Growth hormone is permissive for neoplastic colon growth

Significance

Growth hormone (GH) excess in acromegaly is associated with increased colon polyps and cancer, whereas short-stature humans harboring a GH receptor mutation do not develop cancer. Administration of a GH receptor blocker in acromegaly patients induced colon p53. In contrast, p53 is suppressed by GH in colon cells, in vivo in colon tissue, and in induced pluripotent stem cell-derived intestinal organoids. GH excess leads to cell survival with downregulated adenomatous polyposis coli, nuclear β-catenin accumulation, and increased epithelial–mesenchymal transition factors. Because locally expressed GH is abundant in conditions predisposing to colon cancer, GH appears to be a molecular component of the milieu permissive for neoplastic colon growth. These results explain the protective effects of GH deficiency against development of neoplasms.

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.