Hursting pancreas opac2013

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  • Progression model for pancreatic cancer. Normal duct epithelium progresses to infiltrating cancer (left to right) through a series of histologically defined precursors (PanINs). The overexpression of HER-2/neu and point mutations in the K-ras gene occur early, inactivation of the p16 gene at an intermediate stage, and the inactivation of p53, DPC4, and BRCA2 occur relatively late.
  • Hursting pancreas opac2013

    1. 1. Energy Balance and Pancreatic Cancer: A Mechanistic Perspective Stephen D. Hursting, PhD, MPH Professor and Chair Department of Nutritional Sciences University of Texas at Austin and Professor, Department of Molecular Carcinogenesis University of Texas MD Anderson Cancer Center
    2. 2. Today’s Presentation• Lessons from mice: molecular targets and strategies for breaking obesity- pancreatic cancer links - Inflammatory signals - Growth factors and their signals - Adipokines and their signals• Adipocyte-macrophage-pancreatic epithelial interactions: triggers of inflammatory and metabolic perturbations in pancreata
    3. 3. Inflammation and Pancreatic Cancer ! Farrow and Evers. Surg Oncol 2002 3
    4. 4. • Differential gene expression from humans and mice in response to acute inflammation: sepsis (endotoxemia) and burns• No comparisons of low-level chronic inflammatory responses (as occur with obesity)• Recommendation: “By first requiring comprehensive genomic descriptions in patient studies to define the human disease, the disease altered pathways could be used as a guide to develop the animal model. The quality of the animal model could then be determined by how well it reproduces the human disease on a molecular basis rather than simply phenotype” 4
    5. 5. Modeling Energy Balance and Human Cancer in Mice by Altering Key Genes and Pathways Insert fig. 19.4 Hursting, et al., Mutation Res, 2005
    6. 6. BK5.COX-2 Transgenic Mouse Model of Pancreatitis-Induced Pancreatic Tumors5’ Keratin 5 promoter Murine COX-2 cDNA SV40 poly A 3’ acinar • 100% pancreatitis by 3-4 months islet cells • 20% spontaneous adenocarcinoma by 9 months in normoweight mice • Obesity increases (CR decreases): blood -Pancreatic steatosis vessel duct -Pancreatitis -Malignant conversion (~40%) -Serum IGF-1 levels Pancreatic Pancreatitis -Serum inflammatory cytokine levels adenocarcinoma -IGF-1R/Akt/mTOR signaling -NF-kB signaling Lashinger, et al., Cancer Prev Res, 2011
    7. 7. Pancreatic Cancer Progression Model Hruban R H et al. Clin Cancer Res 2000;6:2969- 2972©2000 by American Association for Cancer Research
    8. 8. Effect of Energy Balance on PanIN and Pancreatic Adenocarcinoma Development in Kras/Ink4A+/- Mice Hypothesis: CR will diminish, and DIO will enhance, PanIN/PDAC formation in Pdx1-Cre/LSL-KrasG12D/INK4A+/- miceDiet Groups qMR(8/20wks) Interim Timepoint (10wks) Survival 30% Calorie Restriction (CR) all 15M 25M Control (CON) all 15M 25M Diet-induced Obesity (DIO) all 15M 25M 45 75Total Mice: 120Primary Endpoints: Prevalence of PanIN/PDACs, fibrosis, inflammation, and atypia; survival
    9. 9. Pathological Assessment at 10-Week Interim Timepoint B. Prevalence of pathological indicesA. Incidence of pancreatic lesions No PanIN- PanIN- PanIN- PDAC lesion 1 2 3 CR 1 5 4 5 0 Control 1 4 4 3 3 DIO 1 1 3 3 7 n=15 ! CR Control DIO mostly normal; mix of normal, mix of PanIns, some PanINs PanINs, PDAC PDAC Lashinger, et al., Cancer Res (under review)
    10. 10. IGF-1 Infusion Restores Growth of Orthotopically Transplanted Kras Ink4A+/- and K5.COX-2 Pancreatic Tumors in LID Mice c a b Dr. L. Lashinger: mTOR pathway a a K. Devlin: MicroRNAs b (Lashinger, et al. Cancer Res, under review) A. Harvey: NF-kB
    11. 11. Serum Cytokine Levels Are Reduced in LID MiceCytokine LID Mice Wildtype Mice P value mean +/- sd(pg/ml) Mean +/- sd(pg/ml)GM-CSF 218.7 + 14.6 307.7 + 15.3 0.0008IFN-γ 65.8 + 4.9 100.5 + 3.4 0.001IL-1 18.3 + 2.6 33.4 + 7.6 0.03IL-2 39.7 + 11.2 56.5 + 22.3 0.47IL-4 7.6 + 0.4 11.7 + 0.5 <0.0001IL-5 16.1 + 1.9 30.8 + 4.1 0.0007IL-6 46.7 + 8.6 56.9 + 9.5 0.48IL-10 199.6 + 17.0 427.4 + 52.2 <0.0001IL-12 401.6 + 47.4 645.5 + 29.1 0.003TNF-α 6.3 + 0.7 11.3 + 1.5 0.002 Lashinger, et al., Cancer Prev Res, 2011P values calculated from Student’s t-test Similar Findings: Olivo-Marston, et al., Mol Carcinog 2009
    12. 12. GF-1 and Leptin Modulate NF- кB Signaling IGF-1, Insulin Lepti n Plasma m embrane JAK PI3K P Akt/mT OR P (raptor) Stat3 26S Proteasome IKKα IKKβ IKKγ s32 s36 IкBα RelA/ p50 p65 Nucleus Inflammatory Gene Transcription (COX-2, Survivin, Cyclin D1, VEGF) 12 Harvey, et al. Mol Carcinogenesis, 2012; Lashinger, et al., Cancer Res, submitted
    13. 13. Obesity, Diabetes and Pancreatic Cancer Dr. Rudolf Kaaks, German Cancer Research Center Diabetes Care 35:299-304, 2012CJ. Currie, C.D. Poole, S. Jenkins-Jones, E.A.M. Gale, J.A. Johnson, C.L. Morgan 1) Cohort 1: Metformin Dr. Michael Pollak 2) Cohort 2: Sulfonylurea McGill Univ.62,809 T2D patients: 3) Cohort 3: Metformin + Sulfonylurea 4) Cohort 4: Insulin
    14. 14. Differential Effects of Glucose-LoweringTherapies on Cancer Survival in Type 2 Diabetes HR (met v sulf)= 1.36 (p<0.001) HR (met v sulf)= 4.95 (p<0.001) Met + Sulf Metformin Metformin Met + Sulf Insulin Insulin Sulfonylurea All Cancers Sulfonylurea Pancreatic Cancer Years to event/censor ! Years to event/censor Currie, et al. Diabetalogia, 2009
    15. 15. Diet-induced obesity causes inflammation in organs and visceral fat. Andrew Dannenberg, Weill-Cornell Cancer Center Crown-like Structures (Macrophage/Adipocyte/Epithelial Tumor Cell Interactions)Subbaramaiah K, et al. Cancer Prev Res2011 Ouchi, et al. Nature Rev Immunol, 2011
    16. 16. Ford, DiGiovanni, Hursting. In: Adipose Tissue and Cancer. M. Kolonin, ed. 2012
    17. 17. AcknowledgementsUniversity of Texas at Austin John DiGiovanni, Michele Forman, Nomeli Nunez, Rong CuiUniversity of Texas-M.D. Anderson Cancer Center Sue Fischer, Donna Kusewitt, JJ Shen, Powel BrownMt. Sinai Medical Center Derek LeRoith, Shoshana YakarNational Cancer Institute Curt Harris, Chuck Vinson, Lyuba VarticovskiKansas University Medical Center Carol Fabian, Brian Petroff, Bruce KimlerUNC-Chapel Hill Chuck PerouWeill-Cornell Cancer Center Andrew Dannenberg Funding: National Cancer Institute, National Institute of Environmental Health Sciences, American Institute for Cancer Research, Breast Cancer Research Foundation, Susan G. Komen Foundation

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