Abstract 1997: Pheochromocytoma developing within the MENX rat model shares gene expression patterns with its human counterpart

Abstract

Abstract Pheochromocytoma is a neoplasia that arises from the chromaffin cells of the adrenal medulla. Pheochromocytoma develops in 100% of rats affected by the multiple endocrine neoplasia syndrome MENX, caused by a loss-of-function mutation in p27. Affected rats develop adreno-medullary hyperplasia by 3-4 months of age, which progresses to pheochromocytoma with time, providing an interesting model for pheochromocytoma development. MENX-affected rats also develop extra-adrenal pheochromocytoma (paraganglioma) (frequency 20%). Aim: The aim of the study is to discover novel molecular mechanisms involved in the pathophysiology of rat adrenal tumors and to validate the findings in human pheochromocytoma. Our ultimate goal is to identify novel molecular markers for diagnosis, prognosis and targeted therapy of pheochromocytoma. Methods: Gene expression array analysis of 8 hyperplasias and 10 pheochromocytomas from MENX rats was performed on Rat 2.0 Affymetrix Genechips. Samples were compared with adreno-medullary RNA from wild-type age-matched littermates. Selected genes overexpressed in the lesions were validated by RealTime quantitative RT-PCR or in situ hybridization. Results: The adrenal lesions associated to the MENX syndrome show distinct gene expression profiles enriched in genes belonging to neuronal development pathways. Hyperplasia and pheochromocytoma show significant overlap of the most dysregulated gene categories. Among the genes overexpressed in the adrenal lesions are Mash1, Bmp7, Phox2a, Neurod1, Gal, Cxcr4, Cdkn2a, Cdkn2c, Sctr, Dgkh, L1Cam, Tcte1, which were validated in additional samples. These genes are already overexpressed in normal-looking adrenal glands of 1 month-old affected rats. Thus, their up-regulation might be a more direct consequence of the genetic mutation in p27. Among these genes, the only one overexpressed also in rat paragangliomas is Sctr, encoding the secretin receptor, indicating that pheochromocytoma arising within or outside the adrenal gland associates with different expression signatures. Interestingly, Sctr is highly expressed in PC12 cells, indicating that it might be a feature of rat pheochromocytoma. A series of 30 sporadic and 13 familial human pheochromocytoma was analyzed for the expression of selected genes overexpressed in the rat tumors. The results showed that a subset of these genes is highly expressed in human pheochromocytoma at both the mRNA and the protein level. Interestingly, several of them, including L1CAM, have not been previously associated to human pheochromocytoma and represent novel potential markers of this tumor. Conclusions: Expression profiling of rat pheochromocytoma can identify molecular pathways involved in its human counterpart and can provide novel biomarkers for clinical use. Our studies support the hypothesis that the MENX syndrome is a good model of human neuroendocrine tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1997.