ASPO Abstracts
Potential tumor suppressive role for IGFBP7 in pancreatic cancer
Category: Lifestyles Behavior, Energy Balance & Chemoprevention
Conference Year: 2019
Abstract Body:
Purpose: Determine and characterize the role of insulin-like growth factor binding protein7 (IGFBP7) in the tumor suppressive effects of caloric restriction (CR). This includes use of bioinformatics totarget CR-induced changes on IGFBP7 in normal (tumor-free) versus oncogenic (pancreatic cancer) murine models.Methods: Using 60 LSL-Kras(G12D)/Pdx-1-Cre/Ink4a/Arf(lox/+) mice, a human-relevant mousemodel of spontaneous pancreatic ductal adenocarcinoma (PDAC), we tested the effects of diet-inducedobesity (DIO) and CR, relative to control diet-fed mice. All mice were monitored for PDAC development andkilled at 26 weeks of age. Serum was analyzed for IGF-1 and IGFBP7. Pancreata collected from a separate groupof wild-type C57BL/6 mice fed DIO, CR, or Control diets for 12 months were analyzed by Affymetrixmicroarrays, with emphasis on IGF-related gene expression signatures. We also treated human PDAC cell linesMIA PaCa-2, BxPC-3, and PANC-1 with exogenous IGFBP7 following IGF-1 stimulation. Modulation of IGF-1signaling was measured by immunoblot analysis for phosphorylated IGF-1R, Akt, and ERK 1/2. Proliferation in response to IGFBP7 was also assessed using MTT-viability assay.Results: CR mice, relative to control, had increased pancreatic tumor-free survival, whileDIO mice had shortened survival. Serum biomarker analyses and gene expression microarray analyses indicateseveral components of the IGF signaling pathway were found to be altered by diet. Specifically, the expression ofIGFBP7 was increased in response to CR and decreased in response to DIO. All cell lines treated with IGFBP7 hadreduced phosphorylation in growth signaling pathways and decreased viability compared to untreatedcells.Conclusion: CR strongly inhibits pancreatic tumor development and progression compared toDIO in Kras Ink4a+/-mice. In wild-type C57BL/6 mice, there was a diet-dependent effect on IGF signalingproteins in serum and pancreatic tissue; in particular, IGFBP7 was modulated by dietary energy balance andappears to have anticancer effects on pancreatic cancer cells. These results suggest IGFBP7 may be a potentialintervention target for preventing and treating pancreatic cancer.
Keywords: pancreatic cancer,PDAC, IGFBP7, caloricrestriction, gene expression