Molecular Mechanisms Underlying Pituitary Pathogenesis

Abstract

During the last years, progress has been made on the identification of mechanisms involved in anterior pituitary cell transformation and tumorigenesis. Oncogene activation, tumor suppressor gene inactivation, epigenetic changes, and microRNAs deregulation contribute to the initiation of pituitary tumors. Despite the high prevalence of pituitary adenomas, they are mostly benign, indicating that intrinsic mechanisms may regulate pituitary cell expansion. Senescence is characterized by an irreversible cell cycle arrest and represents an important protective mechanism against malignancy. Pituitary tumor transforming gene (PTTG) is an oncogene involved in early stages of pituitary tumor development, and also triggers a senescence response by activating DNA-damage signaling pathway. Cytokines, as well as many other factors, play an important role in pituitary physiology, affecting not only cell proliferation but also hormone secretion. Special interest is focused on interleukin-6 (IL-6) because its dual function of stimulating pituitary tumor cell growth but inhibiting normal pituitary cells proliferation. It has been demonstrated that IL-6 has a key role in promoting and maintenance of the senescence program in tumors. Senescence, triggered by PTTG activation and mediated by IL-6, may be a mechanism for explaining the benign nature of pituitary tumors.

Oxidative stress and mitochondrial adaptive shift during pituitary tumoral growth

“…Recently, a substantial improvement has been made in the recognition of the mechanisms and agents implicated at the beginning and during the evolution of pituitary tumours. These tumours do not present the typical oncogene mutations often found in nonendocrine neoplasms and the particular aspects that contribute to the initiation and promotion of their development have already been characterized [1,2]. These factors, such as cell cycle deregulation, growth factor overexpression, hormonal overstimulation, epigenetically silenced tumour suppressor genes, oncogene overexpression, defective signalling pathways and an altered intrapituitary microenvironment, act as mitogenic stimuli that can lead to sustained tumour growth [1,[3][4][5][6][7][8].…”

Downregulation of glucose‑6‑phosphate dehydrogenase by microRNA‑1 inhibits the growth of pituitary tumor cells

“…miRNAs function as key regulators of gene expression via binding to the 3'-untranslated region (UTR) of the target mRNAs, and consequently inducing the degradation or translation inhibition of the mRNAs (5,7,8). Notably, emerging evidence has illustrated the critical roles of miRNAs in the pathogenesis of different cancer types (9)(10)(11)(12)(13)(14)(15)(16). For example, miR-106b targeted the tumor suppressor phosphatase and tensin homolog and promoted the growth of pituitary cancer cells (17).…”

The genetic background of acromegaly

“…In this brief overview, we concentrate on the genetic basis of sporadic and familial acromegaly while refer to an excellent review regarding other molecular mechanisms [3]. …”