Stem cell markers are associated with the regulators of the gonadotroph axis in gonadotroph NF-PitNETs

KA. øystese*^a (Dr), NC. Olarescu^a (Dr), C. Lindskog^b (Dr), JP. Berg^c (Dr), J. Bollerslev^a (Prof), O. Casar-Borota^d (Dr)

^a Institute of Clinical Medicine, University of Oslo; Department of Endocrinology, morbid obesity and preventive medicine, Oslo University Hospital., Oslo, NORWAY ; ^b Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SWEDEN ; ^c Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, NORWAY ; ^d Department of Immunology, Genetics and Pathology, Uppsala University; Department of Clinical Pathology, Uppsala University Hospital, Uppsala, SWEDEN

* kaoystes@medisin.uio.no

Background: Cells with stem cell features have previously been found in human pituitary tumours. SOX2 and SOX9 are principal pituitary stem cell markers, while PROP1, a pituitary transcription factor, is involved in anterior pituitary cell lineage development. We aimed to investigate the presence of these in the gonadotroph NF-PitNETs.

Methods: We investigated the distribution of SOX2, SOX9 and PROP1 in a previously established tissue micro array (N=101) and in frozen tumour tissue by RT-qPCR (N=71) from a retrospective cohort of gonadotroph NF-PitNETs. Immunohistochemical (IHC) staining scores of the selected markers were compared to clinical data, and to previously investigated regulators of the gonadotroph axis in the same cohort. The markers were scored based on the percentage of positive staining cells, ranging from 0 (no positive staining cells) to 5 (>50% positive staining cells).

Results: We found that most gonadotroph tumour samples showed no or scattered cells with positive staining for SOX2, SOX9 and PROP1 (80, 72 and 82 of tumours, respectively). There was no association between the presence of the markers and gender, age at primary pituitary surgery and rate of reintervention.

The staining correlated to the gene expression (∆Ct) counterpart for all markers (SOX2: N=60, ρ=0.538, p <0.001; SOX9: N=63, ρ=0.601, p<0.001 and PROP1: N=63, ρ=0.434, p<0.001).

The staining for SOX2, SOX9 and PROP1 correlated positively to each other (SOX2 and SOX9 N=101, ρ=0.696, p<0.001; SOX2 and PROP1 N=101, ρ=726, p<0.001; SOX9 and PROP1 N=101, ρ=0.617, p<0.001).

The staining for SOX2 and SOX9 correlated to the immunoreactive score of ERα (ie SOX2 and ERα: N=97, ρ =0.315, p=0.002), the staining for FSH (ie SOX2 and FSH: N=99, ρ=0.359, p<0.001) and to the gene expression of GnRHR (ie SOX2 and GnRHR: N=57, ρ=0.445, p<0.001), the latter two also correlated positively with PROP1.

Conclusion: Most gonadotroph NF-PitNETs did not present staining for SOX2, SOX9 and PROP1. Nevertheless, the stem cell markers were associated with regulation of gonadotropin production in NF-PitNETs and did not correlate with the rate of reintervention.

The author has declared no conflict of interest.