title: Apcinactivation, but not obesity, synergizes withPtendeficiency to drive intestinal stem cell-derived tumorigenesis.
abstract: Obesity is a major risk factor for colorectal cancer and can accelerate Lgr5+ intestinal stem cell (ISC)-derived tumorigenesis after the inactivation ofApcHowever, whether non-canonical pathways involving PI3K-Akt signaling in ISCs can lead to tumor formation, and if this can be further exacerbated by obesity is unknown. Despite the synergy betweenPtenandApcinactivation in epithelial cells on intestinal tumor formation, their combined role in Lgr5+-ISCs, which are the most rapidly dividing ISC population in the intestine, is unknown. Lgr5+-GFP mice were provided low-fat diet (LFD) or high-fat diet (HFD) for 8 months, and the transcriptome was evaluated in Lgr5+-ISCs. For tumor studies, Lgr5+-GFP and Lgr5+-GFP-Ptenflox/floxmice were tamoxifen treated to inactivatePtenin ISCs and provided LFD or HFD until 14-15 months of age. Finally, various combinations of Lgr5+-ISC-specific,Apc-andPten-deleted mice were generated and evaluated for histopathology and survival. HFD did not overtly alter Akt signaling in ISCs, but did increase other metabolic pathways.Ptendeficiency, but not HFD, increased BrdU-positive cells in the small intestine (P< 0.05). However, combiningPtenandApcdeficiency synergistically increased proliferative markers, tumor pathology and mortality, in a dose-dependent fashion (P< 0.05). In summary, we show that HFD alone fails to drive Akt signaling in ISCs and thatPtendeficiency is dispensable as a tumor suppressor in Lgr5+-ISCs. However, combiningPtenandApcdeficiency in ISCs synergistically increases proliferation, tumor formation and mortality. Thus, aberrant Wnt/β-catenin, rather than PI3K-Akt signaling, is requisite for obesity to drive Lgr5+ ISC-derived tumorigenesis.
authors.affiliation: Department of Molecular PharmacologyAlbert Einstein College of Medicine, Bronx, New York, USA.|Institute for Aging ResearchAlbert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Tahmineh
authors.initials: T
authors.lastname: Tabrizian
authors.affiliation: Department of Molecular PharmacologyAlbert Einstein College of Medicine, Bronx, New York, USA.|Institute for Aging ResearchAlbert Einstein College of Medicine, Bronx, New York, USA.|Division of EndocrinologyDepartment of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Donghai
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Molecular PharmacologyAlbert Einstein College of Medicine, Bronx, New York, USA.|Institute for Aging ResearchAlbert Einstein College of Medicine, Bronx, New York, USA.|Division of EndocrinologyDepartment of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Fangxia
authors.initials: F
authors.lastname: Guan
authors.affiliation: Department of Molecular PharmacologyAlbert Einstein College of Medicine, Bronx, New York, USA.|Institute for Aging ResearchAlbert Einstein College of Medicine, Bronx, New York, USA.|Division of EndocrinologyDepartment of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Zunju
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Obstetrics & Gynecology and Women's HealthAlbert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Amanda P
authors.initials: AP
authors.lastname: Beck
authors.affiliation: Department of GeneticsAlbert Einstein College of Medicine, Bronx, New York, USA.|Department of PathologyAlbert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Fabien
authors.initials: F
authors.lastname: Delahaye
authors.affiliation: Department of Molecular PharmacologyAlbert Einstein College of Medicine, Bronx, New York, USA derek.huffman@einstein.yu.edu.|Institute for Aging ResearchAlbert Einstein College of Medicine, Bronx, New York, USA.|Division of EndocrinologyDepartment of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Derek M
authors.initials: DM
authors.lastname: Huffman
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D018752:Diet, Fat-Restricted; D059305:Diet, High-Fat; D041981:Gastrointestinal Tract / Q000166:cytology / Q000473:pathology; D005947:Glucose / Q000032:analysis; D049452:Green Fluorescent Proteins / Q000235:genetics; D007328:Insulin / Q000097:blood; D008297:Male; D008822:Mice, Transgenic; D009765:Obesity / Q000097:blood / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D013234:Stem Cells / Q000473:pathology*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D007328:Insulin; C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled; C000613192:adenomatous polyposis coli protein, mouse; D049452:Green Fluorescent Proteins; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D005947:Glucose
keywords: Apc; Lgr5; Pten; colon cancer; obesity