LB3
Loss of PEDF in Pdx1-Cre/LSL-Kras mice leads to invasive pancreatic adenocarcinoma
Kevin Adrian, Christopher Quinn, John Cravero, Morgan Barron, Sue Crawford, Paul Grippo
Northwestern University, Chicago, USA
We have previously demonstrated that loss of pigment epithelium-derived factor (PEDF) can lead to invasive pancreatic cancer in EL-Kras mice. These transgenic mice express human mutant Kras which induces precancerous lesions in the pancreas that never progress to invasive disease. Hence PEDF, through one or more mechanisms in one or more cell types, appears to contribute to the progression of pancreatic cancer, and this is reiterated in human pancreatic cancer where loss of PEDF is observed in at least 70% of all patients. To determine if loss of PEDF in a distinctive progenitor cell type targeted with mutant Kras can also lead to cancer development, Pdx1 positive cells were selected and Pdx1-Cre/LSL-Kras/PEDF null mice were generated. In a small cohort of Pdx1-Cre/LSL-Kras mice with either hemi- or homozygous loss of PEDF, the presence of invasive adenocarcinoma within a thick stromal bed (indicative of human pancreatic cancer) was observed. Two of these mice were 10 months of age. In seven Pdx1-Cre/LSL-Kras mice (wild type PEDF) at 9-10 months of age, mPanINs and other lesions were detected, without any signs of invasive disease with a prominent desmoplastic reaction. A single 14-month-old Pdx1-Cre/LSL-Kras/PEDF null mouse presented with completely infiltrating PDAC with very little normal-appearing parenchyma. Previous work with the Pdx1-Cre/LSL-Kras mice demonstrated a very low incidence of pancreatic cancer in older mice, generally 12 months of age or older. In a PEDF null setting, these mice generated aggressive, invasive disease even at 10 months of age, supporting the role of PEDF loss in mPanIN to PDAC progression. A similar finding was previously observed in EL-Kras mice. Together, this data provides compelling evidence for the ability of PEDF to prevent cancer progression in both EL- and PDX1-positive cells types with mutant Kras expression in the pancreas. The mechanism(s) of PEDF in suppression cancer development is being investigated to determine if the course of disease progression via PEDF loss is common in both systems.
