Pituitary growth hormone (GH) is secreted to the circulation and GH is also expressed in local tissues, where it elicits autocrine/paracrine signaling. GH exerts multiple actions including skeletal and longitudinal growth, as well as maintenance of body and tissue mass and metabolic homeostasis. GH actions are direct, or may be mediated by IGF1. Deficient GH signaling is associated with decreased cancer development, while in contrast, GH excess (e.g., derived from a pituitary adenoma in acromegaly) results in soft tissue overgrowth and increased soft tissue polyps and adenomas, and risk of colon carcinoma. Local colon stromal GH is also induced after DNA damage. We now present several lines of preliminary evidence that pituitary-derived and local GH both act to suppress colon mucosal p53 and reduce apoptosis. These pro-proliferative GH effects lead to increased cell survival with downregulated APC, accumulation of nuclear ?-catenin, as well as increased MMPs and EMT factors. Consistent with these findings, when we suppressed GH signaling with a GH receptor blocker and performed colon biopsies in acromegaly patients, we observed induced colon mucosal p53 and APC, thereby reversing pro-growth GH signals. We propose here that GH is a molecular component of the normal epithelial mucosa ?field change? milieu permissive for neoplastic growth.
In Specific Aim I, using normal human colon cells and a novel 3-D model of iPSC-derived human intestinal gut-on-a-chip microfluidic devices, we will elucidate GH effects on mucosal changes that occur in pre-neoplastic stages of tumor development and also elucidate mechanisms underlying GH-associated p53 suppression.
In Specific Aim II, we will use mouse models of GH excess to determine temporal changes in colon mucosa in vivo. We will crossbreed mice genetically predisposed to colon tumors with mice deficient in GH signaling to confirm GH requirements for colon neoplasia development.
In Specific Aims I and II using intestinal gut-on-a-chip devices and animal models, we will delineate direct from IGF1-mediated effects of GH on colon epithelial cells.
In Specific Aim III, we will examine paracrine actions of GH on DNA damage and chromosomal instability, as well as subsequent effects on colon epithelial mucosa. By elucidating novel p53-mediated mechanisms for GH regulatory actions, we will provide biological and clinical evidence to support the hypothesis that GH excess enables epithelial neoplastic growth, as encountered in acromegaly. Given the multiple soft tissue co-morbidities of acromegaly, these experiments offer mechanistic insights into pathogenesis of deleterious epithelial damage engendered by GH.
We will study mechanisms of growth hormone (GH) action on the tumor suppressor p53 in normal human mucosal cells, in human gut-on-a-chip devices, and in transgenic animals predisposed to colon adenoma growth. We will also analyze effects of GH deficiency onsoft tissue adenoma development in experimental animal models lacking GH signaling in the colon. We will examine effects of mucosal DNA damage on GH expression and localization.
| Yamamoto, Masaaki; Ben-Shlomo, Anat; Kameda, Hiraku et al. (2018) Somatostatin receptor subtype 5 modifies hypothalamic-pituitary-adrenal axis stress function. JCI Insight 3: |
