[en] Cancer represents one of the main challenges for the human being, in that it encompasses some of the most severe and health-threatening pathologies worldwide. Although great efforts are being implemented and significant advances are being reached in basic, translational and clinical research over the last decades, the development of novel and more global and useful therapeutic strategies in Oncology is hampered by the heterogeneity and complexity of this disease. In order to tackle these difficulties, Hanahan and Weinberg proposed in 2000 and updated in 2011 a group of common alterations shared by most cancer types, which were defined as the hallmarks of cancer. Some of those cancer hallmarks are related with hormonal signaling, which is considered an important element in the control of malignant features. In this context, this Thesis has been mainly focused in the study of diverse endocrine-related cancers, such as prostate cancer (PCa), which is strongly influenced by the hormonal milieu, and different types of neuroendocrine tumors (NETs). Indeed, PCa is one of the tumor pathologies with highest incidence in men and one of the most common causes of cancer-related deaths among worldwide population. On the other hand, NETs comprise a markedly heterogeneous group of neoplasia originated from the diffuse neuroendocrine system that have been typically classified by their location. Among them, this Thesis have been focused on pancreatic tumors (PanNETs). Finally, we will also analyze a tumor type closely related, as it is the case of pituitary neuroendocrine tumors (PitNETs). One of the hormonal axes classically related to different types of tumors and that has represented the central interest of our group is the system comprised by somatostatin and its receptors (SST1-SST5). Particularly, this system has been classically linked to neuroendocrine tumors (NETs, PitNETs), wherein synthetic somatostatin agonists are widely used to act on several of its receptors (e.g. SST2, SST5), which represent useful therapeutic targets in these pathologies. In this context, it is remarkable the growing relevance of SST5 as putative therapeutic target of novel somatostatin analogs, and due to the discovery of novel truncated splicing variants (e.g. SST5TMD4), which are related with the aggressiveness of several cancer types. Nonetheless, very little is known about the biogenesis of SST5 from its gene, SSTR5, and about the role of other SST receptors in endocrine-related tumors. The growing identification of abnormal splicing variants that, similar to the above mentioned SST5TMD4, are overexpressed in different cancer types reinforces the idea that the alteration of the splicing process may be involved in the development and aggressiveness of tumor pathologies, through the dysregulation of the normal alternative splicing pattern and the generation of aberrant isoforms with oncogenic potential. In fact, over the last years, the alteration of the splicing process is being considered as a novel and transversal cancer hallmark, in that it seems to be affecting to all the hallmarks previously described. However, the information regarding the splicing process and its dysregulation is still scarce in some tumor pathologies, including NETs. Thus, for all the reasons indicated above, the general aim of this Thesis was to determine the role of somatostatin receptors and splicing machinery in different types of endocrine-related cancers and neuroendocrine tumors, as well as the underlying regulatory mechanisms, with the final purpose of discovering novel biomarkers and pharmacologic targets with potential to improve the diagnostic and therapeutic approaches in these pathologies.

[es] El cáncer es uno de los mayores retos que afronta la humanidad, pues comprende algunas de las patologías más graves que afectan a la salud a nivel mundial. Aunque se están realizado grandes esfuerzos y se han logrado avances significativos en investigación básica, clínica y traslacional durante las últimas décadas, el desarrollo de nuevas estrategias terapéuticas en oncología, más globales y a la vez precisas y eficientes, está limitado por la enorme heterogeneidad y complejidad de esta enfermedad. Para enfrentarse a dichas dificultades, Hanahan y Weinberg propusieron en el año 2000 y actualizaron en 2011 un grupo de alteraciones comunes compartidas por la mayoría de los tipos de cáncer a diferentes niveles, que se conocen como hallmarks o pilares del cáncer. Algunos de estos hallmarks están relacionados con la señalización hormonal, que se considera un componente importante en el control de la malignidad tumoral. En este contexto, la presente Tesis se ha enfocado fundamentalmente en el estudio de cánceres relacionados con el sistema endocrino, como el cáncer de próstata (CaP), fuertemente dependiente de la regulación hormonal, y distintos tipos de tumores neuroendocrinos (TNEs). El CaP es una de las patologías tumorales de mayor incidencia en hombres y una de las causas de muerte más comunes relacionadas con el cáncer en la población mundial. Por su parte, los TNEs son un grupo de neoplasias marcadamente heterogéneo, que surgen del sistema neuroendocrino difuso y se ha clasificado habitualmente según la localización del tumor. Concretamente, esta Tesis se enfoca en los tumores pancreáticos (PanNETs). Por último, analizaremos también un tipo tumoral estrechamente relacionado, los tumores neuroendocrinos hipofisarios (PitNETs).