Yingwei Wu1, Yongming Dai2, Qi Fan1, and Xianfeng Tao1
1Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China, People's Republic of, 2Philips Healthcare, Shanghai, China, People's Republic of
Synopsis
We used oxygenation enhancement (OE)-MRI measurements to investigate hypoxia conditions of gliomas and to evaluate relationship between histopathology measurements and PSC. Oxygen amplitude maps of C6 glioma models were derived. ROI max and ROI non-max were defined. Time-SI curve from ROI areas was obtained and tissues from ROI areas was evaluated for microvessel density and expression of HIF-1a. We found that microvessel density in ROI non-max area were lower than those in ROI max area and expression of HIF-1α in ROI non-max area were higher than that in ROI max area. PSC had a linear positive correlation with vessel density.Purpose
To investigate hypoxia conditions of brain glioma
using oxygenation enhance (OE)-MRI measurements and to evaluate correlation between histopathology measurement of tumor vascularity , expression of
hypoxia-regulated molecules and percentage of signal intensity changes (PSC)
before and after oxygen administration .
Methods
10^6 C6 glioma cells were implanted in rat brains using standard protocals (n=5). OE-MRI using T1-weighted inversion recovery (IR) turbo spin echo (TSE) was performed on a 3.0-T MR scanner, including dynamic T1-weighted IR TSE imaging covering 1) normal room air administration (21% O2) for 5 min; 2) 100% oxygen administration for 5 min; and 3) normal room air administration (21% O2) for 5 min continuously. Oxygen amplitude map were derived from the T1-weighted OE-MRI images, of which each voxel represents the highest percentage of signal intensity changes (PSC) before and after oxygen administration. Regions of interest (ROIs), each contains 4 voxels, are defined as ROI max (PSC > 15%) and ROI non-max (5% < PSC < 10%) on the oxygenation amplitude map. Time-SI (signal intensity) Curve for both ROI max (PSC > 15%) and ROI non-max (5% < PSC < 10%) was obtained using IR-TSE sequence. Tissue obtained from areas of ROI max and ROI non-max was evaluated for microvessel density and expression of hypoxia-inducible factor-1 a (HIF-1a). Spearman rank correlation coefficient was used to identify correlation between PSC and microvessel density. Paired Student tests were used to compare the PSC, microvessel density, and HIF-1a expression from ROI max with the ROI non-max.
Results
Results: PSC of OE-MRI signal regionally varied in C6 glioma models. Both PSC and microvessel density in ROI non-max area were significantly lower than those in ROI max area (P < 0.05). Consistent with MRI results, expressions of HIF-1α in ROI non-max area were obviously higher than that in ROI max area(P < 0.05). Furthermore, PSC had a linear positive correlation with vessel density (r=0.92, P < 0.05).
conclusion
OE-MRI
measurements were capable to demonstrate hypoxia conditions in C6 glioma
models. PSC was a valuable parameter for evaluation of tumor vascularity and
expression of hypoxia-regulated molecules
Acknowledgements
No acknowledgement found.References
Reference
[1] Toda M.Glioma
Stem Cells and Immunotherapy for the Treatment of Malignant Gliomas. ISRN Oncol. 2013
May 15;2013:673-693.
2 Jain RK, di Tomaso E, Duda DG,
Loeffler JS, Sorensen AG, Batchelor TT. Angiogenesis in brain tumours. Nat Rev
Neurosci 2007;8:610–622.
3 Brown JM. The hypoxic cell: a
target for selective cancer therapy—eighteenth Bruce F Cain Memorial
Award lecture. Cancer Res 1999;59:5863–5870.
4 Vaupel P. The role of hypoxia-induced
factors in tumor progression. Oncologist 2004;9:10–17
5 Vaupel P, Mayer A. Hypoxia in
cancer: significance and impact on clinical outcome. Cancer Metastasis Rev
2007;26:225–239.
6 Jensen RL, Mumert ML, Gillespie DL, Kinney AY, Schabel MC, Salzman KL. Preoperative
dynamic contrast-enhanced MRI correlates with molecular markers of hypoxia and
vascularity in specific areas of intratumoral microenvironment and is
predictive of patient outcome. Neuro Oncol. 2014
Jan;16(2):280-291.
7 Zhang Y, Xu H, et
al. Fluorine-18-deoxyglucose positron emission tomography/computed
tomography with Ki67 and GLUT-1 immunohistochemistry for evaluation of the
radiosensitization effect of oleanolic acid on C6 rat gliomas. Nucl Med Commun. 2015 Jan;36(1):21-27.
8 Folkman J. Angiogenesis. Annu
Rev Med. 2006;57:1–18.
9 Rampling R, Cruickshank G, Lewis
AD, et al. Direct measurement of pO2 distribution and bioreductive enzymes in
human malignant brain tumors. Int J Radiat Oncol Biol Phys 1994;29:427–431.
10 Tochon-Danguy HJ, Sachinidis
JI, et al. Imaging and quantitation of the hypoxic cell fraction of viable tumor
in an animal model of intracerebral high grade
glioma using [18F]fluoromisonidazole (FMISO). Nucl Med Biol 2002;29:191–197.
11 Rasey JS, Casciari JJ, Hofstrand
PD, et al. Determining hypoxic fraction in a rat glioma by uptake of
radiolabeled fluoromisonidazole. Radiat Res 2000;153:84–92.
12 Ceelen W, Smeets P, Backes W, et
al. Noninvasive monitoring of radiotherapy-induced microvascular changes using
dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) in a colorectal tumor
model. Int J Radiat Oncol Biol Phys 2006;64:1188–1196.
13 Egeland TA, Gaustad JV, Vestvik
IK, Benjaminsen IC, Mathiesen B, Rofstad EK. Assessment of fraction of radiobiologically
hypoxic cells in human melanoma xenografts by dynamic contrast-enhanced MRI. Magn
Reson Med 2006;55:874–882.
14 Donaldson SB, Betts G,
Bonington SC, et al. Perfusion estimated with rapid dynamic contrast-enhanced
magnetic resonance imaging correlates inversely with vascular endothelial
growth factor expression and pimonidazole staining in head-and-neck cancer: a pilot
study. Int J Radiat Oncol Biol Phys 2011;81:1176–1183.
15 Baudelet C, Gallez B. How does
blood oxygen level-dependent (BOLD) contrast correlate with oxygen partial
pressure (pO2) inside tumors? Magn Reson Med 2002;48:980–986.
16 Griffiths JR, Taylor NJ, et al.
The response of human tumors to carbogen breathing, monitored by
gradient-recalled echo magnetic resonance imaging. Int J Radiat Oncol Biol Phys
1997;39: 697–701.
17 Taha M. Mehemed, Yasutaka Fushimi,
et al. Dynamic Oxygen-Enhanced MRI of Cerebrospinal Fluid. PLoS One. 2014 Jun 23;9(6):e100723.
18 De Donato M, Mariani M,
Petrella L, Martinelli E, Zannoni GF, Vellone V, Ferrandina G, Shahabi S,
Scambia G, Ferlini C. Class III beta-tubulin and the cytoskeletal gateway for
drug resistance in ovarian cancer. J Cell
Physiol. 2012;227:1034–1041.
19 Sundfor K, Lyng H, Rofstad EK.
Tumour hypoxia and vascular density as predictors of metastasis in squamous
cell carcinoma of the uterine cervix. Br J Cancer 20 Hockel M, Schlenger K, Hockel
S, et al. Tumor hypoxia in pelvic recurrences of cervical cancer. Int J Cancer
1998;79: 365–369.
21 Sanna K, Rofstad EK.
Hypoxia-induced resistance to doxorubicin and methotrexate in human melanoma
cell lines in vitro. Int J Cancer 1994;58:258–262.
22 Cuvier C, Jang A, Hill RP.
Exposure to hypoxia, glucose starvation and acidosis: effect on invasive capacity
of murine tumor cells and correlation with cathepsin (L + B) secretion. Clin
Exp Metastasis 1997;15:19–25.
23 Walenta S, Wetterling M, Lehrke
M, et al. High lactate levels predict likelihood of metastases, tumor
recurrence, and restricted patient survival in human cervical cancers. Cancer
Res 2000;60:916–921.
24 Zaharchuk G, Busse RF,
Rosenthal G, Manley GT, Glenn OA, Dillon WP. Noninvasive oxygen partial
pressure measurement of human body fluids in vivo using magnetic resonance
imaging. Acad Radiol 2006;13:1016–1024.
25 Silvennoinen MJ, Kettunen MI,
Kauppinen RA. Effects of hematocrit and oxygen saturation level on blood
spin-lattice relaxation. Magn Reson Med 2003;49:568–571.
26 O’Connor JP,
Naish JH, Parker GJ, et al. Preliminary study of oxygenenhanced longitudinal
relaxation in MRI: a potential novel biomarker of oxygenation changes in solid
tumors. Int J Radiat Oncol Biol Phys 2009;75:1209–1215.
27 Matsumoto K, Bernardo M,
Subramanian S, et al. MR assessment of changes of tumor in response to hyperbaric
oxygen treatment. Magn Reson Med 2006;56:240–