Deregulation of genetic pathways in neuroendocrine tumors.

Complexity and redundancy of functional pathways controlled by the human genome explain that a single type of tumor can be induced by independant defective mutations in various genes that encode proteins acting in different parts of the cell physiology. Neuroendocrine tumors represent a powerful model for understanding such a complexity from the fact that at least six unrelated genetic syndromes have been characterized in the last decade which predispose to endocrine cell proliferation with variable penetrance and expressivity. Multiple Endocrine Neoplasia, von Hippel-Lindau. Carney and uncommonly Recklinghausen and Tuberous Sclerosis syndromes represent almost the whole panel of genetic diseases for which genes have been cloned and most of the functional knowledge has been collected. All the endocrine glands are concerned in these diseases, but the cellular pathways that are deregulated downstream from the deleterious mutations occurring in the genes of these autosomal dominant syndromes. might be related to each step of the cell life, from mitosis to DNA transcription, membrane receptor signalling and growth factor production, protein catabolism and extracellular matrix synthesis, and from transcription regulation to apoptosis and response to hypoxia and cellular stress. Here, we present an overview of genes involved in genetic predisposition to neuroendocrine tumors and highlight the complexity of pathways involved and the need of further studies focussing on genes involved in tumoral progression, most neuroendocrine tumors being benign at initial diagnosis but able to produce highly malignant cellular clones related to secondary genetic alterations or deregulation of growth factor production or cell cell adhesion processes.