Chapter 9 - Pathogenesis of Pituitary Tumors
Section snippets
Introduction to pituitary adenomas
The pituitary gland is composed of two anatomically, functionally and phylogenetically distinct parts: anterior pituitary (adenohypophysis) and posterior pituitary (neurohypophysis). The anterior pituitary is the central regulator of the endocrine system, coordinating signals from the hypothalamus centrally and endocrine organs peripherally. The pituitary gland effectively regulates hormonal secretion of most classical endocrine organs. Tumors frequently arise in the pituitary gland and they
Physiological pituitary cell proliferation
Mechanisms underlying pituitary cell proliferation are best illustrated by four models: embryonic development, pregnancy, the estrous cycle and in deficiencies of peripheral hormones induced by the pituitary. Lineage-specific regulation of pituitary development and proliferation is regulated by homeobox genes during embryonic development but is beyond the scope of this section (Drouin, 2006, Keegan and Camper, 2003, Scully and Rosenfeld, 2002). During embryonic development, the nuclear
General principles of pituitary tumor pathogenesis
The pathogenesis of pituitary tumors appears to be similar to that of other benign tumors. Tumorigenesis generally encompasses two steps (which can be somewhat overlapping), initiation and promotion (Nery, 1976, Potter, 1980). At the initiation step, a cell acquires genetic features that endow it with a higher proliferative potential. At the promotion step, additional genetic abnormalities, growth factors, pro-angiogenesis factors, and tumor micro-environment together promote the further
Monoclonality of pituitary tumors
Pituitary tumors are true tumors rather than hyperplastic pituitary cells. The monoclonal origin of pituitary tumors is supported by X-chromosome inactivation pattern in tumors of female patients (Alexander et al., 1990, Herman et al., 1990). Further experiments helped refine the monoclonal theory by demonstrating that some pituitary tumors may contain several tumor clones arising independently from expansion of individual cells (Clayton et al., 2000). The monoclonal nature of pituitary tumors
Oncogene activation
Oncogene activation probably is responsible for the pathogenesis of most sporadic pituitary tumors. Proto-oncogenes usually encode proteins in these classes: protein tyrosine kinases (e.g. src), protein serine/threonine kinases (e.g. raf), transcriptional factors (e.g. c-myc), small G proteins (e.g. ras), cell cycle regulators (e.g. cyclin D and PTTG) and others. Unlike the few classical viral oncogenes, most oncogenes reported or suggested in the literature so far have not fulfilled the gold
Senescence in pituitary tumor pathogenesis
Senescence refers to premature irreversible cell proliferation arrest (Arzt et al., 2009, Zhang, 2007). Senescent cells maintain cellular function and viability, but are devoid of proliferative potential. Premature senescence is not related to telomere shortening; rather, it is a response to cellular stresses such as oncogene over-expression, oxidative stress, DNA damage and withdrawal of key nutrients or growth factors. Premature senescence is a protective mechanism against tumorigenesis but
Tumor suppression gene inactivation
Familial pituitary tumor syndromes and transgenic pituitary tumor models both indicate that tumor suppression gene inactivation is responsible for specific tumor formation in the pituitary. Tumor suppressor genes are defined as the genes whose homozygous deletion or inactivation causes tumorigenesis (Alexander, 2001). The classical ‘two-hit’ theory of tumorigenesis points out that an individual may inherit a heterozygous inactivating mutation of a tumor suppressor gene; while the normal allele
Epigenetic pathogenesis of pituitary tumors
Epigenetic modification of genes involved in regulating cell proliferation is important in pituitary tumorigenesis. CDKN2A encodes CDKI p16 whose function is to inhibit cyclin D1-dependent kinase CDK4 from interacting with cyclin D1 and phosphorylating Rb. Rb hyperphosphorylation would lead to cell cycle progression from G1 to S. Although mutations or loss of CDKN2A have not been identified in pituitary tumors, hypermethylation of CDKN2A exon 1 is found in non-functioning pituitary tumors (
Humoral factors
Rarely, excess trophic hypothalamic hormones elaborated by neuroendocrine tumors or hypothalamic hamartomas lead to hyperplasia and hormonal hypersecretion of a particular pituitary cell type. Unambiguous pituitary tumors are not common in this situation. GH-releasing hormone (GHRH), CRH and GnRH excess by these tumors produce acromegaly, Cushing’s syndrome and sexual precocity or hypergonadism, respectively (Tasdemiroglu and Kaya, 2004). Absence of peripheral hormone negative feedback
Tumor micro-environment
Tumor angiogenesis, tumor cell interaction and tumor–stroma interaction are important for understanding pituitary tumor pathogenesis. These tumor micro-environment parameters probably are not critical in tumor initiation but are certainly important for tumor promotion and tumor invasiveness.
The role of angiogenesis in pituitary tumor pathogenesis is complex. Pituitary tumors require angiogenesis for nutrient supply. Most pituitary tumors, however, are less vascularized than the normal
Pathogenesis of specific types of pituitary tumors
In this section of the chapter, we apply the principles to the pathogenesis of all the major types of pituitary tumors and describe their specific pathogenetic mechanisms.
Pathogenesis of prolactinoma
Lactotrophs are under tonic inhibition of hypothalamic dopamine and are stimulated by estrogen. Prolactinoma is the second common pituitary tumor but specific pathogenesis of prolactinoma is not well characterized. Pituitary oncogene activation (CCND1, PTTG, etc.) and tumor suppressor gene inactivation (MEN1) as discussed above are both present in prolactinoma. General over-expression of a putative oncogene HMGA2 (high mobility group A2), a non-histone chromatin-associated protein, results in
Pathogenesis of corticotrophinoma (ACTHoma)
Corticotrophs are stimulated by hypothalamic CRH and inhibited by cortisol. As these tumors are rare, very little is known of their specific pathogenesis. It is assumed that the principles of pituitary tumorigenesis also apply for corticotropinoma. Peroxisome proliferator-activated receptor-γ is expressed exclusively in corticotrophs and may be important for ACTH secretion and corticotroph survival (Heaney et al., 2002). Ectopic secretion of CRH by neuroendocrine tumors occasionally causes
Pathogenesis of thyrotropinoma (TSHoma)
Thyrotropinomas are extremely rare and tend to large and invasive. Besides TSH, these tumors may also secrete GH or prolactin. True, spontaneous thyrotropinomas may be associated with multiple endocrine neoplasia syndrome type 1 or more commonly, are sporadic (Beck-Peccoz et al., 1996, Sanno et al., 2001). Over-expression of the pituitary-specific transcription factor Pit-1 may play a role in thyrotropinoma pathogenesis (Teramoto et al., 2004). Gsp and other oncogenes are not found in these
Pathogenesis of gonadotropinoma
Although gonadophinoma is the most common pituitary tumor, few studies address its unique pathogenesis directly but many studies on pituitary tumorigenesis include it as a type among several studied. MEG3, a possible tumor suppressor gene, is expressed only in gonadotrophs but not in gonadotropinomas thus loss of MEG3 may result in gonadotropinoma growth (Ying et al., 2005).
Prospects of the study on pituitary tumor pathogenesis
Pituitary tumor pathogenesis is challenging to study due to unique tumor biology and behavior, difficulty in accessing the pituitary gland, and lack of human pituitary cell lines and few faithful animal models for human pituitary tumors. Much remains to be learned to understand the pathogenesis of pituitary tumors. Oncogene activation, tumor suppressor gene inactivation and tumor micro-environment are all required for pituitary cell transformation. We suggest that future research on pituitary
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