Abstract
BackgroundMost 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.MethodsImmunodeficient 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.ResultsDynamic 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, Ktrans and vp, and their related ex vivo values, MVD (r = 0.78 for Ktrans and r = 0.82 for vp) and MDD (r = 0.77 for Ktrans and r = 0.94 for vp). In addition, higher expression of vascular endothelial growth factor receptors (VEGFR2 and VEFGR3) was seen in GIST430.ConclusionsDynamic 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.
Highlights
Gastrointestinal stromal tumor (GIST) is the most common malignant mesenchymal neoplasm of the digestive tract, with a mean annual incidence of 11–14 patients per million people
The aim of our work was to evaluate the ability of a functional magnetic resonance imaging (MRI)-based approach to highlight differences in tumor microenvironment properties related to imatinib resistance in GIST murine models
We investigated GIST tumor vascularization using a Dynamic contrast-enhanced MRI (DCE-MRI) approach
Summary
Gastrointestinal stromal tumor (GIST) is the most common malignant mesenchymal neoplasm of the digestive tract, with a mean annual incidence of 11–14 patients per million people. 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. Results Dynamic contrast-enhanced magnetic resonance imaging showed significantly increased vessel density (P \ 0.0001) and permeability (P = 0.0002) in imatinibresistant tumors compared to imatinib-sensitive ones. Conclusions Dynamic contrast-enhanced magnetic resonance imaging highlighted marked differences in tumor vasculature and microenvironment properties between imatinib-resistant and imatinib-sensitive GISTs, as 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.
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