Endocrine Abstracts

Hormone-secreting anterior pituitary cells exhibit slow turnover rates. Subsequent postnatal alterations in pituitary size are determined throughout the lifespan by both extrinsic and intrinsic factors. Pituitary tumors account for ~15% of intracranial tumors and arise from differentiated anterior pituitary cell types, and are invariably benign. They may hyper-secrete hormones, or may be clinically silent. Although hypothalamic influences are permissive for adenoma growth, several lines of evidence point to an intrinsic pituitary cell defect giving rise to these tumors. Hereditary syndromes, including MENI, Carney syndrome and AIP mutations account for a very small proportion of sporadic adenomas. Although LOH is well documented, identification of adenoma-specific suppressor gene loss has been largely elusive.

Compound knockout transgenic models utilizing two or more gene deletions, or targeted knock-ins, have provided new insights for understanding the multi step progression of pituitary neoplasia. Several candidate activating genes and growth factors have been identified which mediate tumorigenesis by disrupting the cell cycle leading to aneuploidy and chromosomal imbalance. Curiously, despite these cellular aberrations pituitary adenomas are invariably benign. Cellular senescence is characterized by irreversible cell cycle arrest and constitutes a protective anti-proliferative response, which can be triggered by DNA damage, chromosomal instability and aneuploidy, loss of tumor suppressive signaling or oncogene activation. Cellular senescence may prevent cells from undergoing transformation in vitro, and in vivo senescence is an important protective mechanisms against malignant transformation. Pituitary tumors exhibit an intrinsic predisposition for senescence-associated molecular pathways and show cell-specific and tumor-specific protective mechanisms underlying the benign nature of GH-secreting or non-functioning tumors. These pathways can be bypassed in vitro, leading to rescue of the senescent phenotype. These mechanisms underlying pituitary trophic changes enable the role of the pituitary to maintain vital homeostatic functions.

We will review the current state of knowledge underlying the cascade of transformation of the normal pituicyte through hyperplasia and ultimately adenoma formation, without progressing to malignancy. These observations provide an understanding of molecular mechanisms underlying the multistep pathogenesis of these adenomas and their benign propensity. These observations have enabled development of subcellular approaches for treating these common neoplastic disorders.