Deregulation of genetic pathways in neuroendocrine tumors

Complexity and redundancy of functional pathways controlled by the human ge nome explain that a single type of tumor can be induced by independant defe ctive mutations in various genes that encode proteins acting in different p arts of the cell physiology. Neuroendocrine tumors represent a powerful mod el for understanding such a complexity from the fact that at least six unre lated genetic syndromes have been characterized in the last decade which pr edispose to endocrine cell proliferation with variable penetrance and expre ssivity. Multiple Endocrine Neoplasia, von Hippel-Lindau, Carney and uncomm only Recklinghausen and Tuberous Sclerosis syndromes represent almost the w hole 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 lif e, from mitosis to DNA transcription, membrane receptor signalling and grow th factor production, protein catabolism and extracellular matrix synthesis , and from transcription regulation to apoptosis and response to hypoxia an d cellular stress. Here, we present an overview of genes involved in geneti c predisposition to neuroendocrine tumors and highlight the complexity of p athways involved and the need of further studies focussing on genes involve d in tumoral progression, most neuroendocrine tumors being benign at initia l 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.