Novel markers of gonadectomy-induced adrenocortical neoplasia in the mouse and ferret

Schillebeeckx, Maximiliaan; Pihlajoki, Marjut; Gretzinger, Elisabeth; Yang, Wei; Thol, Franziska; Hiller, Theresa; Löbs, Ann-Kathrin; Röhrig, Theresa; Schrade, Anja; Cochran, Rebecca; Jay, Patrick Y.; Heikinheimo, Markku; Mitra, Robi D.; Wilson, David B.

doi:10.1016/j.mce.2014.09.029

Cited by 27 publications

(28 citation statements)

References 71 publications

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“…In contrast to normal steroidogenic cells (arrows, Fig 4B–D), the RFP + /GATA4 + neoplastic cells did not stain directly with FITC-streptavidin (arrowheads, Fig 4B–D). Another marker known to be expressed in type A cells, FOXL2 (Schillebeeckx et al, 2015), was detected in RFP + neoplastic cells (Sup Fig 2B–D). We also saw neoplastic cells that co-expressed RFP and the platelet derived growth factor receptor PDGFRα (Fig 4E–G), a marker previously shown to be present in fibroblastic stromal cells of normal adrenal cortex (Wood et al, 2013).…”

Section: Resultsmentioning

confidence: 90%

“…A previous transcriptome-wide search (Schillebeeckx et al, 2015) designed to detect novel markers of GDX-induced adrenocortical neoplasia overlooked Pdgfra , because this gene was not represented on the microarray used in the analysis. Platelet derived growth factor (PDGF) signaling is known to control the differentiation of gonadal steroidogenic cells in both sexes (Schmahl et al, 2008), and PDGFRα is a marker of putative Leydig stem cells in rodents and humans (Landreh et al, 2013; Landreh et al, 2014; Odeh et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…This suggests that GDX-induced adrenocortical tumors arise from patches of “neoplasia-ready” progenitors in the capsule. Such neoplasia-ready cells may be defined in part by epigenetic modifications that impact the phenotypic plasticity of adrenocortical stem/progenitor cells, allowing some to respond to the hormonal changes associated with GDX (Bielinska et al, 2009; Schillebeeckx et al, 2013; Schillebeeckx et al, 2015). Epigenetic variability among stem/progenitor cells may explain why GDX of susceptible mouse strains leads to discrete wedges of proliferating neoplastic cells in the adrenal cortex rather than uniform tumor formation along the periphery of the cortex.…”

Section: Discussionmentioning

confidence: 99%

“…At the indicated timepoints, adrenal tissue was harvested for RT-qPCR analysis or overnight fixation in 4% paraformaldehyde in PBS. The fixed tissue was embedded in paraffin, sectioned (4 μm), and subjected to immunoperoxidase staining (Anttonen et al, 2003; Bielinska et al, 2005; Schillebeeckx et al, 2015) using the primary and secondary antibodies listed in Table 1.…”

Section: Methodsmentioning

confidence: 99%

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GLI1+ progenitor cells in the adrenal capsule of the adult mouse give rise to heterotopic gonadal-like tissue

Dörner

Rodriguez

Ziegler

et al. 2017

Molecular and Cellular Endocrinology

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As certain strains of mice age, hyperplastic lesions resembling gonadal tissue accumulate beneath the adrenal capsule. Gonadectomy (GDX) accelerates this heterotopic differentiation, resulting in the formation of wedge-shaped adrenocortical neoplasms that produce sex steroids. Stem/progenitor cells that reside in the adrenal capsule and retain properties of the adrenogonadal primordium are thought to be the source of this heterotopic tissue. Here, we demonstrate that GLI1+ progenitors in the adrenal capsule give rise to gonadal-like cells that accumulate in the subcapsular region. A tamoxifen-inducible Cre driver (Gli1-creERT2) and two reporters (R26R-lacZ, R26R-confetti) were used to track the fate of GLI1+ cells in the adrenal glands of B6D2F2 mice, a strain that develops both GDX-induced adrenocortical neoplasms and age-dependent subcapsular cell hyperplasia. In gonadectomized B6D2F2 mice GLI1+ progenitors contributed to long-lived adrenal capsule cells and to adrenocortical neoplasms that expressed Gata4 and Foxl2, two prototypical gonadal markers. Pdgfra, a gene expressed in adrenocortical stromal cells, was upregulated in the GDX-induced neoplasms. In aged non-gonadectomized B6D2F2 mice GLI1+ progenitors gave rise to patches of subcapsular cell hyperplasia. Treatment with GANT61, a small-molecule GLI antagonist, attenuated the upregulation of gonadal-like markers (Gata4, Amhr2, Foxl2) in response to GDX. These findings support the premise that GLI1+ progenitor cells in the adrenal capsule of the adult mouse give rise to heterotopic tissue.

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Section: Resultsmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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GLI1+ progenitor cells in the adrenal capsule of the adult mouse give rise to heterotopic gonadal-like tissue

Dörner

Rodriguez

Ziegler

et al. 2017

Molecular and Cellular Endocrinology

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“…87 Novel genetic and epigenetic markers were identified recently in mice and ferrets (Tables 4 and 5). 102 The nuclear immunoreactivity of FoxL2, a transcription factor, was upregulated in ferrets with adrenal cortical nodular hyperplasia, adrenocortical adenoma, and adrenocortical carcinoma. 102 The RNA expression profiling and candidate gene approach identified upregulation of genes such as Insl3 , Spinlw1 , and FoxL2 in adrenocortical neoplasms of gonadectomized mice.…”

Section: Adrenal Glandmentioning

confidence: 97%

Endocrinopathy and Aging in Ferrets

Bakthavatchalu¹,

Muthupalani²,

Marini³

et al. 2016

Veterinary Pathology

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Ferrets have become more popular as household pets and as animal models in biomedical research in the past 2 decades. The average life span of ferrets is about 5-11 years with onset of geriatric diseases between 3-4 years including endocrinopathies, neoplasia, gastrointestinal diseases, cardiomyopathy, splenomegaly, renal diseases, dental diseases, and cataract. Endocrinopathies are the most common noninfectious disease affecting middle-aged and older ferrets. Spontaneous neoplasms affecting the endocrine system of ferrets appear to be increasing in prevalence with a preponderance toward proliferative lesions in the adrenal cortex and pancreatic islet cells. Diet, gonadectomy, and genetics may predispose ferrets to an increased incidence of these endocrinopathies. These functional proliferative lesions cause hypersecretion of hormones that alter the physiology and metabolism of the affected ferrets resulting in a wide range of clinical manifestations. However, there is an apparent dearth of information available in the literature about the causal relationship between aging and neoplasia in ferrets. This review provides a comprehensive overview of the anatomy and physiology of endocrine organs, disease incidence, age at diagnosis, clinical signs, pathology, and molecular markers available for diagnosis of various endocrine disorders in ferrets.Keywords adrenal-associated endocrinopathy; adrenocortical neoplasm; aging; cysts; diabetes mellitus; endocrinopathies; endocrine tumors; estrogen-induced anemia; ferret; gonadectomy; insulinoma; islet cell tumor; multiple endocrine neoplasia; neuroblastoma; ovary; pancreatic polypeptidoma; parathyroid; pheochromocytoma; pituitary; review; teratoma; testis; thyroid The domestic ferret Mustela putorius furo, like the skunk, mink, weasel, stoat, otter, and badger, is a carnivorous mammal that belongs to the Mustelidae family. Ferrets were domesticated more than 2000 years ago and were primarily used for hunting rabbits and for fur production in Europe. Introduced in 1875, ferrets are considered companion animals in the United States. Approximately, 7-10 million ferrets are maintained as household pets in the United States. 3,36 In 1882, ferrets were introduced in New Zealand to control the Reprints and permission: sagepub.com/journalsPermissions.nav Corresponding Author: J. G. Fox, Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. jgfox@mit.edu. Supplemental material for this article is available on the Veterinary Pathology website at http://vet.sagepub.com/supplemental. Declaration of Conflicting Interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. HHS Public AccessAuthor manuscript Vet Pathol. Author manuscript; available in PMC 2017 April 20. Author Manuscript Author ManuscriptAuthor Manuscript Author Manuscriptburgeoning European rabbit population are now considered feral animals and they play an important role in the t...

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Identification of novel GLI1 target genes and regulatory circuits in human cancer cells

et al. 2018

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Hedgehog (HH) signaling is involved in many physiological processes, and pathway deregulation can result in a wide range of malignancies. Glioma‐associated oncogene 1 (GLI1) is a transcription factor and a terminal effector of the HH cascade. Despite its crucial role in tumorigenesis, our understanding of the GLI1 cellular targets is quite limited. In this study, we identified multiple new GLI1 target genes using a combination of different genomic surveys and then subjected them to in‐depth validation in human cancer cell lines. We were able to validate >90% of the new targets, which were enriched in functions involved in neurogenesis and regulation of transcription, in at least one type of follow‐up experiment. Strikingly, we found that RNA editing of GLI1 can modulate effects on the targets. Furthermore, one of the top targets, FOXS1, a gene encoding a transcription factor previously implicated in nervous system development, was shown to act in a negative feedback loop limiting the cellular effects of GLI1 in medulloblastoma and rhabdomyosarcoma cells. Moreover, FOXS1 is both highly expressed and positively correlated with GLI1 in medulloblastoma samples of the Sonic HH subgroup, further arguing for the existence of FOXS1/GLI1 interplay in human tumors. Consistently, high FOXS1 expression predicts longer relapse‐free survival in breast cancer. Overall, our findings open multiple new avenues in HH signaling pathway research and have potential for translational implications.

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Novel markers of gonadectomy-induced adrenocortical neoplasia in the mouse and ferret

Cited by 27 publications

References 71 publications

GLI1+ progenitor cells in the adrenal capsule of the adult mouse give rise to heterotopic gonadal-like tissue

GLI1+ progenitor cells in the adrenal capsule of the adult mouse give rise to heterotopic gonadal-like tissue

Endocrinopathy and Aging in Ferrets

Identification of novel GLI1 target genes and regulatory circuits in human cancer cells

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