Molecular Characterization of Growth Hormone-producing Tumors in the GC Rat Model

Acromegaly is a disorder resulting from excessive production of growth hormone (GH) and consequent increase of insulin-like growth factor 1 (IGF-I), most frequently caused by pituitary adenomas. Elevated GH and IGF-I levels results in wide range of somatic, cardiovascular, endocrine, metabolic, and gastrointestinal morbidities. Subcutaneous implantation of the GH-secreting GC cell line in rats leads to the formation of tumors. GC tumor-bearing rats develop characteristics that resemble human acromegaly including gigantism and visceromegaly. However, GC tumors remain poorly characterized at a molecular level. In the present work, we report a detailed histological and molecular characterization of GC tumors using immunohistochemistry, molecular biology and imaging techniques. GC tumors display histopathological and molecular features of human GHproducing tumors, including hormone production, cell architecture, senescence activation and alterations in cell cycle gene expression. Furthermore, GC tumors cells displayed sensitivity to somatostatin analogues, drugs that are currently used in the treatment of human GH-producing adenomas, thus supporting the GC tumor model as a translational tool to evaluate therapeutic agents. The information obtained would help to maximize the usefulness of the GC rat model for research and preclinical studies in GH-secreting tumors. Acromegaly is a disorder resulting from excessive production of growth hormone (GH) and consequent increase of insulin-like growth factor 1 (IGF-I), most frequently caused by pituitary adenomas 1 . Elevated GH and IGF-I levels result in wide range of somatic, cardiovascular, endocrine, metabolic, and gastrointestinal morbidities 1,2 . If untreated, acromegaly leads to reduced life expectancy due primarily to cardiovascular disease 3 . Achieving biochemical control of the disease restores life expectancy to levels similar to that observed in the general population 4 . Therefore, the main goal of treatment for acromegaly is to normalize both GH and IGF-I levels 5 . Currently available treatment options for acromegaly include