scholarly journals SAT-300 Evading Death: Noxa in Cushing’s Disease Pituitary Adenomas

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Reinier Alvarez ◽  
Konstantinos Floros ◽  
Kory Johnson ◽  
Abdel Elkahloun ◽  
Weiwei Wu ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Expression ◽  
Cushing’S Disease ◽  
Fold Increase ◽  
Cushing's Disease ◽  
Benign Tumors ◽  
Human Pituitary ◽  
Human Pituitary Adenoma ◽  
Altered Expression ◽  
Normal Gland

Abstract Introduction: Recurrence of Cushing’s disease (CD) caused by benign pituitary microadenomas are challenging clinical problems. Mechanisms underlying adenoma formation and recurrence remain unknown. PMAIP1 gene codes for Noxa, a Bcl-2 homology 3 (BH3) pro-apoptotic protein frequently downregulated in malignant human tumors.1-6 The role of dysregulated apoptosis remains largely unknown in benign tumors and in CD. We hypothesized that altered expression of Noxa protein is a pro-survival adaptation employed by CD adenomas. Methods: Syngeneic human pituitary adenoma and adjacent normal gland pairs (n=2), and an additional CD adenoma were analyzed with RNAseq. 10 CD, 1 growth hormone (GH) and 1 non-functioning adenoma (NFPA) underwent immunohistochemical (IHC) analysis for Noxa expression, which was graded by a neuropathologist as 0=none, 1=light, 2=medium, 3=strong. Staining grade represents relative protein expression. Results: Compared to adjacent normal pituitary tissue, we found that adenomas (n = 3) had a 3.76 fold increase in PMAIP1 mRNA. However, there was attenuated Noxa IHC staining in adenomas compared to normal pituitary in 8 of 10 CD patients (2:3, respectively), but similar staining in 2 of 10 CD patients (2:2 and 2-3:2-3). In GH and NFPA, we found similar patterns of Noxa suppression in the adenomas compared to the normal gland. Conclusion: Despite elevated PMAIP1 (Noxa) gene expression in adenomas compared to adjacent normal gland in CD, protein expression was reduced in adenomas. This downregulation of Noxa protein expression may contribute to reduced apoptosis of tumor cells. These findings suggest that CD adenomas gain pro-survival advantage by downregulating Noxa protein at post-transcriptional or post-translational level. References 1. Escobar, D. et al. Cell Death Dis.6, 1-14 (2015).2. Brinkmann, K. et al. Cell Rep.3, 881-891 (2013).3. Liu, Y. L. et al. Oncotarget5, 11237-11251 (2014).4. Dengler, M. A. et al. Cell Death Dis.5, 1-10 (2014).5. Liang, L. et al. J. Oral Pathol. Med.48, 52-59 (2019).6. Tahir, S. K. et al. Cancer Res.67, 1176-1183 (2007).

The corticotrophic cells of the canine pituitary gland in pituitary-dependent hyperadrenocorticism

1983 ◽  
Vol 96 (2) ◽  
pp. 303-309 ◽  
Author(s):  
A. M. McNicol ◽  
H. Thomson ◽  
C. J. R. Stewart
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Pituitary Gland ◽  
Cushing’S Disease ◽  
Cushing's Disease ◽  
Human Pituitary ◽  
Human Pituitary Gland ◽  
Single Entity ◽  
Pituitary Glands ◽  
Corticotrophic Cells

The distribution of specifically stained corticotrophic cells has been studied in the pituitary glands of 11 dogs with pituitary-dependent hyperadrenocorticism. The results suggest that the disease is not a single entity, and that some cases are caused by primary abnormality of the pituitary gland whereas others appear to be the result of dysfunction of the hypothalamus or central nervous system. The patterns correspond closely to those demonstrated in the human pituitary gland in Cushing's disease, and confirm that the canine disease is a useful model for the study of the pathogenesis of the variants of the condition.

TISSUE CULTURE STUDIES ON HUMAN PITUITARY TUMOURS: RADIOIMMUNOASSAYABLE ANTERIOR PITUITARY HORMONES IN THE CULTURE MEDIUM

1978 ◽  
Vol 88 (2) ◽  
pp. 239-249 ◽  
Author(s):  
Loren G. Lipson ◽  
Inese Z. Beitins ◽  
Paul D. Kornblith ◽  
Janet W. Mc Arthur ◽  
Henry G. Friesen ◽  
...  
Keyword(s):  
Tissue Culture ◽  
Cushing’S Disease ◽  
Anterior Pituitary ◽  
Pituitary Hormones ◽  
Cushing's Disease ◽  
Hormone Release ◽  
Pituitary Tumours ◽  
Human Pituitary ◽  
Anterior Pituitary Hormones

ABSTRACT A tissue culture study was undertaken to determine if human non-functioning pituitary tumours secrete polypeptide anterior pituitary hormones in vitro and to study the spectrum of hormone release by functioning pituitary neoplasms. Fragments from 48 human pituitary tumours (from patients - 2 with Cushing's disease, 1 with Nelson's syndrome, 5 with amenorrhoea-galactorrhoea, 10 with acromegaly and 30 with non-functioning pituitary tumours) and three normal human anterior pituitary glands (controls) were placed in tissue culture immediately after surgery. The in vitro release of human growth hormone (HGH), prolactin (Prl), thyrotrophin (TSH), adrenocorticotrophin (ACTH), luteinizing hormone (LH) and follicle stimulating hormone (FSH) were measured by radioimmunoassays at the end of one week in culture. Clinical and pathological data were compared to hormone release patterns. In the culture media from control pituitaries the concentrations of the six hormones tested were 100 to 10 000 times greater than in peripheral blood. The medium surrounding the fragments from functioning pituitary tumours contained the following: a) Acromegaly - high levels of HGH and variable concentrations of the other hormones. b) Cushing's disease - ACTH and Prl predominantly. c) Amenorrhcea-galactorrhoea syndrome - prolactin in 4 out of 5 patients, all six polypeptides in one patient. In the media from the 30 patients diagnosed as having non-functioning pituitary tumours, 60 % of the samples contained at least one hormone at a concentration similar to that of the controls and 100 % of the samples contained detectable quantities of at least one hormone.

scholarly journals Two Distinctive POMC Promoters Modify Gene Expression in Cushing’s Disease

2021 ◽  
Author(s):  
Takako Araki ◽  
Yukiko Tone ◽  
Masaaki Yamamoto ◽  
Hiraku Kameda ◽  
Anat Ben-Shlomo ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
Methylation Status ◽  
Regulatory Region ◽  
Pituitary Tumors ◽  
Cushing's Disease ◽  
Human Pituitary ◽  
Ectopic Acth ◽  
Pomc Gene ◽  
Acth Secreting

Abstract Context Mechanisms underlying pituitary corticotroph adenoma ACTH production are poorly understood, yet circulating ACTH levels closely correlate with adenoma phenotype and clinical outcomes. Objective We characterized the 5’ ends of proopiomelanocortin (POMC) gene transcripts, which encode the precursor polypeptide for ACTH, in order to investigate additional regulatory mechanisms of POMC gene transcription and ACTH production. Methods We examined 11 normal human pituitary tissues, 32 ACTH-secreting tumors, as well as 6 silent pituitary corticotroph adenomas (SCA) that immunostain for but do not secrete ACTH. Results We identified a novel regulatory region located near the intron2/exon3 junction in the human POMC gene, which functions as a second promoter and an enhancer. In vitro experiments demonstrated that CREB binds the second promoter and regulates its transcriptional activity. The second promoter is highly methylated in SCA, partially demethylated in normal pituitary tissue, and highly demethylated in pituitary and ectopic ACTH-secreting tumors. In contrast, the first promoter is demethylated in all POMC-expressing cells and is highly demethylated only in pituitary ACTH-secreting tumors harboring the USP8 mutation. Demethylation patterns of the second promoter correlate with clinical phenotypes of Cushing’s disease. Conclusion We identified a second POMC promoter regulated by methylation status in ACTH-secreting pituitary tumors. Our findings open new avenues for elucidating subcellular regulation of the hypothalamic-pituitary-adrenal axis and suggest the second POMC promoter may be a target for therapeutic intervention to suppress excess ACTH production.

scholarly journals MON-407 Tumor Control after Radiotherapy and Temozolomide in a Cushing's Disease Patient with Giant Aggressive Pituitary Tumor

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Hugo Valente do Couto ◽  
Bruna Peres ◽  
Klevia Sampaio ◽  
Nina de Castro Musolino ◽  
Valter Cescato ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
Pituitary Adenomas ◽  
Third Ventricle ◽  
Disease Patient ◽  
Partial Resection ◽  
Cushing's Disease ◽  
Benign Tumors ◽  
Tumor Control ◽  
Ki 67 ◽  
Remnant Tumor

Abstract Introduction: Typical ACTH-producing pituitary adenomas are benign tumors, microadenomas, successfully treated by neurosurgery. However, 10-20% of Cushing’s disease (CD) patients have macroadenomas, sometimes invasive and aggressive cases with poorer surgical prognosis needing additional approaches. Temozolomide (TMZ), second generation alkylating agent, has been used alone or in combination to other medications/radiotherapy (RTX) for tumor control of aggressive pituitary adenomas and carcinomas. We report one patient with giant aggressive corticotropinoma that presented control tumor with RTX and TMZ after four pituitary surgeries unable to uncontroll tumor growth. Clinical Case: A 18-year-old female patient presented with weight gain, red moon face, supraclavicular fullness, dorsal hump, large purple striae, acanthosis nigricans, secondary amenorrhea, frontotemporal headache, visual impairment and right palpebral ptosis. Hormonal analysis confirmed ACTH-dependent Cushing's syndrome. Pituitary MRI showed the presence of a large selar and suprasellar expansive lesion of 5.2X5.1X4.0 cm with displacement of third ventricle, hypothalamus and lateral ventricles. The patient was submitted to the first neurosurgery (transsphenoidal route) with partial resection. Pathological analyses confirmed pituitary adenoma positive for ACTH, Ki-67 8%, negative p53 and 7 mitoses/10 field of great increase. Subsequent surgery was done by craniotomy with partial resection. Cabergoline 2 mg/week was started but the tumor keeps growing with worsening of visual complaints and increase of cortisol levels. At admission in our center, we planned new surgeries do remove the maximal tumor possible (debulking) and subsequent RTX and TMZ. She was submitted to third surgery by transsphenoidal route and the last surgical procedure by craniotomy. MRI pre-RTX done three months after the 4th surgery showed remnant tumor of 3.5X3.0X3.0 cm. Fractioned stereotaxic radiotherapy was done with linear accelerator in a total of 54 Gy divided in 30 sessions. TMZ was initiated in a dose of 150 m2/day, cycles of five days/month, using for 14 months. Pituitary MRI 3, 6 and 10 months after TMZ showed a small reduction of tumor with increase of intratumor cystic areas. Conclusion: The combined use of TMZ and radiotherapy is an important approach for the treatment of rapidly growing, aggressive pituitary ACTH-secreting tumors resistant to conventional treatment.

α-Amidated peptides derived from pro-opiomelanocortin in human pituitary tumours

1988 ◽  
Vol 118 (2) ◽  
pp. 329-338 ◽  
Author(s):  
M. Fenger ◽  
A. H. Johnsen
Keyword(s):  
Molecular Weight ◽  
Cushing’S Disease ◽  
Cushing's Disease ◽  
Molecular Forms ◽  
Low Molecular Weight ◽  
Gel Chromatography ◽  
Pituitary Tumours ◽  
Nelson’S Syndrome ◽  
Human Pituitary ◽  
Nelson's Syndrome

ABSTRACT Human pituitary tumours, obtained at surgery for Cushing's disease and Nelson's syndrome, were extracted and the content and molecular forms of proopiomelanocortin (POMC)-derived peptides determined by radioimmunoassay, gel chromatography, reversed-phase high-performance liquid chromatography (HPLC) and sequence analysis. In the tumours from patients with Cushing's disease the mean concentrations of amidated peptides relative to the total amount of POMC were as follows: α-MSH, 1·7%; amidated γ-MSH (γ1-MSH), 8·5% and the peptide linking γ-MSH and ACTH in the precursor (hinge peptide or joining peptide) in its amidated form (HP-N), 17·1%. The same relative concentrations in the tumours from patients with Nelson's syndrome were 8·5% (α-MSH), 7·5% (γ1-MSH) and 12·2% (HP-N). More than 95% of the ACTH(1–39) immunoreactivity eluted as synthetic ACTH(1–39) by gel chromatography and HPLC. The remaining ACTH(1–39) immunoreactivity eluted as partly glycosylated high molecular weight forms. All the α-MSH and its glycine-extended precursor ACTH(1–14) were of low molecular weight, mainly non- or mono-acetylated forms, but significant amounts of diacetylated analogues were also present. γ1-MSH and γ2-MSH immunoreactivities eluted as high molecular weight forms and were partly glycosylated. No low molecular weight forms of γ1-MSH or γ2-MSH could be detected in the pituitary tumours. Amidated hinge peptide was mainly of the 30 amino acid form. In conclusion, all the molecular forms of the amidated peptides detected in tumours from patients with Cushing's disease and Nelson's syndrome were similar to the molecular forms found in the normal human pituitary. The main difference between the tumours and the normal pituitary was the greater amount of peptides produced, particularly α-MSH and γ1-MSH. J. Endocr. (1988) 118, 329–338

scholarly journals Why don’t corticotroph tumors always produce Cushing’s disease?

2019 ◽  
Vol 181 (3) ◽  
pp. 351-361 ◽  
Author(s):  
A García-Martínez ◽  
D A Cano ◽  
A Flores-Martínez ◽  
J Gil ◽  
M Puig-Domingo ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cushing’S Disease ◽  
Translational Regulation ◽  
Sanger Sequencing ◽  
Secretory Activity ◽  
Genetic Alterations ◽  
Cushing's Disease ◽  
Tumor Subtype ◽  
Quantitative Real Time Pcr ◽  
Gene And Protein Expression

Objective Silent corticotroph tumors are a pituitary neuroendocrine tumor subtype of corticotroph lineage that do not clinically express Cushing’s disease. The silencing of this type of tumor is not fully understood. The aim of the present study was to delve into the lack of secretory activity, studying the post-transcriptional and post-translational regulation of POMC/ACTH in a series of molecularly identified functioning and silent corticotroph tumors. Design We analyzed 24 silent corticotroph, 23 functioning corticotroph and 25 silent gonadotroph tumors. Methods We used Sanger sequencing, quantitative real-time PCR and Western blot to analyze genetic alterations in POMC, gene expression of TBX19, NEUROD1, POMC, PCSK1, PCSK2, CPE and PAM and protein expression of POMC, PC1/3, PC2, CPE and PAM. Results We found different polymorphisms in the POMC gene of corticotroph tumors, some of them related to deficiency of proopiomelanocortin. Silent corticotroph tumors showed lower PC1/3 gene and protein expression than functioning ones, especially compared to micro-functioning corticotroph tumors (all P < 0.05). Moreover, we found a positive correlation between PC2 and CPE gene and protein expression (rho ≥ 0.670, P < 0.009) in silent corticotroph tumors compared with functioning ones. Conclusions By studying the post-transcriptional and post-translational processing of POMC and ACTH, respectively, in a large series of silent and functioning corticotroph tumors, we found that the lack of secretory activity of these tumors is related to an impaired processing of POMC and a high degradation of ACTH, with the macro-functioning corticotroph tumor behaving as an intermediate state between micro-functioning and silent corticotroph tumors.

scholarly journals The genomic profiling and MAMLD1 expression in human and canines with Cushing’s disease

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Andrew Wang ◽  
Stewart G. Neill ◽  
Scott Newman ◽  
Marianna A. Tryfonidou ◽  
Adriana Ioachimescu ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
Canine Model ◽  
Cushing's Disease ◽  
Rna Seq ◽  
Healthy Human ◽  
Human Pituitary ◽  
Whole Exome ◽  
Species Analysis ◽  
Pituitary Glands ◽  
Acth Secreting

Abstract Background Cushing’s disease (CD) is defined as hypercortisolemia caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (corticotroph PA) that afflicts humans and dogs. In order to map common aberrant genomic features of CD between humans and dogs, we performed genomic sequencing and immunostaining on corticotroph PA. Methods For inclusion, humans and dog were diagnosed with CD. Whole exome sequencing (WES) was conducted on 6 human corticotroph PA. Transcriptome RNA-Seq was performed on 6 human and 7 dog corticotroph PA. Immunohistochemistry (IHC) was complete on 31 human corticotroph PA. Corticotroph PA were compared with normal tissue and between species analysis were also performed. Results Eight genes (MAMLD1, MNX1, RASEF, TBX19, BIRC5, TK1, GLDC, FAM131B) were significantly (P < 0.05) overexpressed across human and canine corticotroph PA. IHC revealed MAMLD1 to be positively (3+) expressed in the nucleus of ACTH-secreting tumor cells of human corticotroph PA (22/31, 70.9%), but absent in healthy human pituitary glands. Conclusions In this small exploratory cohort, we provide the first preliminary insights into profiling the genomic characterizations of human and dog corticotroph PA with respect to MAMLD1 overexpression, a finding of potential direct impact to CD microadenoma diagnosis. Our study also offers a rationale for potential use of the canine model in development of precision therapeutics.

Peptides related to α-melanocyte-stimulating hormone are commonly produced by human pituitary corticotroph adenomas: no relationship with pars intermedia origin

1989 ◽  
Vol 120 (3) ◽  
pp. 531-NP ◽  
Author(s):  
P. J. Coates ◽  
I. Doniach ◽  
C. Wells ◽  
A. C. Hale ◽  
L. H. Rees ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
High Performance ◽  
Cushing's Disease ◽  
Pars Intermedia ◽  
Intermediate Lobe ◽  
Nelson’S Syndrome ◽  
Human Pituitary ◽  
Nelson's Syndrome ◽  
Pituitary Glands ◽  
Corticotroph Adenomas

ABSTRACT The presence of immunoreactive (ir)-α-MSH has been investigated by immunocytochemistry in 24 pituitary adenomas and one case of corticotroph hyperplasia causing Cushing's disease, in four adenomas causing Nelson's syndrome, and in ten 'silent' corticotroph adenomas. It was found that a high proportion of these adenomas have a population of cells containing ir-α-MSH in addition to ir-ACTH. In some instances, these adenomas were clearly not associated with the residual intermediate lobe of the pituitary. Radioimmunoassay of plasma from patients with Cushing's disease or Nelson's syndrome showed elevated levels of ir-α-MSH in the majority of cases. Characterization of the ir-α-MSH in adenoma cells by immunocytochemistry, using an antiserum selective for acetylated forms of α-MSH, suggested that only the desacetyl form was present in each case examined. High-performance liquid chromatography of adenoma tissue extracts revealed material co-eluting with acetylated forms of α-MSH in only one of six cases. These results have been compared with corticotroph adenomas in animal pituitary glands, and it is concluded that the presence of α-MSH peptides cannot be used as a marker for intermediate lobe tumours, and that desacetyl α-MSH is commonly produced by corticotroph adenomas. Journal of Endocrinology (1989) 120, 531–536

Analysis of Cyclooxygenase 2, Programmed Cell Death Ligand 1, and Arginase 1 Expression in Human Pituitary Adenoma

2020 ◽  
Vol 144 ◽  
pp. e660-e673
Author(s):  
Guodong Zhao ◽  
Weike Chen ◽  
Juanjuan He ◽  
Changmeng Cui ◽  
Lihua Zhao ◽  
...  
Keyword(s):  
Cell Death ◽  
Pituitary Adenoma ◽  
Programmed Cell Death ◽  
Cyclooxygenase 2 ◽  
Human Pituitary ◽  
Human Pituitary Adenoma ◽  
Arginase 1
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