Abstract
Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of rare malignancies, mainly originating from hormone-secreting cells, which are widespread in human tissues. The identification of mutations in ATRX/DAXX genes in sporadic NENs, as well as the high burden of mutations scattered throughout the multiple endocrine neoplasia type 1 (MEN-1) gene in both sporadic and inherited syndromes, provided new insights into the molecular biology of tumour development. Other molecular mechanisms, such as the NOTCH signalling pathway, have shown to play an important role in the pathogenesis of NENs. NOTCH receptors are expressed on neuroendocrine cells and generally act as tumour suppressor proteins, but in some contexts can function as oncogenes. The biological heterogeneity of NENs suggests that to fully understand the role and the potential therapeutic implications of gene mutations and NOTCH signalling in NENs, a comprehensive analysis of genetic alterations, NOTCH expression patterns and their potential role across all NEN subtypes is required.
Highlights
Neuroendocrine cells are sensor cells, which play an important role in the connection between the nervous system and endocrine organs
Recurrent mutations have been identified in multiple endocrine neoplasia type 1 (MEN1) and von Hippel–Lindau (VHL) genes, in chromatin remodelling genes, such as DAXX and ATRX, in mechanistic target of rapamycin pathway genes, especially in phosphatase and tensin homolog (PTEN), tuberous sclerosis complex 2 (TSC2), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), in checkpoint kinase 2 (CHEK2) tumour suppressor gene, in telomerase maintenance genes, in the cell cycle regulator cyclin dependent kinase inhibitor 1B (CDKN1B) and in the DNA repair gene mutY DNA glycosylase (MUTYH) [15,16]
Recent findings suggest that the presence of inactivating mutations in NOTCH signalling is involved in the pathogenesis of neuroendocrine neoplasms of the lung, being defined as more than 25% of the cases for small cell lung carcinomas (SCLC) [58,103]
Summary
Neuroendocrine cells are sensor cells, which play an important role in the connection between the nervous system and endocrine organs. Neuroendocrine cells are widely scattered throughout the human body They are present in the gastro-entero-pancreatic tract, uro-genital apparatus, lung, breast and skin, as well as in the central and peripheral nervous system. Little is known about the mechanisms of oncogenic transformation and metastatic dissemination of neuroendocrine cells, but it is known that despite some common molecular characteristics, NENs originating in different organs have distinct signatures and display significant biological heterogeneity In this heterogeneous neoplastic setting, the NOTCH pathway has shown to have a role by triggering both tumour suppressor and oncogenic functions in some neuroendocrine cell lines and in different subtypes of NENs [5,6,7,8,9,10]. This review will summarize the current knowledge on the molecular heterogeneity of NENs and the complex function of NOTCH signalling in different types of NENs, as well as the new therapeutic approaches based on NOTCH pathway modulation
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