Review
Identification of Wnt family inhibitors: A pituitary tumor directed whole genome approach

https://doi.org/10.1016/j.mce.2010.02.039Get rights and content

Abstract

Wnt signaling pathways are important regulators of normal embryological development including that of the pituitary gland. Altered Wnt pathway expression is common in many human tumors however until recently the role of these pathways in human pituitary tumorigenesis has received little attention. The advent of microarray analysis has identified several Wnt pathway inhibitors that are frequently perturbed in pituitary tumors. In this review we summarize the role of these inhibitors in other human tumor types and review the current state of knowledge of Wnt inhibitor expression in pituitary tumors.

Introduction

Clinically detected pituitary adenomas have a prevalence of approximately 1/1000 (Daly et al., 2006) although so-called incidentalomas found at autopsy or radiological imaging are much more common (14.4% from autopsy studies and 22.5% in radiological studies) (Ezzat et al., 2004). The majority of these tumors are sporadic and their etiology is currently unknown. The powerful new tools of modern molecular biology, in particular microarray analysis, have identified several previously unrecognized pathways that are dysregulated in pituitary tumors. In this review, we focus on the discovery of alterations in Wnt inhibitor expression in pituitary tumors, consistent with the known importance of Wnt signaling in pituitary development (Gueorguiev and Grossman, 2009). We will begin by briefly summarizing the well-characterized role of Wnt pathway inhibitors in other human tumors and will then describe the identification of altered expression of Wnt pathway inhibitors in human pituitary tumors by the use of whole genome analysis.

Section snippets

Wnt signaling pathways

Wnts are an evolutionary conserved family of secreted glycoproteins important for normal development in both invertebrates and vertebrates. The term “Wnt” is an amalgam of Int-1 (the preferred integration site for Mouse Mammary Tumor Virus in virally-induced breast tumors) (Nusse and Varmus, 1982) and its Drosophila homologue wingless (Rijsewijk et al., 1987). Wnt signaling is a carefully orchestrated balance between various Wnt ligands, their cognate frizzled receptors, and a number of

Wnt signaling and pituitary development

Wnt signaling is crucial to the developing pituitary gland. The pituitary gland has dual embryonic origins from oral and neural ectoderm and develops under a series of temporally and spatially produced transcription factors. These processes occur under the control of extrinsic developmental signals such as bone morphogenic protein-4 (BMP4), and members of the fibroblast growth factor (FGF) and Wnt signaling families as well as intrinsic signals from the oral ectoderm such as Sonic hedgehog (

Wnt pathway inhibitors

Wnt signaling is inhibited by two main groups of Wnt antagonists which can be classified according to the mechanism by which inhibition occurs. The first group, which includes the SFRP family, WIF1 and Cerberus, bind directly to the Wnt ligand inhibiting its binding to the frizzled receptor complex therefore theoretically may inhibit either canonical or non-canonical pathways. The second group of Wnt inhibitors includes the DKK and Sclerostin families (Itasaki et al., 2003, Semenov et al., 2005

Pituitary tumor whole genome studies

Many genes investigated in pituitary tumorigenesis have been selected using a candidate gene approach, i.e. genes which are known to be associated with tumorigenesis in other organs or that are involved with normal function and so altered expression may be expected to result in disease. Genes may also be selected to be studied based on chromosomal location, for example selecting genes in a known area of frequent loss such as 11q13. A more global approach may also be taken such as by performing

Identification of Wnt family inhibitors from microarray studies

The first human pituitary microarray study to report the differential expression of a Wnt pathway inhibitor in pituitary tumors as compared with normal pituitary was that of Moreno et al. (2005) who used Affymetrix HGU95av2 GeneChips to compare 11 NFAs to 8 normal pituitary samples. This group identified elevated expression of SFRP1 in NFAs although this gene was not selected for further validation (Table 1). They noted that SFRP1 could act as either a Wnt antagonist or agonist (Uren et al.,

β-Catenin and pituitary tumorigenesis

The central mediator of the canonical Wnt signaling pathway is β-catenin. Loss of Wnt pathway inhibitors, such as WIF1 would be expected to result in increased Wnt signaling leading to stabilization of β-catenin due to disassembly of the destruction complex, and translocation of β-catenin into the nucleus. This would result in nuclear accumulation of β-catenin which is readily detectable by immunohistochemistry. Six papers assessing nuclear β-catenin immunohistochemistry in pituitary adenomas

Wnt pathway target gene expression

Loss of or decreased expression of Wnt pathway inhibitors would be expected to result in increased expression of Wnt pathway target genes. Assessment of Wnt target genes is complicated not only by the number of potential target genes and potential tissue specificity but also by the different Wnt signaling pathways and determining which pathway(s) is affected. Increased expression of the well-known Wnt-β-catenin target gene cyclin D1 has been demonstrated by a number of groups (Jordan et al.,

Future directions

Identification of altered expression of Wnt pathway inhibitors is intriguing but further work is needed to determine the exact mechanisms by which this promotes pituitary tumorigenesis, in particular the possible use of non-canonical signaling. Wnt pathway inhibitors may be potential therapeutic targets although cross-talk between signaling pathways is well known, for example interaction of the Wnt and Hedgehog pathways through SFRP1 (Katoh and Katoh, 2006) and the commonality of GSK3β to Wnt

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