Pituitary adenoma growth: a model for cellular senescence and cytokine action

Abstract

New findings have emerged about the mechanism of oncogene-induced senescence, and its involvement in a highly prevalent disorder, pituitary adenomas. These observations point to senescence as a target for effective therapy for both tumor silencing and growth restraint towards development of pituitary malignancy.

Activated oncoproteins or loss of tumor suppressor proteins (oncogenic stress) trigger oncogene-induced cellular senescence (OIS). However, other factors may affect pituitary tumors so as to induce OIS. In Kuilman et al.’s model (2) in melanocytic nevi, when OIS occurs there is an upregulation of p15^INK4B, p16^INK4A, p21^CIP and CDK inhibitors. IL-6 is also upregulated in OIS and the IL-6/IL6-R pathway is essential for mediating OIS, inducing and maintaining senescence in an autocrine fashion, but acting pro-mitogenically in a paracrine fashion. Since IL-6 also regulates normal and tumoral pituitary cell growth, this process may also occur in incipient neoplastic pituitary cells. In Kuilman’s findings, p15^INK4B was upregulated and its induction linked to IL-6 and CEBP/β, indicating regulation by oncogenic stress. Deranged intracellular PTTG levels, results in pituitary-specific senescent features, including increased p21 levels and elevated senescence-associated β-galactosidase expression.