DCE-MRI of Sunitinib-Induced Changes in Tumor Microvasculature and Hypoxia: A Study of Pancreatic Ductal Adenocarcinoma Xenografts12

Autor: Wegner, Catherine S., Hauge, Anette, Simonsen, Trude G., Gaustad, Jon-Vidar, Andersen, Lise Mari K., Rofstad, Einar K.
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Male
Original article
Indoles
endocrine system diseases
PDAC
pancreatic ductal adenocarcinoma
ROI
region of interest
Contrast Media
urologic and male genital diseases
DCE-MRI
dynamic contrast-enhanced magnetic resonance imaging
FOV
field of view
HF
hypoxic fraction
Mice
Cell Line
Tumor
Sunitinib
Tumor Microenvironment
Animals
Humans
Pyrroles
Ktrans
volume transfer constant
Hypoxia
ANGPT/TIE
angiopoietin/tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains
TE
echo time
ve
fractional distribution volume
Neovascularization
Pathologic
HE
hematoxylin and eosin
MVD
microvessel density
Image Enhancement
Immunohistochemistry
Magnetic Resonance Imaging
Xenograft Model Antitumor Assays
digestive system diseases
TR
repetition time
Pancreatic Neoplasms
Disease Models
Animal
Female
VEGF/VEGF-R
vascular endothelial growth factor/VEGF-receptor
αSMA
α smooth muscle actin
Biomarkers
IL-8/NF-κB
interleukin-8/nuclear factor-κB
Carcinoma
Pancreatic Ductal
Zdroj: Neoplasia (New York, N.Y.)
ISSN: 1476-5586
1522-8002
Popis: The purpose of this study was dual: to investigate (a) whether sunitinib may induce changes in tumor microvasculature and hypoxia in pancreatic ductal adenocarcinoma (PDAC) and (b) whether any changes can be detected by DCE-MRI. Sunitinib-treated and untreated control tumors of two PDAC xenograft models (BxPC-3 and Panc-1) were subjected to DCE-MRI before the imaged tumors were prepared for quantitative analysis of immunohistochemical preparations. Pimonidazole was used as a hypoxia marker, and fraction of hypoxic tissue (HFPim), density of CD31-positive microvessels (MVDCD31), and density of αSMA-positive microvessels (MVDαSMA) were measured. Parametric images of Ktrans and ve were derived from the DCE-MRI data by using the Tofts pharmacokinetic model. BxPC-3 tumors showed increased HFPim, decreased MVDCD31, unchanged MVDαSMA, and increased vessel maturation index (VMI = MVDαSMA/MVDCD31) after sunitinib treatment. The increase in VMI was seen because sunitinib induced selective pruning rather than maturation of αSMA-negative microvessels. Even though the microvessels in sunitinib-treated tumors were less abnormal than those in untreated tumors, this microvessel normalization did not improve the function of the microvascular network or normalize the tumor microenvironment. In Panc-1 tumors, HFPim, MVDCD31, MVDαSMA, and VMI were unchanged after sunitinib treatment. Median Ktrans increased with increasing MVDCD31 and decreased with increasing HFPim, and the correlations were similar for treated and untreated BXPC-3 and Panc-1 tumors. These observations suggest that sunitinib may induce significant changes in the microenvironment of PDACs, and furthermore, that Ktrans may be an adequate measure of tumor vascular density and hypoxia in untreated as well as sunitinib-treated PDACs.
Databáze: OpenAIRE
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