Transcriptional comparison of testicular adrenal rest tumors with fetal and adult tissues

Author:

Schröder Mariska A M12ORCID,Sweep Fred C G J2,van Herwaarden Antonius E2,Mitchell Rod T3,Eliveld Jitske4,van Pelt Ans M M4,Rowan Alan E5,Korbie Darren5,Stikkelbroeck Nike M M L6,Claahsen-van der Grinten Hedi L1ORCID,Span Paul N7ORCID

Affiliation:

1. Department of Pediatrics, Radboud Amalia Children's Hospital, Radboud University Medical Center , Nijmegen, The Netherlands

2. Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center , Nijmegen, The Netherlands

3. MRC Centre for Reproductive Health, University of Edinburgh , Edinburgh, UK

4. Center for Reproductive Medicine, Reproductive Biology Laboratory, Amsterdam Reproduction and Development Research Institute, Amsterdam UMC, University of Amsterdam , Amsterdam, The Netherlands

5. Australian Institute for Bioengineering and Nanotechnology, The University of Queensland , Brisbane, Queensland, Australia

6. Department of Internal Medicine, Radboud University Medical Center , Nijmegen, The Netherlands

7. Radiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center , Nijmegen, The Netherlands

Abstract

Abstract Background Testicular adrenal rest tumors (TART) are a common complication of unknown cellular origin in patients with congenital adrenal hyperplasia (CAH). These benign tumors have both adrenal and testicular characteristics and are hypothesized to either derive from cells of adrenal origin from the fetal adrenogonadal primordium or by atypical differentiation of adult Leydig-progenitor cells. Objective This study aims to unravel the identity and etiology of TART. Methods Co-expression of adrenal-specific CYP11B1 and Leydig cell-specific HSD17B3 in TART was studied using immunohistochemistry. We studied the possibility of TART being derived from atypical differentiation of adult Leydig-progenitor cells by the quantification of adrenal-specific enzyme expression upon adrenocorticotrophic hormone (ACTH)-like stimulation of ex vivo cultured platelet-derived growth factor receptor alpha-positive cells. By comparing the transcriptome of TART (n = 16) with the transcriptome of fetal adrenal (n = 13), fetal testis (n = 5), adult adrenal (n = 11), and adult testis (n = 10) tissues, we explored the identity of TART. Results We demonstrate co-expression of adrenal-specific CYP11B1 and testis-specific HSD17B3 in TART cells, indicating the existence of a distinct TART cell exhibiting both adrenal and testicular characteristics. Ex vivo cultured adult Leydig-progenitor cells did not express the ACTH-receptor MC2R but did express CYP11B1 upon stimulation. Unsupervised clustering of transcriptome data showed that TART was most similar to adult adrenal tissue, followed by adult testis tissue, and least similar to either fetal tissue. Conclusion Our data suggest that TART is induced — most likely via activation of a cAMP/protein kinase A-dependent receptor — from a progenitor cell into a unique mature adrenal-like cell type, sometimes exhibiting both adrenal and testicular features.

Publisher

Oxford University Press (OUP)

Subject

Endocrinology,General Medicine,Endocrinology, Diabetes and Metabolism

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