Craniopharyngiomas express embryonic stem cell markers (SOX2, OCT4, KLF4, and SOX9) as pituitary stem cells but do not coexpress RET/GFRA3 receptors.
BACKGROUND
Adult stem cells maintain some markers expressed by embryonic stem cells and express other specific markers depending on the organ where they reside. Recently, stem/progenitor cells in the rodent and human pituitary have been characterized as expressing GFRA2/RET, PROP1, and stem cell markers such as SOX2 and OCT4 (GPS cells).


OBJECTIVE
Our objective was to detect other specific markers of the pituitary stem cells and to investigate whether craniopharyngiomas (CRF), a tumor potentially derived from Rathke's pouch remnants, express similar markers as normal pituitary stem cells.


METHODS
We conducted mRNA and Western blot studies in pituitary extracts, and immunohistochemistry and immunofluorescence on sections from normal rat and human pituitaries and 20 CRF (18 adamantinomatous and two papillary).


RESULTS
Normal pituitary GPS stem cells localized in the marginal zone (MZ) express three key embryonic stem cell markers, SOX2, OCT4, and KLF4, in addition to SOX9 and PROP1 and β-catenin overexpression. They express the RET receptor and its GFRA2 coreceptor but also express the coreceptor GFRA3 that could be detected in the MZ of paraffin pituitary sections. CRF maintain the expression of SOX2, OCT4, KLF4, SOX9, and β-catenin. However, RET and GFRA3 expression was altered in CRF. In 25% (five of 20), both RET and GFRA3 were detected but not colocalized in the same cells. The other 75% (15 of 20) lose the expression of RET, GFRA3, or both proteins simultaneously.


CONCLUSIONS
Human pituitary adult stem/progenitor cells (GPS) located in the MZ are characterized by expression of embryonic stem cell markers SOX2, OCT4, and KLF4 plus the specific pituitary embryonic factor PROP1 and the RET system. Redundancy in RET coreceptor expression (GFRA2 and GFRA3) suggest an important systematic function in their physiological behavior. CRF share the stem cell markers suggesting a common origin with GPS. However, the lack of expression of the RET/GFRA system could be related to the cell mislocation and deregulated growth of CRF.
Instituto de Investigaciones Sanitarias & Centro de Investigaciones Médicas de la USC (IDIS-CIMUS), Department of Physiology, School of Medicine, University of Santiago de Compostela (USC), E-15782 Santiago de Compostela, Spain.
Montserrat
M
Garcia-Lavandeira
Carmen
C
Saez
Esther
E
Diaz-Rodriguez
Sihara
S
Perez-Romero
Ana
A
Senra
Carlos
C
Dieguez
Miguel A
MA
Japon
Clara V
CV
Alvarez
D000328:Adult; D053687:Adult Stem Cells / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D003397:Craniopharyngioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053595:Embryonic Stem Cells / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism
D015415:Biomarkers; D014408:Biomarkers, Tumor; C494993:GFRA3 protein, human; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; C000715467:KLF4 protein, human; C000715469:Klf4 protein, rat; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C527782:SOX2 protein, human; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D055748:SOXB1 Transcription Factors; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human