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
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
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.
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
Leptin induces 3-4 Hallmarks of Cancerin IMCE cells
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
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
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
Zauber 2012 NEJMRemoval of Colorectal Polyps DecreasesMortality from Colorectal Cancer
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
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
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.
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