Evaluation of pancreatic tumor development in KPC mice using multi-parametric MRI

Abstract

Background: Pancreatic ductal adenocarcinoma (PDA) is a fatal disease with very poor prognosis. Development of sensitive and noninvasive methods to monitor tumor progression in PDA is a critical and unmet need. Magnetic resonance imaging (MRI) can noninvasively provide information regarding underlying pathophysiological processes such as necrosis, inflammatory changes and fibrotic tissue deposition.

Methods: A genetically engineered KPC mouse model that recapitulates human PDA was used to characterize disease progression. MR measures of T₁ and T₂ relaxation times, magnetization transfer ratio (MTR), diffusion and chemical exchange saturation transfer were compared in two separate phases i.e. slow and rapid growth phase of tumor. Fibrotic tissue accumulation was assessed histologically using Masson's trichrome staining. Pearson correlation coefficient (r) was computed to assess the relationship between the fibrotic tissue accumulation and different MR parameters.

Results: There was a negative correlation between amide proton transfer signal intensity and tumor volume (r = - 0.63, p = 0.003) in the slow growth phase of the tumor development. In the terminal stage of rapid growth phase of the tumor development MTR was strongly correlated with tumor volume (r = 0.62, p = 0.008). Finally, MTR was significantly correlated with % fibrosis (r = 0.87; p < 0.01), followed by moderate correlation between tumor volume (r = 0.42); T₁ (r = - 0.61), T₂ (r = - 0.61) and accumulation of fibrotic tissue.

Conclusions: Here we demonstrated, using multi-parametric MRI (mp-MRI), that MRI parameters changed with tumor progression in a mouse model of PDA. Use of mp-MRI may have the potential to monitor the dynamic changes of tumor microenvironment with increase in tumor size in the transgenic KPC mouse model of pancreatic tumor.

Keywords: KPC; Multi-parametric MRI; Pancreatic ductal adenocarcinoma; Tumor microenvironment.

Fig. 1

a Progressive tumor volumes for individual KPC mice (n = 9) that were imaged longitudinally. There was an exponential increase in tumor volume, in 6 out of 9 animals, once it reached a certain threshold value i.e. 250 mm³ (dotted line) in this study. b Correlation between US and MRI measurements for tumor volume. c Representative whole body image of tumor in KPC mice (Bioinvision, Cleveland, OH) and coronal MR image of the same mouse. d Representative axial MR and US image of tumor in the same KPC mouse. Red arrows point towards pancreatic tumor (c and d)

Fig. 2

Relationship between tumor volume and different MR parameters. a-d show the relationship between tumor volume and T₁, T₂, MTR and APT signal intensity respectively, when the tumor volume is less than 250 mm³. e-h show the relationship between tumor volume and T₁, T₂, MTR and APT signal intensity respectively, when the tumor volume exceeds 250 mm³

Fig. 3

Relationship between tumor volume and diffusion measurements. a and b show the relationships between tumor volume and ADC (pseudo-diffusion), and ADC (high-b values), respectively, when the tumor volume is smaller than 250 mm³. c and d show the relationships between tumor volume and ADC (pseudo-diffusion), and ADC (high-b values), respectively, when the tumor volume is larger than 250 mm³

Fig. 4

a Representative figure of frequency distribution of the pixels of different MR parameters in a KPC mouse at baseline and final time points. b Representative figure of percentage pixels above T₁, T₂, MTR, ADC and APT value in a KPC mouse at baseline and final time points

Fig. 5

Area under curve (AUC) demonstrating differences in multi-parametric MR measures in PDA of < 250 mm³ and > 250 mm³ in 5 KPC mice

Fig. 6

Representative Masson’s Trichrome and H&E stains for a smaller tumor (a) and larger tumor (b) from KPC mice and corresponding anatomic images and colored maps with T₁, T₂, MTR and ADC measures for pancreatic tumor

Fig. 7

Correlation between % fibrosis and tumor volume and other MR parameters. There was moderate correlation between increase in tumor volume, T₁, T₂ and increase in fibrotic tissue accumulation (a, b, c). MTR % was significantly correlated with increase in fibrotic tissue accumulation (d)