Endocrine Abstracts

Endocrine-related cancers comprise a complex group of heterogeneous pathologies whose development and progression are profoundly conditioned by endocrine–metabolic deregulations. The well-known capacity of somatostatin (SST) to inhibit hormone secretion and cell proliferation in a wide variety of cell types, coupled to the ubiquitous expression of SST receptors (ssts) in normal and tumoral tissues, has led SST analogs (SSAs) to be extensively used in clinical practice for the treatment of endocrine-related cancers, such as pituitary and neuroendocrine tumors (NETs). However, despite ssts being present in their tumor cells, a significant proportion of patients are (or become) resistant to SSA therapy, and effectiveness of SSAs is thus limited to certain groups of patients. Moreover, clinical studies exploring the utility of SSAs in other ssts-positive, endocrine-related tumors, such as breast or prostate cancers, are lacking or also unsatisfactory. Lack of responsiveness to SSA therapy has been suggested to be associated to the intrinsic nature of ssts. In an attempt to further characterize the sst family, our group has identified new functional truncated variants of the sst5, with less than 7TMD, in various mammalian species (human, pig, mouse and rat). These truncated receptors are originated by the elimination of a cryptic intron in the sst5 sequence during the mRNA maturation through a non-canonical splicing event. Remarkably, these truncated variants have unique, ligand-selective signaling properties, distinct distribution in normal tissues, and different subcellular localization to that shown by the originally identified, long sst5 variant. Interestingly, human sst5 truncated receptors, and specially the truncated receptor with 4TMDs (sst5TMD4), are barely expressed in normal tissues, but have been found to be highly expressed in a subset of pituitary tumors, NETs, thyroid or breast cancers, wherein its expression has been associated to poorer prognosis. Indeed, the expression of sst5TMD4 has been correlated with impaired response to SSA treatment in pituitary adenomas and, likely, in thyroid carcinoma. Our data suggest that sst5TMD4 could act, at least partially, through the blockade of the normal activity of full-length canonical receptors, particularly sst2, thus acting as a dominant-negative receptor. Finally, sst5TMD4 has been linked to increased malignant phenotype in in vitro models of NETs, thyroid and breast cancer through increased proliferation, migration and invasion abilities, which altogether indicate the pivotal role of sst5TMD4 in the malignancy of these tumors, and pave the way to the identification of new molecular targets for the diagnosis, prognosis and therapy in endocrine-related tumors.