Nerve growth factor in pituitary development and pituitary tumors

Cells in the anterior pituitary originate from a common pluripotent precursor whose phenotypic development is determined by intrapituitary transcription factors as well as by hypothalamic and peripheral signals. A rapidly growing body of evidence revealed that essential to the differentiation and proliferation of pituitary cells are an array of growth factors that are produced within the pituitary and act mainly through autocrine mechanisms. Growth factors are polypeptides that are released in carefully measured amounts by some cells to regulate cell growth and differentiation by activating specific tyrosine kinase receptors in the plasma membrane of target cells. Both overproduction of mitogenic growth factors and loss of factors inhibiting cell proliferation result in uncontrolled cell growth and tumor development. There is now increasing evidence that disruption of the calibrated signalling network activated by pituitary growth factors plays a central role in pituitary tumorigenesis. This paper is focussed on the role of nerve growth factor (NGF) in pituitary physiology and pathology. In particular, we propose that NGF plays a dual role in the gland: a local one as a stimulator of differentiation and proliferation of lactotrope cells during pituitary development and a systemic one as a neurohormone which is cosecreted with prolactin into the bloodstream. Furthermore, we discuss the evidence that NGF is an autocrine differentiation factor for prolactin-secreting cells. Escape from NGF control appears to be one of the mechanisms involved in the development and progression of prolactinomas. Along the same line, exposure of prolactinomas refractory to dopaminergic therapy to exogenous NGF results in their differentiation into lactotrope-like cells reexpressing the D2 receptor protein. This observation may open the way to a sequential therapy with NGF and bromocriptine for patients refractory to the conventional therapy.