MRI of human tumor xenografts in vivo: Proton relaxation times and extracellular tumor volume

Proton T1 and T2 differ substantially between tumors, but the tumor properties causing heterogeneity in T1 and T2 have not been fully recognized. The purpose of the study reported here was to investigate whether differences in T1 and T2 between tumors are mainly a consequence of differences in the fractional volume of the extracellular compartment. The study was performed using a single human tumor xenograft line showing large naturally occurring intratumor heterogeneity in the size of the extracellular compartment. The size of the extracellular compartment was calculated from the volume and the density of the tumor cells. Cell volume was measured by an electronic particle counter. Cell density was determined by stereological analysis of histological preparations. T1 and T2 were measured by MRI in vivo both in the absence and presence of Gd-DTPA. Two spin-echo pulse sequences were used, one with a repetition time (TR) of 600 ms and echo times (TEs) of 20, 40, 60, and 80 ms and the other with a TR of 2,000 ms and TEs of 20, 40, 60, and 80 ms. Measurements of T1 and T2 in the presence of Gd-DTPA were performed in a state of semi-equilibrium between uptake and clearance of Gd-DTPA. MR-images and histological preparations of tumor subregions homogeneous in extracellular volume were analysed in pairs. The extracellular volume differed between tumor subregions from 5 to 70%. T1 and T2 measured in the absence of Gd-DTPA differed between tumor subregions by a factor of approximately 1.5 and increased with increasing extracellular volume. The relative decrease in T1 caused by Gd-DTPA, represented by (T1 control−T1 Gd-DTPA)T1 control, also increased with increasing extracellular volume. The relative decrease in T2 did not change significantly as the extracellular volume increased. These observations strongly suggest that the size of the extra-cellular compartment is a major determinant of proton T1s and T2s of tumors, possibly because the ratios of free to structured and free to bound water increase with increasing extracellular tumor volume.