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 Apcmin+/- 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.
|Proceedings of the National Academy of Sciences of the United States of America
|Published - Jun 7 2016
Bibliographical noteFunding Information:
The authors thank Dr. M. Pimentel for performing colon biopsies and Ms. Shira Berman for assistance in preparing the manuscript. This work was supported by NIH Grants DK103198 and DK007770; the Doris Factor Molecular Endocrinology Laboratory; and investigator-initiated research Grant WS921563 from Pfizer (to S.M.).
- Growth hormone
- Growth hormone deficiency