Wnt signalling in pituitary development and tumorigenesis

Abstract

Wnt signalling is activated in both pituitary organogenesis and its mature function. Wnt ligands and Wnt signalling pathways are critical for the regulation of the formation of the pituitary. In the mature pituitary, Wnt signalling pathways control cell activity and may stimulate cell proliferation in both physiological and pathological processes. This review compares Wnt signalling pathways active in the developing and mature pituitary and explores how this gives us further insight into the development of pituitary adenomas. The pituitaryThe anterior pituitary produces peptide hormones under the control of feedback from hormones secreted by the hypothalamus and the peripheral endocrine glands. This is enabled by five different populations of cells: corticotrophs which make ACTH; gonadotrophs which secrete FSH and LH; somatotrophs making GH; thyrotrophs making TSH; and lactotrophs secreting prolactin. Homeostasis is maintained by adjusting hormone expression and release from the cells of the pituitary and by varying the size of the populations of cells producing each hormone.The control of the size of the populations of cells within the pituitary is thus critical to maintain endocrine homeostasis, and when cell proliferation becomes uncontrolled, tumours develop. Pituitary adenomas are surprisingly common with an estimated prevalence of 17% (Ezzat et al. 2004). The proliferation of tumours differs from the physiological expansion in cell populations in that tumours are thought to be monoclonal. However, the distinction between these two processes is not always clear, and some pituitary microadenomas have been observed to be transient, spontaneously resolving, indicating the maintenance of at least some control of the population size. Furthermore, malignant transformation in these tumours is extremely uncommon, showing that they do not behave like adenomas in other tissues (Levy & Lightman 2003).In the fetus, the anterior pituitary develops from an invagination of the oral ectoderm which forms Rathke's pouch. Rathke's pouch later forms the anterior pituitary, making contact with the diencephalon which later becomes the posterior pituitary. During development, multipotent cells differentiate into the five hormoneproducing cells of the anterior pituitary.Wnt signalling is important both for the differentiation of pluripotent cells and in the proliferation of mature cells. This review covers the role that Wnt signalling plays in the development of the anterior pituitary and potential roles in tumorigenesis and plasticity in the adult gland. Wnt signallingWnt proteins are cell-signalling molecules. Their main effects are to stimulate cell proliferation, differentiation and migration. Wnt1, initially called integration 1 (Int-1) The Wnt/planar cell polarity pathway involves the activation of GTPases that activate downstream targets including JNK or rho kinase. This signalling pathway is associated with transmembrane proteins and reconfiguration of the cytoskeleton, thus allowing epithelial cells to set up pl...

Pituitary stem cell regulation: who is pulling the strings?

“…Increased expression of WNT4 has been observed in somatotropinomas, prolactinomas and thyrotropinomas when compared to normal pituitary tissue (Miyakoshi et al 2008, Chambers et al 2013. Since no change in subcellular β-catenin distribution was seen, it was proposed that the non-canonical WNT pathway is activated in these PIT1 lineage tumors, in agreement with WNT4 being a typical ligand in this pathway.…”

“…After translocation to the nucleus, β-catenin converts several transcriptional repressors, such as T-cell factor (TCF) 7 (previously called TCF1), TCF7-like 1 (TCF7L1, previously called TCF3), TCF7L2 (previously called TCF4) and lymphoid enhancer factor (LEF) 1, to activators by competing with corepressors like amino-terminal enhancer of split (AES) and transducin-like enhancer of split (TLE). The subsequent expression of downstream target genes like Axin2, Myc, Lef1 and CyclinD1 is often used as readout for the activation status of this canonical WNT/β-catenin pathway (Andoniadou et al 2013, Chambers et al 2013.…”

Limitations of high throughput methods for miRNA expression profiles in non-functioning pituitary adenomas

“…The Gene ontology and pathway analysis showed that these miRNAs are involved in regulation of developmental processes through targeting Wnt and TGF signaling. Wnt signaling is described to be activated in both pituitary organogenesis and its mature function [28]. In pituitary similarly to other tissue types Wnt signaling pathways control cell activity and may stimulate cell proliferation [28].…”

Low expression of secreted frizzled-related protein 2 and nuclear accumulation of β-catenin in aggressive nonfunctioning pituitary adenoma

“…Aggressive NFPAs are difficult to resect completely, which often leads to tumor recrudescence (5). It is therefore important to identify the aggressiveness of NFPAs for selection of the appropriate (30)(31)(32)(33)(34). sFRPs have been identified as possible antagonists of the Wnt signaling pathway, and sFRP2, a member of the sFRPs family, has been associated with the degree of tumor malignancy and invasive ability of various types of human cancer (20,22).…”