Determination of the maturity and functionality of tumor vasculature by MRI: Correlation between BOLD‐MRI and DCE‐MRI using P792 in experimental fibrosarcoma tumors

Abstract

Using hypercapnia and carbogen as functional markers of vessel maturation and function, we compared blood oxygen leveldependent (BOLD) contrast with standard dynamic contrastenhanced (DCE)-MRI quantitative parameters in murine fibrosarcoma. Our results show that there was no correlation between vessel maturity and contrast-agent uptake rate (K Trans in ) or contrast agent efflux rate (k ep ). In addition, DCE-MRI provided higher estimates of the fraction of functional tumor compared to BOLD-MRI. The two putative markers of regional vascular density, i.e., the magnitude of BOLD signal change during carbogen challenge (VF) and the fractional plasma volume found by DCE-MRI (V p ), were only weakly correlated (r 2 ‫؍‬ 0.02-0.14). Furthermore, VF showed no correlation with K Both blood oxygenation level-dependent (BOLD) (1) MRI and dynamic contrast enhanced (DCE) MRI have emerged as useful techniques for noninvasive imaging of tumor vasculature (2,3). BOLD-MRI has been used to study tumor vascular growth (4), hemodynamic changes in response to treatments (5-12), acute hypoxia (13), vessel maturation (14 -17), and functional status of the vascular bed (14,15,18,19). DCE-MRI also provides important information regarding tumor function and anatomy. Parameters such as blood flow, capillary permeability, interstitial space, and blood volume can be determined by analyzing the kinetics of contrast-media uptake and wash-out (3,20,21).Assessment of vessel maturation and function with BOLD-or DCE-MRI is an approach whose utility for cancer investigations is well recognized. However, few studies have examined these two techniques simultaneously on the same subject. Thus, our understanding of mechanisms that may relate BOLD-and DCE-MRI remains relatively underdeveloped. Among the few investigators who have focused on this issue, Rijpkema et al. (22) compared BOLD-MRI (response to 98%O 2 /2%CO 2 gas) and DCE-MRI in meningioma patients. In their study, changes in T* 2 were found to correlate inversely with the wash-out rate of the Gd contrast agent. In two other papers, Peller et al. (23) and Jiang et al. (24) found no relationship between BOLD-and DCE-MRI. However, the latter two studies employed semiquantitative DCE-MRI analyses instead of pharmacokinetic modeling. Although the reported parameters (maximum rate of enhancement and peak enhancement) may be related to physiological parameters, their lack of clear physiological significance could make their interpretation difficult (25).In this study we compared BOLD-MRI measurement of vessel maturation (using hypercapnia, i.e., elevated levels of CO 2 ) and BOLD-MRI measurement of vessel functionality (using carbogen breathing, i.e., elevated levels of O 2 and CO 2 ) with DCE-MRI using standardized pharmacokinetic quantities (25).DCE-MRI measurement of uptake and wash-out of a contrast agent can help to characterize vasculature during the neoangiogenesis process (20). In this study we assessed how these parameters correlated with BOLD-MRI measurements of neovascular maturation and...

Caveolin-1 Is Critical for the Maturation of Tumor Blood Vessels through the Regulation of Both Endothelial Tube Formation and Mural Cell Recruitment

“…[23][24][25][26] In brief, MRI was obtained with a 4.7-T (200 MHz, 1 H) 40-cm inner diameter bore system (Bruker Biospec, Ettlingen, Germany) using the 6.5-kDa blood pool contrast agent P792 (Vistarem, Guerbet, France). High-resolution multislice T2-weighted spin echo anatomical imaging was performed just before dynamic contrast-enhanced imaging.…”

“…The tracer concentration changes were fitted to a two-compartment pharmacokinetics model as previously described. 23,27,28 An operator-defined region of interest encompassing the tumor was analyzed on a voxel-by-voxel basis to obtain parametric maps. The K trans and K ep values (min…”

Molecular and Functional MRI of the Tumor Microenvironment

“…This abnormal vasculature results in areas of hypoxia, acidic extracellular pH partly due to poor perfusion, increased glycolysis, and substrate deprivation that result in radiation and drug resistance (7). MRI techniques using blood oxygen level-dependent contrast (8) or dynamic contrastenhanced MRI have been applied for several decades to characterize tumor vasculature (9), whereas MRS and MR spectroscopic imaging have been used to measure pH and metabolism (10).…”

Detecting gas‐induced vasomotor changes via blood oxygenation level‐dependent contrast in healthy breast parenchyma and breast carcinoma

“…Administering either pure oxygen or carbogen (conventionally 95% O 2 , 5% CO 2 ) increases blood oxygen levels, but with opposite effects on vascular tone, since carbon dioxide is a potent vasodilator. Several groups have therefore proposed exploiting the differential vasomotor effects of hyperoxia and hypercapnia to employ BOLD contrast as a functional biomarker of vascular maturity 3, 12, 13. Immature tumor vessels lacking appropriate smooth muscle vasculature should be unable to either dilate or constrict in response to vasoactive challenges, whereas surrounding healthy mature vessels should show a response.…”