Fenton opac2013


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  • Relationship between obesity and colorectal polyps?Relationship between adipokines and colorectal polyps?
  • Sidney WinawerSloan KetteringPrevention and diagnosis of colorectal cancer.
  • At time of colonoscopy
  • Clinical and Translational Science Institute
  • Fenton opac2013

    1. 1. Linking Adipokines and Obesitywith Colorectal Cancer RiskJenifer I. Fenton, PhD, MPHMichigan State UniversityEast Lansing, MIIASO/WCRF April, 2013
    2. 2. Diet and cancer risk: Is it bodycomposition?The Shape of Things to Come. The Economist; Dec 11, 2003.(http://www.economist.com/displaystory.cfm?story_id=2282754)
    3. 3. Obesity-induced inflammatory changes inadipose tissue
    4. 4.  Serum leptin levels elevated in endometrial,breast, prostate and colon cancer patients Leptin levels associated with greater risk ofbeing diagnosed with larger and riskier tumors Increased proliferation of breast, esophagus,colon and prostate cancer cells stimulated the growth and proliferation of coloncancer cells (HT-29 and CACO-2) promotes invasiveness of kidney and colonicepithelial cellsLeptin and cancer
    5. 5. Copyright ©2005 American Association for Cancer ResearchOtake, S. et al. Clin Cancer Res 2005;11:3642-3646Adenoma risk
    6. 6. Evolution of a lethal cancerJones S et al. PNAS 2008;105:4283-4288©2008 by National Academy of Sciences
    7. 7. Hallmarks of cancer paradigm• The authors suggest that most if not all cancers haveacquired the same set of functional capabilities duringtheir development, albeit through various mechanisticstrategies.Cell. 2000; Cell Press. 2011
    8. 8. Model system
    9. 9. Cell characteristics Two cell lines: “Normal” (Apc+/+; YAMC) and “Preneoplastic” (ApcMin/+; IMCE) Neither will grow in soft agar or form tumors in athymicmice Cells are grown in presence of IFN-gamma at 33º C(growth permissive); experiments done in IFN-free,serum-free media at 39ºC (non-permissive for growth). Under non-permissive conditions: cells form tightjunctions, polarize, differentiate and undergo apoptosisover 5 to 8 days.These cells serve as an excellent model to study early events in colon carcinogenesisFenton et al, Carcinogenesis, 2005.
    10. 10. Colon epithelial cellsNormal MetastaticNon-tumorigenic TumorigenicYAMCIMCESMAD3-/-YAMC-Ras IMCE-RasMC38Modeling colon epithelial cellcarcinogenesis
    11. 11. Cell culture methodologyCells grow to 70%confluence in flasksin growth media.33ºCCells are transferredto 39ºC, media isaspirated, andserum-free, IFN freemedia is placed oncells.39ºC 24hr• Collect cellsin lysis bufferfor Westernblot• Angiogenesis• Cell signaling• CellproliferationTreat cells
    12. 12. Leptin induces IMCE cell proliferationYAMC IMCEOb-RProliferation results verified by flow cytometric analysis
    13. 13. Microarray analysisUp in IMCEIMCE Time-independent217 genesIMCE Time-dependent2-fold 707 genesDown in YAMCYAMC Time-independent588 genesYAMC Time dependent 2-fold 229 genesFenton et al, Molecular Carcinogenesis, 2007
    14. 14. Gene CategoryNumber ofgenesGenesProliferation Up 42 Btg2, Bub1, Bub1b, Ccna2, Ccnf, Cd68, Cdc25b,Cdc25c, Cdkn2c, Cdkn2d, Crip1, Gsg2, Il18, Incenp,Lxn, Mxd4, Mdm2, Mki67, Gadd45b, Nmyc1, Pdgfa,Pdgfra, Plk1, Dusp1, Kif20a, Rb1, Aurkb, Aurka, Tacc3,Tgfb2, Gadd45g, Pttg1, Cks2, 1190002H23Rik, Cdca1,Kntc2, Rprm, Ube2c, Rhou, Sesn3, Pard6g, Cdc20Down 14 Cdkn2a, Cpeb1, Ddit3, Dst, Ereg, Igfbp4, Cxcl12, Plk2,Vegfa, Zfr, Ets2, Pdgfc, Atf5, Sesn2Cell cycle Up 34 Bub1, Bub1b, Ccna2, Ccnf, Cdc25b, Cdc25c, Cdkn2c,Cdkn2d, Gsg2, Incenp, Mdm2, Mki67, Gadd45b,Nmyc1, Pdgfa, Plk1, Dusp1, Rb1, Aurkb, Aurka, Tacc3,Tgfb2, Gadd45g, Pttg1, Cks2, 1190002H23Rik, Cdca1,Kntc2, Rprm, Ube2c, Rhou, Sesn3, Pard6g, Cdc20Down 11 Cdkn2a, Cpeb1, Ddit3, Dst, Ereg, Plk2, Vegfa, Zfr,Ets2, Atf5, Sesn2MAPK signaling Up 10 Cd14, Cdc25b, Hspb1, Gadd45b, Pdgfa, Pdgfra,Dusp1, Tgfb2, Gadd45g, Dusp14Down 9 Atf4, Casp11, Ddit3, Fgfr1, Mknk1, Pdgfrb, Fgf21,Pla2g12a, Rasa1IMCE (Apc-/+): EASE Analysis
    15. 15. Leptin induces angiogenic potentialColon epithelial cellsLeptin↑ VEGFChemoattact endothelial cells to site↑ SAPK/MAPK in endothelial cell↑ NFkB activationEndothelial cell proliferation Adhesion protein upregulation↑ Capillary formation/AngiogenesisEnd result=↑ blood supply to Apc (min/+) cellsCarcinogenesis. 2009 Apr;30(4):690-7
    16. 16. Leptin induces 3-4 Hallmarks of Cancerin IMCE cells
    17. 17. Adiponectin Inhibits leptin-induced IMCE cell proliferation Via reduced IL-6 production by the IMCE cells Increases sgp130 to inhibit trans-IL-6 signaling Blocks NFkB nuclear translocation and DNA bindingFenton and Birmingham. Mol Carcinog. 2010
    18. 18. Adipokines and Colon Epithelial Cell HomeostasisLEPTIN IL-6 INSULINIL-6 HomeostaticApoptosisCaspase ActivationProliferationProliferationNFκB activation/bindingMAPKLeptin induced sIL-6RLeptin-induced IL-6VEGF productioncapillary formationPromotion of TransformedCellsYAMC (Apc +/+) Normal IMCE (Apc Min/+) TransformedSupports Normal PhenotypeAdenocarcinoma (MC38)•No leptin receptor•No response to leptin treatment•IL-6 induces proliferation•Insulin key proliferative signal•VEGF ?Rapid Expansion of TumorAdiponectinOverarchinginhibitor
    19. 19. The Question How is obesity and its associated factors relatedto colorectal polyp formation and severity? Hypothesis: Obesity and its related factors would be associatedwith increased #’s of polyps as well as increasedpolyp severity
    20. 20. Zauber 2012 NEJMRemoval of Colorectal Polyps DecreasesMortality from Colorectal Cancer
    21. 21. The Study Population Caucasian men (n=126) 48 to 65 yrs old Asymptomatic BMI distribution:1WHO Global Database on BMI02550lean(n=28)overweight(n=46)obese(n=52)%ofPopulationstudy population U.S. males102550lean(n=28)overweight(n=46)obese(n=52)%ofStudyPopulation
    22. 22. Methods Blood sample, weight, height, waistcircumference, clinical metadata, colonoscopy reports Categorical variables were constructed using eithernatural biological cut off points (BMI) or tertiles within thedata (waistcircumference, leptin, adiponectin, HMW, MMW, LMW, IL-6, TNF-alpha, IP-10) Odds Ratios were determined using polytomous logisticregression Test for trend was carried out across categories. p ≤ 0.05 indicates significance
    23. 23. Conclusions In vitro, leptin induces 3-4 hallmarks of cancer. In men 50-65 years of age BMI, waistcircumference and leptin were associated withtubular adenoma risk. If these observations are confirmed in largerpopulations, the recommended age for firstcolonoscopy in individuals with a BMI over 30and elevated adipokines should be revisited.
    24. 24. Acknowledgements Kari Hortos Sarah Comstock Sarah McCaskey Dorothy Pathak Funding from: NCI-CPF Program NCI 1R03CA142000 MSU CTSI Steve Hursting Julia Busik JP Steibel Norman Hord Sarah Comstock Bruce Kovan Tri-CountyGastroenterology Macomb, MI
    25. 25. Question???