Dear Colleagues,

Pituitary tumors are usually benign and relatively common intracranial tumors, with under- and overexpression of pituitary hormones and local mass effects causing considerable morbidity and increased mortality. Some of them are associated with clinical syndromes, which limit the expectancy and quality of life of the patients. Others have only local mass effects without associating an endocrine syndrome. They are the non-functioning pituitary tumors (NFPA). Incorporating the molecular and immunohistochemical determination of the three pituitary transcription factors, PIT-1, TPIT, and SF-1/GATA 2, to the pathological study of pituitary tumors has allowed a more precise characterization of the different subtypes, especially of the silent counterparts, previously aggregated as a whole under the acronym NFPA. The precise identification of PT subtypes is crucial as a silent corticotroph tumor's behavior is very different from that of a gonadotroph tumor. Therefore, the silent counterparts of PT should be studied separately.

Pituitary tumorigenesis does not fit into the most common model of cancer development, driven by gene mutations. Contrarily, the epigenetic plays a predominant role in the pathogenesis of pituitary tumors. The epigenetic machinery involves several mechanisms such as 1. Chromatin remodeling; 2. Post-transcriptional histone modifications; 3. Non-coding RNAs (miRNAs), and 4. Aberrant DNA methylation at CpG in gene regulatory sites (promoters or enhancers). Different subtypes of PT show distinct signatures of DNA methylation. While POUF1F1/PIT1 lineage PT shows an epigenetic signature of diffuse DNA hypomethylation, the TPIT lineage tumors present three forms:  USP8-mutations with overt secretion, USP8-negative mutations aggressive tumors, and large tumors with gonadotroph transdifferentiation. Moreover, unexpected expression of gonadotroph markers is also showed by some POUF1/PIT1 lineage tumors, specifically some somatotroph tumors, challenging the SF-1/GATA 2 tumors lineage. The association with chromosomal instability and expression of transposable elements points toward an original association of genomic instability with lineage differentiation highlighting the hypothesis that PT subtypes should be considered different tumors and studied separately.

Since microRNAs were first observed in the normal pituitary, several scientific publications have addressed their role and microRNA function on the pituitary tumorigenesis. MicroRNAs have been reported as suppressors and inducers of PT and have a functional role in tumorigenesis, functionality, progression, and aggressiveness of these tumors and can modulate their response to medical treatment.

Recently, there has been a great interest in the study of the tumor immune microenvironment (TIME). TIME includes resident and infiltrative non-tumor cells and blood and lymph vessels, extracellular matrix molecules, and numerous soluble factors, such as cytokines and chemokines. While the TIME is considered a prognostic tool and a therapeutic target for many cancers, little is known about its composition in pituitary tumors.

This Special Issue of IJMS will focus on the advances in the epigenetic regulation of PT over the last ten years and in their relevance in the development of new therapeutics. This collection will include aspects of how methylation, miRNAs, and TIME determine the functionality, aggressiveness, and response to the medical treatment of PT subtypes.

Prof. Dr. Antonio M. Picó Alfonso
Guest Editor

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• pituitary tumors
• pituitary tumor subtypes: corticotroph, somatotroph, gonadotroph tumors
• craniopharyngiomas
• microRNAs
• chromosome alterations
• exome
• genomic
• methylome
• miRNome
• transcriptome
• tumor microenvironment
• angiogenesis
• extracellular matrix
• folliculostellate cells
• immune infiltrate
• immunotherapy