
authors.lastname: Lindholm
authors.forename: Tone F
authors.initials: TF
authors.lastname: Bathen
authors.forename: Hawa
authors.initials: H
authors.lastname: Nalwoga
authors.forename: Kristi
authors.initials: K
authors.lastname: Krüger
authors.forename: Anna
authors.initials: A
authors.lastname: Bofin
authors.forename: Gunhild M
authors.initials: GM
authors.lastname: Maelandsmo
authors.forename: Lars A
authors.initials: LA
authors.lastname: Akslen
authors.forename: Olav
authors.initials: O
authors.lastname: Engebraaten
authors.forename: Ingrid S
authors.initials: IS
authors.lastname: Gribbestad
mesh_terms: D000818:Animals; D019540:Area Under Curve; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000503:physiopathology*; D002199:Capillary Permeability / Q000187:drug effects; D003287:Contrast Media / Q000008:administration & dosage; D038524:Diffusion Magnetic Resonance Imaging; D004195:Disease Models, Animal; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D019786:Gadolinium DTPA / Q000008:administration & dosage; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D018709:Statistics, Nonparametric; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
chemical_list: D003287:Contrast Media; D042461:Vascular Endothelial Growth Factor A; D004958:Estradiol; C064925:gadodiamide; D019786:Gadolinium DTPA