Imaging Hallmarks of the Tumor Microenvironment in Glioblastoma Progression

Abstract

Glioblastoma progression involves multifaceted changes in vascularity, cellularity, and metabolism. Capturing such complexities of the tumor niche, from the tumor core to the periphery, by magnetic resonance imaging (MRI) and spectroscopic imaging (MRSI) methods has translational impact. In human-derived glioblastoma models (U87, U251) we made simultaneous and longitudinal measurements of tumor perfusion (Fp), permeability (Ktrans), and volume fractions of extracellular (ve) and blood (vp) spaces from dynamic contrast enhanced (DCE) MRI, cellularity from apparent diffusion coefficient (ADC) MRI, and extracellular pH (pHe) from an MRSI method called Biosensor Imaging of Redundant Deviation in Shifts (BIRDS). Spatiotemporal patterns of these parameters during tumorigenesis were unique for each tumor. While U87 tumors grew faster, Fp, Ktrans, and vp increased with tumor growth in both tumors but these trends were more pronounced for U251 tumors. Perfused regions between tumor periphery and core with U87 tumors exhibited higher Fp, but Ktrans of U251 tumors remained lowest at the tumor margin, suggesting primitive vascularization. Tumor growth was uncorrelated with ve, ADC, and pHe. U87 tumors showed correlated regions of reduced ve and lower ADC (higher cellularity), suggesting ongoing proliferation. U251 tumors revealed that the tumor core had higher ve and elevated ADC (lower cellularity), suggesting necrosis development. The entire tumor was uniformly acidic (pHe 6.1-6.8) early and throughout progression, but U251 tumors were more acidic, suggesting lower aerobic glycolysis in U87 tumors. Characterizing these cancer hallmarks with DCE-MRI, ADC-MRI, and BIRDS-MRSI will be useful for exploring tumorigenesis as well as timely therapies targeted to specific vascular and metabolic aspects of the tumor microenvironment.

Assessing Tumour Haemodynamic Heterogeneity and Response to Choline Kinase Inhibition Using Clustered Dynamic Contrast Enhanced MRI Parameters in Rodent Models of Glioblastoma

“…In addition, physiologic characteristics such as apparent diffusion coefficient and perfusion have been found to correlate to tumoural cellularity and angiogenesis [ 49 ]. The spatial distribution of DCE-MRI-based perfusion parameters within the tumour area is a very important tool allowing for the assessment of the angiogenic compositions of the tumour [ 22 , 23 ]. The profound intra-tumour vascular heterogeneity in GBMs is due to aberrant microvasculature and inefficient nutrient delivery [ 50 ].…”

“…They are typically heterogeneous both on genetic and histo-pathological levels, with intratumoural spatial variation in the cellularity, angiogenesis, extravascular extracellular matrix, and areas of necrosis [ 20 , 21 ]. The heterogeneity can be with regards to cellular morphology, gene expression, metabolism, and angiogenic and proliferative potential, some of which can be investigated using DCE-MRI, for example, in investigating angiogenic processes [ 22 , 23 ]. Substantial intra-tumour heterogeneity correlates with increased morbidity, mortality, and recurrence rates in patients [ 24 ].…”

Comparison of Lanthanide Macrocyclic Complexes as 23Na NMR Sensors

“…32 This GdDOTP 5− dose was based on prior work with TmDOTP 5− which at this dose allows longitudinal MRI scans of tumors in rats. 50 Post-GdDOTP 5− 23 Na-MRSI was first performed 30 min after the start of infusion and repeated subsequently thereafter during the infusion. The final scan was a post-GdDOTP 5− 1 H-MRI.…”

Methylated tetra‐amide derivatives of paramagnetic complexes for magnetic resonance biosensing with both BIRDS and CEST

“…MRI and MRSI experiments with CEST and BIRDS techniques, respectively, using a variety Ln 3+ (e.g., thulium Tm 3+ , europium Eu 3+ or ytterbium Yb 3+ ) conjugated with various chelate designs is a rapidly growing area of research 8,18–21 . For example, TmDOTP 5− , which is Tm 3+ complexed with 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetrakis(methylenephosphonate) (DOTP 8− ), has shown great potential for pH (and temperature) imaging in various pathological/disease states 22–27 …”

“…8,[18][19][20][21] For example, TmDOTP 5À , which is Tm 3+ complexed with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylenephosphonate) (DOTP 8À ), has shown great potential for pH (and temperature) imaging in various pathological/disease states. [22][23][24][25][26][27] Among lanthanide complexes for BIRDS, Tm 3+ complexed with a methylated version of DOTA 4À (i.e., DOTMA 4À , which is 1,4,7,10-tetraazacyclododecane-α, α 0 , α 00 , α 000 -tetramethyl-1,4,7,10-tetraacetate) shows promise in temperature mapping because the hyperfineshifted methyl proton resonance is $100 ppm away from water proton resonance. These protons also have very short relaxation times (i.e., T 1 of 4.7 ms and T 2 of 4.2 ms), and have high temperature sensitivity (i.e., 0.7 ppm/ C at 35 C).…”