Abstract
BackgroundPancreatic 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.MethodsA 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.ResultsThere 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.ConclusionsHere 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.
Highlights
Pancreatic ductal adenocarcinoma (PDA) is a fatal disease with very poor prognosis
Increase in pancreatic tumor volume with age in K-rasLSL-G12D/+; Trp53LSL-R172H/+; Cre (KPC) mice Longitudinal Magnetic resonance imaging (MRI) demonstrated two distinct phases existed in tumor progression in KPC mice i.e. slow phase and rapid phase
There was a strong correlation between tumor volume and amide proton transfer (APT) signal intensity (r = − 0.63, p = 0.003) in < 250 mm3 whereas no correlation was present between APT signal intensity and tumor volume (r = − 0.03) when the tumor size was > 250 mm3
Summary
Development of sensitive and noninvasive methods to monitor tumor progression in PDA is a critical and unmet need. Pancreatic ductal adenocarcinoma (PDA) is the most lethal form of human cancer [1]. Clear understanding of tumor progression may help in identifying PDA at an early stage. In order to characterize the tumor progression, As an experimental model for pancreatic cancer, tumors have been implanted subcutaneously and within the pancreas [3,4,5]. Both of these models do not parallel the human disease progression. A genetically engineered mouse model, having genetic alterations in genes K-rasLSL-G12D/+; Trp53LSL-R172H/+; Cre (KPC) offers an alternative to transplantation models for preclinical therapeutic evaluation as it expresses mutations similar to
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