Microvascular Characteristics And Early Therapy Evaluation In The Murine Orthotopic Pancreatic Cancer Model By Diffusion And Perfusion MRI

Pancreatic cancer is a relatively common cancer, with a high degree of malignancy, low diagnosis rate, poor efficacy and poor prognosis, which is close to 100% mortality and the overall 5-year survival rate of less than 5%. In recent years, the incidence of pancreatic cancer showed an increasing trend in the world. Shanghai is the highest incidence of pancreatic cancer in China. Study of pathogenesis of pancreatic cancer, advances in the development of new anti-pancreatic cancer strategies and preclinical evaluation of anti- pancreatic cance drugs highlight the need for animal models that are hopefully more reflective of human pancreatic cancer.In this study,We successfully establish a orthotopic murine model using two different human pancreatic adenocarcinoma cell lines SW1990 and MIAPaCa-2, the monitoring of tumor growth and the formation of metastases was examined by 3.0 Tesla MRI, it can reduce injury and death of animals. Our aim was to discuss the assessment value of animal models in 3.0 T MRI.On the one hand, when the model successfully established, a small molecular weight (Gd-DTPA) and a reversible albumin-binding (Gd-EOB-DTPA) contrast agent were used to evaluate the murine orthotopic pancreatic cancer model in DCE-MRI. The volume transfer constant (Ktrans), extracellular extravascular volume fraction (Ve), reflux rate constant (KeP) and initial area under the concentration curve in 60 seconds (AUC) were generated from DCE-MRI combined with Tofts dynamic two-compartment model. It will be explored that the value of quantitative assessment of DCE-MRI for pancreatic cancer microvascular characteristics. On the other hand, Referring to gemcitabine regimen in the clinical treatment, the value in the early assessment of efficacy was compared between conventional DW-MRI (select 3 b values, b=50,400,800 s/mm2) and IVIM-DWI (select 8 b values, b=0,25,50, 80,100,300,500,800 s/mm2) in this model. This study will provide experimental evidence for implementation of DCE-MRI and DW-MRI as response biomarkers in the clinic.Part I The new diagnosed application of 3.0 Tesla magnetic resonance imaging in the orthotopic nude mouse model of pancreatic cancerObject:To successfully establish a orthotopic murine model using two different human pancreatic adenocarcinoma cell lines and to propose a protocol of 3.0 Tesla MRI for noninvasive characterization of this model.Materials and Methods:Tumor cells SW1990 and MIAPaca-2 were injected into the pancreas of BALB/C nu/nu mice. Tumor growth rate and morphological information was assessed by 3.0 Tesla MRI (T1WI,T2WI and DCE-MRI) and immunohistology.Results:Proliferation of SW1990 was significantly faster than those of MIAPaca-2 (P=0.000), but MIAPaca-2 mice had a significantly shorter survival than SW1990 mice (41 days and 44days respectively, P= 0.027). MRI could reliably monitor tumor growth in both cell lines:the tumors resembled a spherical growth pattern showed high-intensity signal, the SW1990 group developed significantly larger tumors compared to MIAPaCa-2 group. There were not statistical difference between two groups in which tumors size were assessed using electronic callipers and MRI scan (P=0.680). Both tumor showed a slow gradual enhancement pattern. Immunohistochemistry demonstrated tumor tissues indicated high expression of Ki-67.Conclusion:This model closely mimics human pancreatic cancer and permits monitoring of tumor growth and morphological information by noninvasive 3.0 Tesla MRI studies reducing the number of mice required.Part â…¡ Dynamic contrast-enhanced(DCE) MRI Assessment of microvascular characteristics in the murine orthotopic pancreatic cancer modelObject:To assess the dynamic contrast enhanced magnetic resonance imaging (DCE-MRI)-derived pharmacokinetic parameters between two contrast agents in a murine orthotopic pancreatic cancer model and to evaluate the tumor heterogenity and the potential association between kinetic parameters and angiogenic markers such as the microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression by immunohistochemistry.Materials and Methods:Human pancreatic adenocarcinoma cell line MIAPaCa-2 was injected into the pancreas of BALB/C nu/nu mice. DCE-MRI was performed using Gd-DTPA and Gd-EOB-DTPA. Quantitative and semi-quantitative vascular parameters (Ktrans, Kep, Ve and AUC) were calculated by using a dedicated postprocessing software program.Values were compared with tumor rim, tumor core and the entire tumor. The MVD and VEGF expression between tumor rim and tumor core were also compared.Results:There were no significant differences in Ktrans, Kep, Ve, and AUC values of the three groups when using Gd-DTPA. But there were significant differences in Ktrans, Kep, and AUC values of the three groups when using Gd-EOB-DTPA (P=0.014,0.022, 0.007, respectively), in addition, the Ktrans and KeP values of tumor core were significantly lower than those of the entire tumor (adjusted P=0.014 and 0.027, respectively), the AUC values of core were significantly lower than those of the entire tumor and rim (adjusted P=0.039 and 0.009, respectively). Immunohistology results revealed that MVD and VEGF expression in the tumor rim was significantly higher than that in the core. There was positive correlation between AUC and MVD, VEGF.Conclusion:The murine orthotopic pancreatic cancer model provides an ideal animal model to study human pancreatic cancer. It can more sensitively semi-quantitatively and quantitatively analyze tumor angiogenesis through selecting the albumin-binding contrast agent.Partâ…¢ Early Therapy Evaluation in the murine orthotopic pancreatic cancer model by Diffusion-Weighted Intravoxel Incoherent Motion ImagingObject:Early pancreatic cancer response following gemcitabine therapy was measured by diffusion-weighted imaging (DWI) and intravoxel incoherent motion DWI (IVIM-DWI).Materials and Methods:Two groups (n=6/group) of BALB/C nu/nu mice bearing orthotopic pancreatic adenocarcinoma xenografts were treated with saline and gemcitabine. DWI with 3 b values (b=50,400 and 800 s/mm2) and IVIM-DWI with multiple b values (b=0,25,50,80,100,300,500,800 s/mm2) were performed on days-1,1,10 after therapy initiation. The changes of ADC values, Dslow values, Dfast values and fp were compared with each other of both groups. At day 28, all tumors were collected for further histologic analyses.Results:ADC values and Dslow values increased gradually in gemcitabine group and were significant differences between two groups at 1 day. At 10 day, ADC values were significant differences, and Dfast values and fp were no significant differences. Immunohistochemical results showed that cell proliferation significantly reduced and cell apoptosis significantly increased compared to saline group. MVD was no significant difference.Conclusion:ADC value measurement, especially Dsiow value measurement can be used as an effective means of early evaluation in treating pancreatic cancer with gemcitabine.