Oncogenesis and Molecular Biology of Pituitary Tumors

This volume is a timely summary of the state of the art of several research initiatives that have taken place over the last 5 years. Many, though not all, advances are covered in depth. Notable omissions include the roles of FGF and cytokines, although TGFand PTH-RP are covered. The latter is of interest as a potential angiogenic factor and, although expressed in some pituitary tumours, most of the actions with respect to PTH-RP’s role in tumorigenesis derive from animal models and in vitro studies with highly atypical (cf human tumours) animal cell lines. The volume starts with a chapter describing in some detail, the microanatomy of the hypothalamus and median eminence including the topographical localization of hypothalamic releasing factors. Many of the data derive from experimental animals. Although this opening chapter is of interest to experimental neuroendocrinologists it has little relevance to pituitary tumorigenesis. For example, there is no discussion of the microcirculation of human pituitary adenomas and how this may relate to their pathogenesis. The second chapter is devoted to the description of Pit-1, its function and expression in normal rodent and human pituitary glands. Although Pit-1 is undoubtedly crucial for somatotroph/ lactotroph differentiation and possibly proliferation during oncogenesis there is no evidence that this factor plays a ro ˆle in somatotrophinoma and prolactinoma initiation or progression. It was perhaps surprising that there was not an analogous chapter of SF-1, the transcription factor responsible for gonadotroph differentiation. The next three chapters consider the role of CRF, GRF, and GnRH in pituitary tumours. Much is made of the role of overexpression of the first two of these in transgenic mouse models, and the occasional human case of Cushing’s or acromegaly caused by ectopic expression of these factors. The best evidence that a hypothalamic factor may conceivably initiate the adenoma phenotype comes from GRF, especially by either hypothalamic or intrapituitary over-production of the hormone. In such rare cases somatotroph adenomas are frequently multifocal leading to the hypothesis that GRF over-stimulation predisposes to somatic mutations in several cells independently. The chapter on GnRH and non-functional adenomas/gonadotrophinimas is largely descriptive of the responses of such tumours in vivoor in vitro to GnRH agonists and antagonists, neither of which agents are of clinical value in tumour management. One is really left questioning the relevance of this chapter from either a mechanistic or a therapeutic viewpoint. The chapter on somatostatin receptor subtypes by contrast offers the prospect that knowledge of the detailed molecular biology of the 5 subtypes may lead to rational analogue design which might be selective as GH inhibiting or antiproliferative agents. The now well trodden Gsp oncogene story is reproduced. The presence/absence of these mutations in somatotroph adenomas does not correlate with any specific clinical features. Furthermore, despite the identification of these mutations some 6 years ago there have been no attempts to determine whether these are truly pathogenetic (i.e. in transgenic mice expressing a mutant protein). There are two chapters on tumour suppressor genes (TSG) which describe the principles of TSG action and detection of abnormalities. Ras, p53, retinoblastoma, and the MEN-1 locus are considered in some detail. This is clearly an area of intense interest though unfortunately little progress is likely until the MEN-1 gene has been cloned, its function established, and detection of single activating point mutations is feasible. Even when this can be done a causation will require confirmation in animal models. In general this is a useful addition to the field but it is highly specialized and will probably find its place with the pituitary tumour researchers and aficionados rather than the clinical endocrinologist. R. N. Clayton