Native T1 Mapping Magnetic Resonance Imaging as a Quantitative Biomarker for Characterization of the Extracellular Matrix in a Rabbit Hepatic Cancer Model

Abstract

To characterize the tumor extracellular matrix (ECM) using native T1 mapping magnetic resonance imaging (MRI) in an experimental hepatic cancer model, a total of 27 female New Zealand white rabbits with hepatic VX2 tumors were examined by MRI at different time points following tumor implantation (day 14, 21, 28). A steady-state precession readout single-shot MOLLI sequence was acquired in a 3 T MRI scanner in prone position using a head-neck coil. The tumors were segmented into a central, marginal, and peritumoral region in anatomical images and color-coded T1 maps. In histopathological sections, stained with H&E and Picrosirius red, the regions corresponded to central tumor necrosis and accumulation of viable cells with fibrosis in the tumor periphery. Another region of interest (ROI) was placed in healthy liver tissue. T1 times were correlated with quantitative data of collagen area staining. A two-way repeated-measures ANOVA was used to compare cohorts and tumor regions. Hepatic tumors were successfully induced in all rabbits. T1 mapping demonstrated significant differences between the different tumor regions (F(1.43,34.26) = 106.93, p < 0.001) without interaction effects between time points and regions (F(2.86,34.26) = 0.74, p = 0.53). In vivo T1 times significantly correlated with ex vivo collagen stains (area %), (center: r = 0.78, p < 0.001; margin: r = 0.84, p < 0.001; peritumoral: r = 0.73, p < 0.001). Post hoc tests using Sidak’s correction revealed significant differences in T1 times between all three regions (p < 0.001). Native T1 mapping is feasible and allows the differentiation of tumor regions based on ECM composition in a longitudinal tumor study in an experimental small animal model, making it a potential quantitative biomarker of ECM remodeling and a promising technique for future treatment studies.

Multiparametric MRI enables for differentiation of different degrees of malignancy in two murine models of breast cancer

“…Furthermore, the heterogeneity increased over time in 4T1 tumors, as reflected inter alia in a wider range and kurtosis of the histogram analysis and contrary, the heterogeneity of 67NR tumors as assessed with analysis of diffusion-weighted imaging did not increase during tumor progression. These features of tumoral composition correlate with native T1 times as well, which increase with the amount of necrotic areas and were thus higher in high malignant than low malignant tumors ( 48 ), as confirmed here. In the clinical setting examining patient with kidney tumors, native T1 times enabled to differentiate high grade clear cell renal cell carcinoma (cRCCs) from lower grade cRCCs ( 49 ).…”

“…In the clinical setting examining patient with kidney tumors, native T1 times enabled to differentiate high grade clear cell renal cell carcinoma (cRCCs) from lower grade cRCCs (49). The results also show the increase in T1 values during tumor progression (50), likely due to areas of dense proliferative undifferentiated tumor cells (51, 52) and increasing density of the extracellular matrix and collagen contents, assessed in a rabbit hepatic cancer model (48) and in specimens of breast cancer patients (53). However, in some studies, including a study evaluating the effect of anti-angiogenic therapy in a mouse ovarian cancer model, T1 times did not change during tumor growth (51).…”

Quantification of contrast agent uptake in the hepatobiliary phase helps to differentiate hepatocellular carcinoma grade

“…Only a limited number of studies are available investigating the potential of plain T1 mapping to characterize tumors. Keller et al showed the potential of plain T1 mapping as a reliable non-invasive method for quantification and characterization of primary liver tumors in a rabbit model 23 . In our study, G3 tumors had a slightly higher mean T1 time than G1 and G2 tumors.…”

Therapeutic and diagnostic targeting of fibrosis in metabolic, proliferative and viral disorders

“…For example, on the basis of different T1 relaxation times in different tumor areas, T1-mapping MRI allows for the visualization of the tumor extracellular matrix (ECM) in a preclinical rabbit model of liver cancer (Fig. 8c; image 1,2) [300]. High T1 relaxation times in tumor and short T1 relaxation times in regions surrounding the tumor suggest native T1 mapping as a possible quantitative means to assess ECM remodeling.…”

“…Color-coding: the analysis of manuscripts described in section 4.2 reveal the frequency in which each organ and imaging modality are investigated and used for the detection of fibrosis in cancer; light red = low frequency; red = medium frequency; dark red = high frequency. All images were adapted with permission [300,302,303,309,312,314].…”