Human pituitary tumors of a gonadotroph cell origin represent up to 30% of all diagnosed pituitary neoplasms. Clinically, these tumors cause considerable morbidity because of mass effect, resulting in cranial nerve compression syndromes, including visual loss and other neurologic deficits, and there are no established adjunctive medical therapies to control tumor growth. A major finding regarding the pathogenesis of human pituitary tumors in our previous grant period was that such tumors are monoclonal in origin, demonstrating that somatic mutation is a requisite event in tumor formation. The next critical questions are what mechanisms underlie selective clonal proliferation in pituitary tumors, and what mechanisms underlie the pathogenesis of specific adenoma phenotypes. Activins are TGF beta- related cytokines which function as both growth and differentiation factors, and have been shown to the synthesized by human pituitary tumors. Locally secreted activin has been demonstrated to be a novel, potent and selective growth and differentiation factor in normal pituitary. Novel preliminary data presented in this proposal demonstrates that exogenous activin can decrease cellular proliferation in vitro in human tumors of a gonadotroph or, somatotroph cell origin, This is the first demonstration of a pituitary-derived autocrine factor which has anti-proliferative effects in a significant percentage of these tumors. However, a subset of human gonadotroph tumors do not respond to exogenous activin. A lack of responsiveness to activin by a subset of human tumors strongly suggests that there are underlying receptor, and/or, intracellular signal defects in such tumors, a hypothesis which will be investigated in this proposal. Alterations in cell-surface receptor gene expression by pituitary adenomas may be an underlying cellular mechanism modulating cell proliferation. The loss of activin-responsiveness by the significant number of tumors may be indicative of loss of functional activin cell-surface receptors, as has been shown for, human lymphoid and colorectal cancers. This proposal will examine activin receptor, gene expression in human pituitary tumors. We have now identified novel human pituitary tumor-specific activin type I receptor isoforms which lack a full-length intracellular serine/threonine kinase signaling domain. Our proposed studies will investigate tumor-specific expression of these potential dominant- negative truncated receptor forms and whether expression of these receptor forms prevents activin anti-proliferative effects. We will functionally test this hypothesis by introducing full length Alk4 type I receptor into primary human pituitary tumor cultures and re- establishing activin responsiveness to exogenous activin. The hypothesized dominant negative phenotype of truncated Alk4 receptor, isoforms will also be functionally tested in human cell lines,including an erythroleukemic cell line known to growth arrest in response to activin, as well as established pituitary somatotroph and corticotroph cell lines. Our proposal focuses on the molecular, mechanisms of pituitary tumorigenesis and the potential anti-proliferative role of activin and its receptors in regulating pituitary tumor growth.
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