A comparative investigation of the perfusion of spontaneous and transplanted pancreatic ductal adenocarcinoma (PDA) tumours in genetically engineered mice by dynamic contrast-enhanced MRI


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Leanne Bell1, Davina Honess1, Dominick McIntyre1, David Tuveson1, John Griffiths1
1Cancer Research UK Cambridge Research Institute, Cambridge, United Kingdom

Background

The genetically engineered KPC mouse model conditionally expresses mutant kras and p53 alleles specifically in the pancreas, resulting in spontaneous PDAs with pathology, molecular features and sensitivity to gemcitabine that closely resemble those of the clinical tumour. Subcutaneously transplanted low-passage cells from KPC tumours generate tumours of contrasting architecture, with minimal desmoplastic stroma and greater gemcitabine sensitivity, suggesting a causal relationship between stromal content and gemcitabine response (Ref). To assess relative tumour perfusion profiles we conducted longitudinal DCE-MRI studies in both tumour types.

Method

Anaesthetised mice were imaged in a 40mm millipede coil in a 9.4T Varian magnet. Anatomical T2W FSE images were acquired for tumour measurement and selection of tumour and paraspinal muscle regions of interest on each 1mm slice.  The DCE-MRI time course was acquired using T1W RF-spoiled echo sequences before and for 10 min after an i/v bolus of 0.1 mmol/kg Gd-DTPA, with 6s time resolution. Data were analysed to calculate Ktrans, the Gd-DTPA transfer constant, (related to perfusion, blood flow and vessel surface area) which was normalised to muscle values to correct for inter-animal differences in e.g. arterial input. Tumours imaged ranged from ~100mm3 to 500mm3 (spontaneous) and ~50mm3 to 1000mm3 (transplanted).

Results

Tumour doubling times were faster for transplanted (~7-8days) than spontaneous (~10 days) tumours.  Normalised median Ktrans values for transplanted tumours typically dropped rapidly with increase in tumour size from ~50mm3 to 250mm3 (from up to 0.006 to ~ 0.002 sec-1), with a smaller decrease on further growth. Normalised median Ktrans values in spontaneous tumours also decreased with tumour growth from 100mm3 to 500mm3 (from ~0.002-0.0005 sec-1) but this decrease was essentially linear.

Conclusion

The presence of desmoplastic stroma in spontaneous pancreatic tumours appears to be associated with initially poorer perfusion than in transplanted tumours and with different perfusion patterns as tumours develop.