title: Assessing tumor vascularization as a potential biomarker of imatinib resistance in gastrointestinal stromal tumors by dynamic contrast-enhanced magnetic resonance imaging.
abstract: BACKGROUND
  Most metastatic gastrointestinal stromal tumors (GISTs) develop resistance to the first-line imatinib treatment. Recently, increased vessel density and angiogenic markers were reported in GISTs with a poor prognosis, suggesting that angiogenesis is implicated in GIST tumor progression and resistance. The purpose of this study was to investigate the relationship between tumor vasculature and imatinib resistance in different GIST mouse models using a noninvasive magnetic resonance imaging (MRI) functional approach.
  
  
  METHODS
  Immunodeficient mice (n = 8 for each cell line) were grafted with imatinib-sensitive (GIST882 and GIST-T1) and imatinib-resistant (GIST430) human cell lines. Dynamic contrast-enhanced MRI (DCE-MRI) was performed on GIST xenografts to quantify tumor vessel permeability (Ktrans) and vascular volume fraction (vp). Microvessel density (MVD), permeability (mean dextran density, MDD), and angiogenic markers were evaluated by immunofluorescence and western blot assays.
  
  
  RESULTS
  Dynamic contrast-enhanced magnetic resonance imaging showed significantly increased vessel density (P < 0.0001) and permeability (P = 0.0002) in imatinib-resistant tumors compared to imatinib-sensitive ones. Strong positive correlations were observed between MRI estimates, Ktransand vp, and their related ex vivo values, MVD (r = 0.78 for Ktransand r = 0.82 for vp) and MDD (r = 0.77 for Ktransand r = 0.94 for vp). In addition, higher expression of vascular endothelial growth factor receptors (VEGFR2 and VEFGR3) was seen in GIST430.
  
  
  CONCLUSIONS
  Dynamic contrast-enhanced magnetic resonance imaging highlighted marked differences in tumor vasculature and microenvironment properties between imatinib-resistant and imatinib-sensitive GISTs, as also confirmed by ex vivo assays. These results provide new insights into the role that DCE-MRI could play in GIST characterization and response to GIST treatment. Validation studies are needed to confirm these findings.
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Turin, Italy.|CAGE Chemicals srl, Via Bovio 6, 28100, Novara, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Consolino
authors.affiliation: Institute of Biostructure and Bioimaging, National Research Council of Italy (CNR) c/o Molecular Biotechnologies Center, Via Nizza 52, 10126, Turin, Italy. dario.longo@unito.it.
authors.forename: Dario Livio
authors.initials: DL
authors.lastname: Longo
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Turin, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Sciortino
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Turin, Italy.
authors.forename: Walter
authors.initials: W
authors.lastname: Dastrù
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Turin, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Cabodi
authors.affiliation: CAGE Chemicals srl, Via Bovio 6, 28100, Novara, Italy.|Department of Pharmaceutical Sciences, University of Eastern Piedmont, Largo Donegani 2/3, 28100, Novara, Italy.
authors.forename: Giovanni Battista
authors.initials: GB
authors.lastname: Giovenzana
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Turin, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Aime
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D045744:Cell Line, Tumor; D003287:Contrast Media; D019008:Drug Resistance, Neoplasm; D046152:Gastrointestinal Stromal Tumors / Q000000981:diagnostic imaging* / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D000068877:Imatinib Mesylate; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging*
chemical_list: D000970:Antineoplastic Agents; D003287:Contrast Media; D000068877:Imatinib Mesylate
keywords: Angiogenesis; DCE-MRI; Gadolinium contrast agent; Gastrointestinal stromal tumor; Imatinib