title: Growth hormone is permissive for neoplastic colon growth.
abstract: Growth hormone (GH) excess in acromegaly is associated with increased precancerous colon polyps and soft tissue adenomas, whereas short-stature humans harboring an inactivating GH receptor mutation do not develop cancer. We show that locally expressed colon GH is abundant in conditions predisposing to colon cancer and in colon adenocarcinoma-associated stromal fibroblasts. Administration of a GH receptor (GHR) blocker in acromegaly patients induced colon p53 and adenomatous polyposis coli (APC), reversing progrowth GH signals. p53 was also induced in skin fibroblasts derived from short-statured humans with mutant GHR. GH-deficient prophet of pituitary-specific positive transcription factor 1 (Prop1)(-/-) mice exhibited induced colon p53 levels, and cross-breeding them with Apc(min+/-) mice that normally develop intestinal and colon tumors resulted in GH-deficient double mutants with markedly decreased tumor number and size. We also demonstrate that GH suppresses p53 and reduces apoptosis in human colon cell lines as well as in induced human pluripotent stem cell-derived intestinal organoids, and confirm in vivo that GH suppresses colon mucosal p53/p21. GH excess leads to decreased colon cell phosphatase and tensin homolog deleted on chromosome 10 (PTEN), increased cell survival with down-regulated APC, nuclear β-catenin accumulation, and increased epithelial-mesenchymal transition factors and colon cell motility. We propose that GH is a molecular component of the "field change" milieu permissive for neoplastic colon growth.
authors.affiliation: Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
authors.forename: Vera
authors.initials: V
authors.lastname: Chesnokova
authors.affiliation: Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
authors.forename: Svetlana
authors.initials: S
authors.lastname: Zonis
authors.affiliation: Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
authors.forename: Cuiqi
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
authors.forename: Maria Victoria
authors.initials: MV
authors.lastname: Recouvreux
authors.affiliation: Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
authors.forename: Anat
authors.initials: A
authors.lastname: Ben-Shlomo
authors.affiliation: Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
authors.forename: Takako
authors.initials: T
authors.lastname: Araki
authors.affiliation: Department of Medicine, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048; Department of Medicine, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
authors.forename: Robert
authors.initials: R
authors.lastname: Barrett
authors.affiliation: Department of Medicine, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048; Department of Medicine, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
authors.forename: Michael
authors.initials: M
authors.lastname: Workman
authors.affiliation: Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
authors.forename: Kolja
authors.initials: K
authors.lastname: Wawrowsky
authors.affiliation: Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Ljubimov
authors.affiliation: Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
authors.forename: Magdalena
authors.initials: M
authors.lastname: Uhart
authors.affiliation: Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048; melmed@csmc.edu.
authors.forename: Shlomo
authors.initials: S
authors.lastname: Melmed
mesh_terms: D000172:Acromegaly / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D003106:Colon / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D013006:Growth Hormone / Q000378:metabolism*; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000235:genetics; D012867:Skin / Q000166:cytology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult; D051176:beta Catenin / Q000378:metabolism
chemical_list: D011986:Receptors, Somatotropin; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D013006:Growth Hormone; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: acromegaly; colon; growth hormone; growth hormone deficiency