The Experts below are selected from a list of 2370 Experts worldwide ranked by ideXlab platform
Shane T Hentges - One of the best experts on this subject based on the ideXlab platform.
-
involvement of bone morphogenetic protein 4 bmp 4 in pituitary Prolactinoma pathogenesis through a smad estrogen receptor crosstalk
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Marcelo Paezpereda, Damiana Giacomini, Damian Refojo, Alberto Carbia Nagashima, U Hopfner, Yvonne Grubler, Alberto Chervin, V Goldberg, Rodolfo G Goya, Shane T HentgesAbstract:Pituitary tumor development involves clonal expansion stimulated by hormones and growth factors/cytokines. Using mRNA differential display, we found that the bone morphogenetic protein (BMP) inhibitor noggin is down-regulated in Prolactinomas from dopamine D2-receptor-deficient mice. BMP-4 is overexpressed in Prolactinomas taken from dopamine D2-receptor-deficient female mice, but expression of the highly homologous BMP-2 does not differ in normal pituitary tissue and Prolactinomas. BMP-4 is overexpressed in other Prolactinoma models, including estradiol-induced rat Prolactinomas and human Prolactinomas, compared with normal tissue and other pituitary adenoma types (Western blot analysis of 48 tumors). BMP-4 stimulates, and noggin blocks, cell proliferation and the expression of c-Myc in human Prolactinomas, whereas BMP-4 has no action in other human pituitary tumors. GH3 cells stably transfected with a dominant negative of Smad4 (Smad4dn; a BMP signal cotransducer) or noggin have reduced tumorigenicity in nude mice. Tumor growth recovered in vivo when the Smad4dn expression was lost, proving that BMP-4/Smad4 are involved in tumor development in vivo. BMP-4 and estrogens act through overlapping intracellular signaling mechanisms on GH3 cell proliferation and c-myc expression: they had additive effects at low concentrations but not at saturating doses, and their action was inhibited by blocking either pathway with the reciprocal antagonist (i.e., BMP-4 with ICI 182780 or 17β-estradiol with Smad4dn). Furthermore, coimmunoprecipitation studies demonstrate that under BMP-4 stimulation Smad4 and Smad1 physically interact with the estrogen receptor. This previously undescribed Prolactinoma pathogenesis mechanism may participate in tumorigenicity in other cells where estrogens and the type β transforming growth factor family have important roles.
Yazhuo Zhang - One of the best experts on this subject based on the ideXlab platform.
-
Use of micro-positron emission tomography with (18)F-fallypride to measure the levels of dopamine receptor-D2 and (18)F-FDG as molecular imaging tracer in the pituitary glands and Prolactinomas of Fischer-344 rats.
OncoTargets and Therapy, 2016Co-Authors: Ping Li, Chuzhong Li, Yazhuo ZhangAbstract:: Dopamine receptor-D2 (DRD2) is the most important drug target in Prolactinoma. The aim of this current study was to investigate the role of using micro-positron emission tomography (micro-PET) with (18)F-fallypride and (18)F-fluorodeoxyglucose ((18)F-FDG) as molecular imaging tracer in the pituitary glands and Prolactinomas of Fischer-344 (F344) rats and detect the difference of the levels of DRD2 in the pituitary glands and Prolactinomas of F344 rat Prolactinoma models. Female F344 rat Prolactinoma models were established by subcutaneous administration of 15 mg 17β-estradiol for 8 weeks. The growth of tumors was monitored by the small-animal magnetic resonance imaging and micro-PET. A series of molecular biological experiments were also performed 4 and 6 weeks after pump implantation. The micro-PET molecular imaging with (18)F-fallypride revealed a decreased expression of DRD2 in F344 rat Prolactinoma models, but the micro-PET molecular imaging with (18)F-FDG presented an increased uptake in the Prolactinoma compared with the pituitary gland. A decreasing trend of levels of DRD2 in F344 rat Prolactinoma models was also detected by molecular biological experiments. From this, we can conclude that micro-PET with (18)F-fallypride and (18)F-FDG can be used to assess tumorigenesis of the Prolactinomas in vivo and molecular imaging detection of DRD2 level in Prolactinoma may be an indication of treatment effect in the animal experiment.
-
effects of the estrogen receptor antagonist fulvestrant on f344 rat Prolactinoma models
Journal of Neuro-oncology, 2014Co-Authors: Lei Cao, Hua Gao, Songbai Gui, Giwei Bai, Fei Wang, Yazhuo ZhangAbstract:The relationship between estrogen and Prolactinoma is well documented. But the anti-tumor effects of a pure estrogen receptor antagonist fulvestrant on Prolactinomas, especially in vivo, and the possible mechanisms are still unclear. Therefore, the aim of this study was to evaluate the effects of fulvestrant and the involvement of the Wnt signaling pathway on rat Prolactinoma models. Forty female F344 rat Prolactinoma models were established by subcutaneous administration of 10 mg 17β-estradiol for 6 weeks. Rats were intramuscularly injected with fulvestrant (0, 0.5, 3, 20, 40 mg/kg), and tumor size, weight and serum prolactin (PRL) levels were evaluated before and after fulvestrant treatment at 3, 7 and 14 days. Expression of estrogen receptor α (ERα), β-catenin and Wnt inhibitory factor-1 (WIF-1) in Prolactinomas was measured using quantitative PCR and western blotting, and methylation of the WIF-1 promoter was investigated using pyrosequencing. Tumor size, weight and serum PRL levels were inhibited in dose-dependent and time-dependent manners after fulvestrant treatments. β-catenin expression was downregulated but WIF-1 expression was upregulated following fulvestrant treatment. The methylation of the CpG site of the WIF-1 promoter was negatively correlated to the expression of WIF-1. In addition, the anti-cell proliferation of fulvestrant on GH3 cells was partly disrupted by Wnt signaling pathway agonist SB 216763. In conclusion, fulvestrant inhibited tumor proliferation and PRL secretion of Prolactinomas via ERα, and the Wnt signaling pathway was involved in this anti-tumor effect. Therefore, fulvestrant may be a potential new drug for Prolactinomas.
-
effects of an estrogen receptor antagonist on proliferation prolactin secretion and growth factor expression in the mmq pituitary Prolactinoma cell line
Journal of Clinical Neuroscience, 2011Co-Authors: Lige Leng, Yazhuo ZhangAbstract:Abstract The aim of this study was to investigate the functional role of estrogen receptor α (ERα) in MMQ pituitary Prolactinoma cells in the absence of estrogen with respect to proliferation, prolactin (PRL) secretion, and expression of growth factors. MMQ cells were treated with the ERα antagonist fulvestrant, then proliferation and PRL secretion were measured using MTS and enzyme-linked immunosorbent assays. Levels of ERα, vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9) and B cell leukemia/lymphoma-2 (BCL-2) were measured using quantitative polymerase chain reaction and western blot analysis. Fulvestrant acted as a potent inhibitor of ERα expression, and significantly inhibited cell proliferation (by up to 57.6 ± 2.2%) and PRL secretion (by up to 81.0%). Fulvestrant also significantly altered the expression levels of VEGF, MMP-9 and BCL-2. We conclude that ERα plays an important functional role in pituitary Prolactinomas and is also involved in the expression of particular growth factors, even in the absence of estrogen. Fulvestrant treatment may be an effective therapy for such tumors.
-
effects of estrogen receptor antagonist on biological behavior and expression of growth factors in the Prolactinoma mmq cell line
Journal of Neuro-oncology, 2011Co-Authors: Songbai Gui, Meizhen Sun, Yazhuo ZhangAbstract:The relationship between estrogen and pituitary Prolactinoma is well documented. The biological effects of estrogen are mainly mediated by estrogen receptor α (ERα). Several lines of evidence demonstrate that growth factors such as pituitary tumor transforming gene (PTTG), basic fibroblast growth factor (bFGF), transforming growth factor β1 (TGFβ1), transforming growth factor β3 (TGFβ3), and transforming growth factor β receptor type II (TGFβRII) play an important role in Prolactinoma pathogenesis induced by estrogen, but the relationship between ERα and such growth factors is still unclear. The aims of this study are to investigate the functional role of ERα in proliferation, prolactin (PRL) secretion, and expression of the above-mentioned growth factors in MMQ cells in the absence of estrogen and to discuss the feasibility of using an estrogen receptor antagonist to treat Prolactinoma. Fulvestrant, a “pure” antiestrogen without any estrogen-like activity, was used to block expression of ERα in the MMQ cell line. Proliferation and PRL secretion of MMQ cells were measured using CellTiter 96® AQueous One Solution Cell Proliferation Assay (MTS) and the enzyme-linked immunosorbent assay (ELISA) method. Levels of ERα, PTTG, bFGF, TGFβ1, TGFβ3, and TGFβRII were analyzed by real-time polymerase chain reaction (PCR) and Western blot. Fulvestrant significantly inhibited cell proliferation (up to 60.80%) and PRL secretion (up to 77.95%), and changed expression of TGFβ3 and TGFβRII in the absence of estrogen. In conclusion, ERα plays an important functional role in proliferation and PRL secretion of pituitary Prolactinomas and also can change expression of some growth factors even under the condition of no estrogen. Fulvestrant could potentially be an effective therapy for treating such tumors.
Marcelo Paezpereda - One of the best experts on this subject based on the ideXlab platform.
-
involvement of bone morphogenetic protein 4 bmp 4 in pituitary Prolactinoma pathogenesis through a smad estrogen receptor crosstalk
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Marcelo Paezpereda, Damiana Giacomini, Damian Refojo, Alberto Carbia Nagashima, U Hopfner, Yvonne Grubler, Alberto Chervin, V Goldberg, Rodolfo G Goya, Shane T HentgesAbstract:Pituitary tumor development involves clonal expansion stimulated by hormones and growth factors/cytokines. Using mRNA differential display, we found that the bone morphogenetic protein (BMP) inhibitor noggin is down-regulated in Prolactinomas from dopamine D2-receptor-deficient mice. BMP-4 is overexpressed in Prolactinomas taken from dopamine D2-receptor-deficient female mice, but expression of the highly homologous BMP-2 does not differ in normal pituitary tissue and Prolactinomas. BMP-4 is overexpressed in other Prolactinoma models, including estradiol-induced rat Prolactinomas and human Prolactinomas, compared with normal tissue and other pituitary adenoma types (Western blot analysis of 48 tumors). BMP-4 stimulates, and noggin blocks, cell proliferation and the expression of c-Myc in human Prolactinomas, whereas BMP-4 has no action in other human pituitary tumors. GH3 cells stably transfected with a dominant negative of Smad4 (Smad4dn; a BMP signal cotransducer) or noggin have reduced tumorigenicity in nude mice. Tumor growth recovered in vivo when the Smad4dn expression was lost, proving that BMP-4/Smad4 are involved in tumor development in vivo. BMP-4 and estrogens act through overlapping intracellular signaling mechanisms on GH3 cell proliferation and c-myc expression: they had additive effects at low concentrations but not at saturating doses, and their action was inhibited by blocking either pathway with the reciprocal antagonist (i.e., BMP-4 with ICI 182780 or 17β-estradiol with Smad4dn). Furthermore, coimmunoprecipitation studies demonstrate that under BMP-4 stimulation Smad4 and Smad1 physically interact with the estrogen receptor. This previously undescribed Prolactinoma pathogenesis mechanism may participate in tumorigenicity in other cells where estrogens and the type β transforming growth factor family have important roles.
Shlomo Melmed - One of the best experts on this subject based on the ideXlab platform.
-
egfr erbb2 targeting lapatinib therapy for aggressive Prolactinomas
The Journal of Clinical Endocrinology and Metabolism, 2021Co-Authors: Odelia Cooper, Vivien Bonert, Jeremy Rudnick, Barry D Pressman, Roberto Salvatori, Kevin C J Yuen, Maria Fleseriu, Shlomo MelmedAbstract:CONTEXT Approximately 10% to 20% of Prolactinomas are resistant to dopamine agonist therapy. The ErbB signaling pathway may drive aggressive Prolactinoma behavior. OBJECTIVE We evaluated lapatinib, an ErbB1-epidermal growth factor receptor (EGFR)/ErbB2 or human EGFR2 (HER2) tyrosine kinase inhibitor (TKI), in aggressive Prolactinomas. DESIGN A prospective, phase 2a multicenter trial was conducted. SETTING This study took place at a tertiary referral pituitary center. PATIENTS Study participants included adults with aggressive Prolactinomas showing continued tumor growth despite maximally tolerated dopamine agonist therapy. INTERVENTION Intervention included oral lapatinib 1250 mg/day for 6 months. MAIN OUTCOME MEASURES The primary end point was 40% reduction in any tumor dimension assessed by magnetic resonance imaging at study end; tumor response was assessed by Response Evaluation Criteria in Solid Tumors criteria. Secondary end points included prolactin (PRL) reduction, correlation of response with EGFR/HER2 expression, and safety. RESULTS Owing to rigorous inclusion criteria, of 24 planned participants, only 7 consented and 4 were treated. None achieved the primary end point but 3 showed stable disease, including 2 with a 6% increase and 1 with a 16.8% decrease in tumor diameter. PRL response was not always concordant with tumor response, as 2 showed 28% and 59% increases in PRL. The fourth participant had a PRL-secreting carcinoma and withdrew after 3 months of lapatinib because of imaging and PRL progression. EGFR/HER2 expression did not correlate with treatment response. Lapatinib was well tolerated overall, with reversible grade 1 transaminitis in 2 patients, grade 2 rash in 2 patients, and grade 1 asymptomatic bradycardia in 2 patients. CONCLUSIONS An oral TKI such as lapatinib may be an effective option for a difficult-to-treat patient with an aggressive Prolactinoma.
-
her2 erbb2 receptor signaling in rat and human Prolactinoma cells strategy for targeted Prolactinoma therapy
Molecular Endocrinology, 2010Co-Authors: Hidenori Fukuoka, Odelia Cooper, Serguei Bannykh, Jun Mizutani, Yunguang Tong, Songguang Ren, Shlomo MelmedAbstract:Dopamine agonist resistance or intolerance is encountered in approximately 20% of Prolactinoma patients. Because human epidermal growth factor receptor 2 (HER2)/ErbB2 is overexpressed in Prolactinomas and ErbB receptor ligands regulate prolactin (PRL) gene expression, we tested the role of HER2/ErbB2 in Prolactinoma hormone regulation and adenoma cell proliferation to assess the rationale for targeting this receptor for Prolactinoma therapy. As we showed Prolactinoma HER2 overexpression, we generated constitutively active HER2-stable GH3 cell transfectants (HER2CA). PRL mRNA levels were induced approximately 250-fold and PRL secretion was enhanced 100-fold in HER2CA cells, which also exhibited increased proliferation. Lapatinib, a dual tyrosine kinase inhibitor (TKI) of both epidermal growth factor receptor (EGFR)/ErbB1 and HER2, blocked receptor signaling, and suppressed PRL expression more than gefitinib, a TKI of EGFR/ErbB1. Lapatinib also suppressed colony formation in soft agar more than gefitinib. Oral lapatinib treatment caused tumor shrinkage and serum PRL suppression both in HER2CA transfectant-inoculated Wistar-Furth rats and in estrogen-induced Fischer344 rat Prolactinomas. In cultured human cells derived from resected Prolactinoma tissue, lapatinib suppressed both PRL mRNA expression and secretion. These results demonstrate that Prolactinoma HER2 potently induces PRL and regulates experimental Prolactinoma cell proliferation. Because pituitary HER2 signaling is abrogated by TKIs, this receptor could be an effective target for Prolactinoma therapy.
-
Prolactinomas express human heparin binding secretory transforming gene hst protein product marker of tumour invasiveness
Clinical Endocrinology, 1998Co-Authors: Ilan Shimon, David R Hinton, Martin H Weiss, Shlomo MelmedAbstract:BACKGROUND AND OBJECTIVE We have shown previously that heparin-binding secretory transforming gene (hst) overexpression in rat pituitary cells mediates lactotroph tumour growth and stimulates PRL transcription, and that transforming sequences of the gene, which encode fibroblast growth factor-4 (FGF-4), are expressed in human Prolactinomas. To further determine the role of hst in human PRL-secreting adenoma pathogenesis we studied the presence of hst protein in these tumours and other types of human pituitary adenoma. PATIENTS AND DESIGN Pituitary adenoma tissue samples were obtained at surgery from 14 patients with PRL-secreting adenomas, 5 patients with GH-secreting tumours, 3 with ACTH-secreting, and 13 patients with nonfunctioning tumours. Two normal pituitary tissue specimens were also studied. Clinical data, including tumour invasiveness assessed by preoperative MRI studies, were available. For hst protein immunolocalization, tumour frozen sections were immunostained with antihuman FGF-4 antibody. Immunoperoxidase staining for the proliferation-related nuclear antigen Ki-67 was performed using MIB-1 monoclonal antibody. RESULTS Normal anterior pituitary cells did not contain immunoreactive hst protein. Lactotrophs in five of 14 Prolactinomas (36%) stained strongly for hst compared with immunoreactive pituicytes in only one of 21 nonfunctioning, GH-, and ACTH-secreting adenomas (P = 0.05). Immunoreactive hst in adenoma cells was detected in 3 of 5 invasive Prolactinomas, and in 2 of 9 noninvasive PRL-cell adenomas. Immunostaining for the proliferation-related antigen Ki-67 showed a higher proliferation index in hst-positive adenomas (3.94 + 0.85%) as compared with those immunonegative for hst (1.98 + 0.7%; P = 0.05). CONCLUSIONS hst protein may be directly involved in Prolactinoma development or progression, particularly in invasive tumours, probably due to the growth promoting effects of FGF-4.
-
somatostatin receptor sstr subtype selective analogues differentially suppress in vitro growth hormone and prolactin in human pituitary adenomas novel potential therapy for functional pituitary tumors
Journal of Clinical Investigation, 1997Co-Authors: Ilan Shimon, Martin H Weiss, John E Taylor, Michael D Culler, Shlomo MelmedAbstract:Previously, we have shown somatostatin receptor (SSTR) subtype-specific regulation of growth hormone (GH), thyroid-stimulating hormone, and prolactin (PRL) secretion in human fetal pituitary cultures, where GH and thyroid-stimulating hormone are mediated by both SSTR2 and SSTR5, whereas SSTR2 preferentially mediates PRL secretion. We now tested SSTR subtype-selective analogues in primary human GH- and PRL-secreting pituitary adenoma cultures. Analogue affinities determined by membrane radioligand binding in cells stably expressing human SSTR forms were either SSTR2 or SSTR5-selective. Analogues preferential either for SSTR2, including octreotide, lanreotide, and novel compounds with improved affinity for SSTR2, or new SSTR5-selective compounds suppressed GH in tumor cell cultures (up to 44% of control; P < 0.0005). However, novel analogues from both groups were 30-40% more potent than octreotide and lanreotide in suppressing GH (P < 0.05). Heterologous analogue combinations containing both SSTR2- and SSTR5-selective compounds were more potent in decreasing GH than analogues used alone (P < 0.05), or than combinations of compounds specific for the same receptor subtype (P < 0.005). In contrast, SSTR2-selective analogues did not suppress PRL release from six cultured Prolactinomas studied. However, new SSTR5-selective analogues suppressed in vitro PRL secretion (30-40%; P < 0.05) in four of six Prolactinomas. These results suggest that both SSTR2 and SSTR5 are involved in GH regulation in somatotroph adenoma cells, whereas SSTR5 exclusively regulates PRL secretion from Prolactinoma cells. Thus, somatostatin analogues with improved selective binding affinity for these receptor subtypes may be effective in the treatment of either GH- or PRL-secreting adenomas.
Raul Pisabarro - One of the best experts on this subject based on the ideXlab platform.
-
brain and optic chiasm herniation into sella after pituitary tumor apoplexy
Frontiers in Endocrinology, 2017Co-Authors: Maria M. Pineyro, Patricia Furtenbach, Ramiro Lima, Saul Wajskopf, Nicolas Sgarbi, Raul PisabarroAbstract:Brain and optic chiasm herniation have been rarely reported following dopamine agonist treatment for large Prolactinomas. We report a case of brain and optical chiasm herniation, secondary to an empty sella due to apoplexy of a Prolactinoma and we focus on the specific presentation of this case. A 32-year-old female presented to a neurologist complaining of headaches. Her past medical history was significant for acute vision loss in both eyes accompanied by right 3rd nerve palsy when she was 16 years old. She does not recall any endocrine or imaging evaluation at that time and she had spontaneous partial recovery of left eye vision within 3 months, with permanent blindness of right eye. She did not return to any follow-up until her neurologist consultation. Brain magnetic resonance imaging (MRI) revealed herniation of frontal lobe and optic chiasm into the pituitary sella, as well as a pituitary hypointense lesion measuring 5x5 mm after gadolinium injection. Prolactin levels were 206 ng/ml (4.79-23.3 ng/ml). Repeated prolactin was 258 ng/ml (4.79-23.3 ng/ml). She was started on bromocriptine 2.5 mg/day. Prolactin levels and menstrual cycles normalized. A repeat brain MRI performed 5 months later showed disappearance of pituitary mass, with no changes in brain and chiasmal herniation. To our knowledge, this is the first reported case of brain associated with chiasm herniation secondary to pituitary apoplexy of a Prolactinoma. In conclusion, this case highlights that frontal lobe herniation in combination with optic chiasm herniation can be a complication of pituitary tumor apoplexy. Long-term surveillance of patients with pituitary apoplexy is warranted to detect delayed complications.
-
Brain and Optic Chiasm Herniation into Sella after Pituitary Tumor Apoplexy
Frontiers Media S.A., 2017Co-Authors: Maria M. Pineyro, Patricia Furtenbach, Ramiro Lima, Saul Wajskopf, Nicolas Sgarbi, Raul PisabarroAbstract:Brain and optic chiasm herniation has been rarely reported following dopamine agonist treatment for large Prolactinomas. We report a case of brain and optical chiasm herniation, secondary to an empty sella due to apoplexy of a Prolactinoma, and we focus on the specific presentation of this case. A 32-year-old female presented to a neurologist complaining of headaches. Her past medical history was significant for acute vision loss in both eyes accompanied by right third nerve palsy when she was 16 years old. She does not recall any endocrine or imaging evaluation at that time and she had spontaneous partial recovery of left eye vision within 3 months, with permanent blindness of right eye. She did not return to any follow-up until her neurologist consultation. Brain magnetic resonance imaging (MRI) revealed herniation of frontal lobe and optic chiasm into the pituitary sella, as well as a pituitary hypointense lesion measuring 5 mm × 5 mm after gadolinium injection. Prolactin levels were 206 ng/ml (4.79–23.3 ng/ml). Repeated prolactin was 258 ng/ml (4.79–23.3 ng/ml). She was started on bromocriptine 2.5 mg/day. Prolactin levels and menstrual cycles normalized. A repeat brain MRI performed 5 months later showed disappearance of pituitary mass, with no changes in brain and chiasmal herniation. To our knowledge, this is the first reported case of brain associated with chiasm herniation secondary to pituitary apoplexy of a Prolactinoma. In conclusion, this case highlights that frontal lobe herniation in combination with optic chiasm herniation can be a complication of pituitary tumor apoplexy. Long-term surveillance of patients with pituitary apoplexy is warranted to detect delayed complications
