Expression of the pituitary stem/progenitor marker GFRα2 in human pituitary adenomas and normal pituitary

Abstract

Purpose Recent studies suggest that adult pituitary stem cells may play a role in pituitary tumorigenesis. We sought to explore whether the Glial cell-line derived neurotrophic factor receptor alpha 2 (GFRα2), a recently described pituitary stem/progenitor marker, might be differentially expressed in pituitary adenomas versus normal pituitary. Methods The expression of GFRα2 and other members of the GFR receptor family (GFRα1, α3, α4) were analyzed using RT-PCR, western blot, and immunohistochemistry in 39 pituitary adenomas, 14 normal pituitary glands obtained at autopsy, and cDNA from 3 normal pituitaries obtained commercially. Results GFRα2 mRNA was ~2.6 fold under-expressed in functioning adenomas (P <0.01) and ~3.5 fold over-expressed in non-functioning adenomas (NFAs) (P <0.05) compared to normal pituitary. Among NFAs, GFRα2 was significantly over-expressed (~5-fold) in the gonadotropinoma subtype only (P<0.05). GFRα2 protein expression appeared to be higher in most NFAs, although there was heterogeneity in protein expression in this group. GFRα2 protein expression appeared consistently lower in functioning adenomas by IHC and western blot. In normal pituitary, GFRα2 was localized in Rathke’s remnant, the putative pituitary stem cell niche, and in corticotropes. Conclusion Our results suggest that the pituitary stem cell marker GFRα2 is under-expressed in functioning adenomas and over-expressed in NFAs, specifically gonadotropinomas. Further studies are required to elucidate whether over-expression of GFRα2 in gonadotropinomas might play a role in pituitary tumorigenesis.

Dopamine receptor type 2 (DRD2) and somatostatin receptor type 2 (SSTR2) agonists are effective in inhibiting proliferation of progenitor/stem‐like cells isolated from nonfunctioning pituitary tumors

“…These putative parenchymal tumor stem cells expressed stem cell markers, were able to self-renew and had a high efflux capacity. [1][2][3][4] Consistent with the previous observation that stem cellassociated markers are particularly overexpressed by NFPTs, 2,29,30 we observed spheres formation in about 70% of cultured NFPTs, a success rate nearly identical to that obtained by Murth et al in NFPTs and GH-secreting pituitary tumors. 4 The spheres were able to self-renew in culture, although with a limited potential, restricted to secondary spheres, in agreement with published data on spheres derived from both rodent normal pituitary and human pituitary adenomas.…”

“…Consistent with the previous observation that stem cell‐associated markers are particularly overexpressed by NFPTs, we observed spheres formation in about 70% of cultured NFPTs, a success rate nearly identical to that obtained by Murth et al . in NFPTs and GH‐secreting pituitary tumors .…”

“…We found a low proportion of cells positive for CD133, considered a common marker of cancer stem cells in different tumors. Previous studies reported the presence of CD133 in pituitary adenomas, although in spheres derived from these tumors contrasting data have been reported, showing both CD133 expression and low or absent CD133 expression, accordingly with the results of the present study.…”

Pituitary Cell Turnover: From Adult Stem Cell Recruitment through Differentiation to Death

“…However, Mathioudakis et al [104] did not find colocalization of RET with GH+ cells in the AP, a result that contradicts previous research in both rodents and humans [18,90,91,97]. Overall, the study strongly suggests that NFPA are niche cell derived, but secretory adenomas are not [104].…”

“…More recently, a series of somatotroph (n = 14) and nonfunctioning pituitary adenomas (NFPA, n = 21) have been compared with normal human pituitary (n = 10) in relation to GPS markers, using qRT-PCR and immunostaining [104]. Interestingly, NFPA expressed substantially (>3×) more GFRA2 mRNA than did the normal pituitaries.…”