Heparin-binding secretory transforming gene (hst) facilitates rat lactotrope cell tumorigenesis and induces prolactin gene transcription.

Shimon, Ilan; Hüttner, Anita; Said, Joanne; Spirina, Olga; Melmed, Shlomo

doi:10.1172/jci118388

Cited by 72 publications

(45 citation statements)

References 49 publications

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“…Although the actions of many of these estrogen-responsive growth regulatory factors have been tested in tumor lactotropes (e.g. GH3 cells) or in mixed pituitary cell populations [52][53][54][55][56][57][58], the actions of most of these factors in primary lactotropes have not been tested or persistent hyperprolactinemia was observed in 16 alcoholic women during a 6-week treatment trial [32]. These patients reported daily alcohol intake of 170 g for a period between 2 and 16 years period but had no clinical evidence of alcoholic liver cirrhosis.…”

Section: Cell Cycle Genomic Instability and Tumorigenesis In Lactotmentioning

confidence: 99%

Genesis of Prolactinomas: Studies Using Estrogen-Treated Animals

Sarkar

2006

Frontiers of Hormone Research

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Prolactin-secreting adenomas (prolactinomas) are the most prevalent form of pituitary tumors in humans. Our knowledge of the formation of these tumors is limited. Experimental work in animal has uncovered that estradiol exposure leads to prolactinoma formation via orchestrated events involving dopamine D2 receptors, transforming growth factor-β (TGF-β) isoforms and their receptors, as well as factors secondary to TGF-β action. Additionally, these studies determined that TGF-β and b-FGF interact to facilitate the communication between lactotropes and folliculo-stellate cells that is necessary for the mitogenic action of estradiol. The downstream signaling that governs lactotropic cell proliferation involves activation of the MAP kinase p44/42-dependent pathway.Pituitary tumors are primarily adenomas; they account for approximately 10-15% of intracranial tumors. They cause significant morbidity due to local invasion, hypopituitarism or hormone hypersecretion [1,2]. Pituitary tumors are classified as either functioning and secreting excessive amounts of active hormones, or as endocrinologically inactive and secreting no hormones or inactive hormones. Pituitary tumors are also classified by virtue of their size into the arbitrary division of those less than 1 cm as microadenomas and those more than 1 cm as macroadenomas. Pituitary tumors secreting excess prolactin are characterized as prolactinomas. Prolactinomas are the most frequently occurring neoplasm in the human pituitary [3,4]. In the general population, 1:2,800 men and 1:1,050 women are considered to have prolactinomas [5]. In human subjects, prolactinomas occur as both macroadenomas and microadenomas. In addition, mixed growth hormone and prolactin-secreting adenomas are documented to exist in a substantial number of acromegaly patients.Hyperprolactinoma is a condition in which plasma prolactin (PRL) levels are elevated above normal levels. Hyperprolactinemia, with elevation of serum prolactin of more than 200 ng/ml, is characteristically associated with prolactinomas [6]. Hyperprolactinemia causes reproductive dysfunction such as amenorrhea, galactorrhea, and infertility in women [7]. Amenorrhea and galactorrhea may occur alone or together [8]. Up to 25% of patients with secondary amenorrhea have been diagnosed with hyperprolactinemia. Many of these patients showed micro-prolactin adenomas or macro-prolactin adenomas in the pituitary. Although treatments that alter central dopaminergic neuronal functions cause an elevated serum PRL level, in most cases hyperprolactinemia is due to a pituitary tumor. In women, prolactinomas are mainly microadenomas. These microadenomas are rarely associated with hypopituitarism or central nervous system dysfunction. Idiopathic hyperprolactinemia, without demonstrable pituitary or hypothalamic disease, has also been identified. In men, prolactinomas are mainly

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Section: Cell Cycle Genomic Instability and Tumorigenesis In Lactotmentioning

confidence: 99%

Genesis of Prolactinomas: Studies Using Estrogen-Treated Animals

Sarkar

2006

Frontiers of Hormone Research

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“…One possibility is an involvement of the hormonal balance. Although we did not perform an analysis on hormones' serum levels, it is known that FGF4 can stimulate prolactin expression and promote prolactinomas development (Shimon et al, 1996(Shimon et al, , 1998.…”

Section: Discussionmentioning

confidence: 99%

Hyperplasia and impaired involution in the mammary gland of transgenic mice expressing human FGF4

et al. 2000

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Fgf4, a member of the ®broblast growth factor family, is frequently ampli®ed in a variety of human cancers, however, its expression in neoplastic tissues is rarely detectable. This makes uncertain its involvement in tumour aetiology, although several in-vitro studies link Fgf4 overexpression to malignant transformation and metastatization of culture cells. We generated a transgenic mouse model in which the whey acidic protein (WAP) promoter directs expression of human Fgf4 to mammary tissues during late pregnancy and throughout lactation, with the purpose of studying the involvement of this growth factor in mammary tumorigenesis. Expression of the transgene was speci®cally detected in lobularalveolar cells of lactating mammary glands that, by histological analysis, displayed hyperplastic areas and a disorganized structure. This was accompanied by an increased number of red blood cells and expression, in alveolar epithelial cells, of the vascular endothelial growth factor, which is absent in wild type controls. The most striking e ect caused by FGF4 overexpression was on the remodelling of mammary tissue at the end of lactation. Indeed, transgenic animals showed a delayed involution of the gland due to a dramatic reduction in the overall number of apoptotic cells, which are normally present in the organ after weaning. Nevertheless, none of the animals examined developed neoplastic lesions of the mammary gland even after several pregnancies and at old age. Our work represents the ®rst in-vivo demonstration of the anti-apoptotic and angiogenic properties of FGF4. Oncogene (2000) 19, 6007 ± 6014.

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“…O FGF-4, proteína codifica- da pelo heparin-binding secretory transforming gene (h s t), tem potente atividade angiogênica e é expresso em prolactinomas. O oncogene hst transfectado (ou a própria proteína FGF-4) estimula a secreção de prolactina, e a hiperexpressão do hst é associada com a agressividade de tumores experimentais (50). Foi demonstrada recentemente imunoexpressão da FGF-4 em três de cinco prolactinomas invasivos e em apenas dois de nove adenomas lactotróficos não invasivos (48).…”

Section: Prolactinomasunclassified

Tumorigênese hipofisária

Bronstein

Melmed²

2005

Arq Bras Endocrinol Metab

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RESUMOOs tumores hipofisários, adenomas na sua quase totalidade, representam de 10% a 15% das neoplasias intracranianas (1) e são encontrados em até 27% de autópsias não selecionadas, como achado incidental (2). Morfologicamente são classificados em microadenomas (< 1cm de diâmetro) e macroadenomas, que podem ser circunscritos, invasivos e/ou expansivos. Do ponto de vista funcional, são divididos em adenomas secretores (de PRL, GH, ACTH, TSH, LH e FSH, podendo co-secretar dois ou mais hormônios) e clinicamente não secretores ou "não funcionantes". O diagnóstico é feito pelo fenótipo da hipersecreção (acromegalia, Cushing etc.) e, nos macroadenomas com efeito de massa, por hipopituitarismo e/ou distúrbios neurológicos, onde predominam as queixas visuais e cefaléia. Quanto aos mecanismos de tumorigênese hipofisária, a disputa entre causa primária hipotalâmica versus hipofisária ganhou força a favor da segunda graças às evidên-cias da monoclonalidade dos tumores, juntamente com outros argumentos como a ausência de tecido hiperplásico circundando o adenoma cirurgicamente removido e a relativa independência do controle hipotalâmico. No entanto, admite-se que um papel permissivo do hipotálamo é importante para a progressão tumoral. Muitos mecanismos moleculares envolvidos na tumorigenese hipofisária já foram desvendados, incluindo oncogenes, genes supressores tumorais e fatores de crescimento, e serão descritos neste artigo de revisão. ABSTRACT Pituitary Tumorigenesis.Pituitary adenomas, almost invariably adenomas, account for 10% to 15% of all intracranial neoplasms and are incidentally detected in up to 27% of non selected autopsies. They are morphologically classified as microadenomas (diameter < 1cm) or macroadenomas, which can be enclosed, invasive and/or expansive. Functionally, they are classified as secreting adenomas (PRL, GH, ACTH, TSH, LH, and FSH, and those cosecreting two or more hormones), and clinically non secreting or "non functioning" tumors. Diagnosis is based on the hypersecretion phenotype (acromegaly, Cushing, etc), and on mass effect of macroadenomas leading to neurological disturbances, mainly visual complaints and headache. Pituitary tumorigenesis mechanisms include those of primary hypothalamic versus pituitary origin, the latter is supported by evidence of pituitary adenoma monoclonality, as well as the absence of hyperplastic tissue surrounding the surgically removed tumor, and the relative independence of tumor hypothalamic control. Nevertheless, a permissive role of the hypothalamus on tumor progression is also postulated. Several molecular mechanisms involved in pituitary tumorigenesis have been unraveled including oncogenes, tumor suppressor genes and growth factors involved in neoplastic development, and will be

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Heparin-binding secretory transforming gene (hst) facilitates rat lactotrope cell tumorigenesis and induces prolactin gene transcription.

Abstract: We have shown previously that human prolactinomas express transforming sequences of the heparin-binding secretory transforming gene (

Cited by 72 publications

References 49 publications

Genesis of Prolactinomas: Studies Using Estrogen-Treated Animals

Genesis of Prolactinomas: Studies Using Estrogen-Treated Animals

Hyperplasia and impaired involution in the mammary gland of transgenic mice expressing human FGF4

Tumorigênese hipofisária

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