Mutation of the Cell Cycle Regulator p27kip1 Drives Pseudohypoxic Pheochromocytoma Development

Pheochromocytomas and paragangliomas (PPGLs) can be subdivided into at least three different subgroups associated with different clinical manifestations and depending on the risk to metastasize. A shortage in human tumor material, the lack of a functional human cell line and very limited animal models were major drawbacks for PPGL research and consequently for the development of patient-tailored targeted therapies. We have previously reported that the MENX rat model develops pheochromocytoma with a full penetrance at the age of 8–10 months, however, it was unclear which human group the rat tumors modeled best. In order to characterize the rat pheochromocytomas, we analyzed gene expression, the catecholamine profile, TCA-cycle metabolism, methylation, angiogenesis, histology and mitochondrial ultrastructure. In all aspects, rat MENX pheochromocytomas resemble the features of the human pseudohypoxia group, the most aggressive one and in need of effective therapeutic approaches.