The expression profile of Dopamine D2 receptor, MGMT and VEGF in different histological subtypes of pituitary adenomas: a study of 197 cases and indications for the medical therapy

Wang, Youwei; Li, Junyang; Tohti, Mamatemin; Hu, Yuebing; Wang, Sheng; Li, Wanchun; Lu, Zhengfeng; Ma, Chiyuan

doi:10.1186/preaccept-1232491055121159

Cited by 4 publications

(6 citation statements)

References 24 publications

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“…Not only VEGFD , but also an adaptor protein involved in VEGF signaling, SH2D2A , and five other genes LTBP1, ISL1, PTGS1, PTPRZ1 , and ROBO1 ( 30 – 34 ), known to promote angiogenesis, were overexpressed in men. A high expression of VEGF was observed by immunohistochemistry in 60.7% of the lactotroph tumors ( 35 ). Its expression was higher in pituitary carcinomas compared to benign adenomas ( 36 ), as was microvascular density ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

Sex-Related Differences in Lactotroph Tumor Aggressiveness Are Associated With a Specific Gene-Expression Signature and Genome Instability

et al. 2018

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Sex-related differences have been reported in various cancers, in particular men with lactotroph tumors have a worse prognosis than women. While the underlying mechanism of this sexual dimorphism remains unclear, it has been suggested that a lower estrogen receptor alpha expression may drive the sex differences observed in aggressive and malignant lactotroph tumors that are resistant to dopamine agonists. Based on this observation, we aimed to explore the molecular importance of the estrogen pathway through a detailed analysis of the transcriptomic profile of lactotroph tumors from 20 men and 10 women. We undertook gene expression analysis of the selected lactotroph tumors following their pathological grading using the five-tiered classification. Chromosomic alterations were further determined in 13 tumors. Functional analysis showed that there were differences between tumors from men and women in gene signatures associated with cell morphology, cell growth, cell proliferation, development, and cell movement. Hundred-forty genes showed an increased or decreased expression with a minimum 2-fold change. A large subset of those genes belonged to the estrogen receptor signaling pathway, therefore confirming the potent role of this pathway in lactotroph tumor sex-associated aggressiveness. Genes belonging to the X chromosome, such as CTAG2, FGF13, and VEGF-D, were identified as appealing candidates with a sex-linked dysregulation in lactotroph tumors. Through our comparative genomic hybridization analyses (CGH), chromosomic gain, in particular chromosome 19p, was found only in tumors from men, while deletion of chromosome 11 was sex-independent, as it was found in most (5/6) of the aggressive and malignant tumors. Comparison of transcriptomic and CGH analysis revealed four genes (CRB3, FAM138F, MATK, and STAP2) located on gained regions of chromosome 19 and upregulated in lactotroph tumors from men. MATK and STAP2 are both implicated in cell growth and are reported to be associated with the estrogen signaling pathway. Our work confirms the proposed involvement of the estrogen signaling pathway in favoring the increased aggressiveness of lactotroph tumors in men. More importantly, we highlight a number of ER-related candidate genes and further identify a series of target molecules with sex-specific expression that could contribute to the aggressive behavior of lactotroph tumors in men.

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Section: Discussionmentioning

confidence: 99%

Sex-Related Differences in Lactotroph Tumor Aggressiveness Are Associated With a Specific Gene-Expression Signature and Genome Instability

et al. 2018

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“…Up to 75% of human corticotroph adenomas express D2R ( 8 , 9 ). In 15 of 20 ACTH-secreting adenomas, D2R immunostaining was moderate or strong, and D2R mRNA was detected in 10 of 12 cases.…”

Section: Cushing's Diseasementioning

confidence: 99%

“…GH-secreting tumors commonly express D2R ( 9 , 10 , 42 , 43 ), albeit at levels lower than those in normal pituitary ( 44 ). DA treatment of cultured somatotropinomas suppresses GH secretion by 20–25% or more ( 45 – 47 ), while tumors lacking D2R expression show resistance ( 48 ).…”

Section: Acromegalymentioning

confidence: 99%

“…Most NFPT express D2R ( 3 , 9 , 44 ), and DA has been shown to reduce gonadotropin secretion ( 65 ) and inhibit thymidine incorporation in vitro ( 66 ). D2R mRNA expression is higher in gonadotroph and null-cell NFPT compared with plurihormonal and silent corticotroph adenomas ( 67 , 68 ), although D2L/D2S ratios tend to be similar among the histological types ( 69 ).…”

Section: Nonfunctioning Pituitary Tumorsmentioning

confidence: 99%

“…NFPT show higher D2R mRNA expression levels compared with somatotroph adenomas, but lower expression compared with normal pituitaries ( 44 ) and significantly lower compared with prolactinomas ( 69 ). High D2R protein expression levels were found in 26 of 70 NFPT, 26 of 28 prolactinomas, and 18 of 20 GH-secreting adenomas, as well as 31 of 37 FSH-secreting adenomas, 18 of 27 ACTH-secreting adenomas, and 9 of 15 thyrotropinomas ( 9 ).…”

Section: Nonfunctioning Pituitary Tumorsmentioning

confidence: 99%

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Dopamine Agonists for Pituitary Adenomas

Cooper

Greenman

2018

Front. Endocrinol.

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Dopamine agonists (DA) are well established as first-line therapy for prolactinomas. These tumors express high levels of dopamine 2 receptors (D2R), leading to the strong efficacy of DA in reducing tumor size and hormonal secretion. Other pituitary tumor subtypes express D2R to varying degrees, leading to an extensive body of research into potential off-label use of DA in non-prolactinoma pituitary tumors. Preclinical models of Cushing's disease, acromegaly, and nonfunctioning pituitary tumors (NFPT) demonstrate D2R expression in cell lines and cultured tumors as well as effectiveness of DA in reducing hormonal secretion in functioning tumors and arresting tumor proliferation. Clinical studies have shown some efficacy of DA in treatment of these tumors. In Cushing's disease, DA therapy results in normalization of urinary cortisol levels in approximately 25% of patients, but reported rates of tumor shrinkage are very low; in acromegaly, DA therapy leads to normalization of insulin-like growth factor I and tumor shrinkage in approximately one-third of patients, and improved responses when used in combination with somatostatin receptor ligands. Among patients with NFPT, pooled results show 30% experience reduction of tumor size and 58% show stabilization of disease. DA therapy appears to have some clinical benefit in patients with non-prolactinoma pituitary tumors, and may be an option for medical therapy in some clinical scenarios.

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Successful management of octreotide-insensitive thyrotropin-secreting pituitary adenoma with bromocriptine and surgery

Yang¹,

Wu²,

Wang³

et al. 2017

Medicine

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The expression profile of Dopamine D2 receptor, MGMT and VEGF in different histological subtypes of pituitary adenomas: a study of 197 cases and indications for the medical therapy

Abstract: Background: To study the expression of D2R, MGMT and VEGF for clinical significance in pituitary adenomas, and to predict the potential curative medical therapy of dopamine agonists, temozolomide and bevacizumab on pituitary adenomas.

Cited by 4 publications

References 24 publications

Sex-Related Differences in Lactotroph Tumor Aggressiveness Are Associated With a Specific Gene-Expression Signature and Genome Instability

Sex-Related Differences in Lactotroph Tumor Aggressiveness Are Associated With a Specific Gene-Expression Signature and Genome Instability

Dopamine Agonists for Pituitary Adenomas

Successful management of octreotide-insensitive thyrotropin-secreting pituitary adenoma with bromocriptine and surgery

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