摘要:

In the past decade we have witnessed an explosion in our knowledge of the molecular bases of hyperparathyroidism. In spite of the generally benign phenotype of parathyroid tumors, several of the well-recognized mechanisms in tumor biology are applicable to parathyroid tumorigenesis. The concept of evolution of nonneoplastic endocrine hyperplasia into a true tumor is as operative for the parathyroid tissue as for any other neoplasia. The molecular mechanisms underlying parathyroid tumor development, either on the ground of tissue hyperplasia or as neoplasia ‘ab initio’, are starting to be recognized. Oncogenes as well as tumor-suppressor genes and trophic factors appear to play a role in the process of parathyroid tissue growth. The unique opportunity of evaluating at least four distinct organs greatly contributed to the knowledge of the genetic basis of parathyroid tumor development, a field relatively undeveloped in comparison to that of other canc

ISSN:1663-2818    

DOI:10.1159/000185464

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Multiple endocrine neoplasias (MEN) are familial diseases characterized by endocrine neoplasms and transmitted in an autosomal dominant manner. In MEN type I, the major lesions affect parathyroid glands, pancreatic islet cells and anterior pituitary. The MEN-1 gene has been mapped to chomosome 11q13 and a set of DNA-polymorphic markers localized close to this region provides a useful tool for presymptomatic diagnosis in MEN-1 families. MEN type 2 refers to the inherited forms of medullary thyroid carcinoma (MTC) associated or not with pheochromocytoma and hyperparathyroidism. In MEN-2, germinal mutations of the C-RET proto-oncogene which is localized on chromosome 10q11 have been found in the three clinical and allelic forms of the syndrome respectively, MEN-2 type A, B and familial isolated MTC. Mutations of C-RET are found in more than 90% of MEN-2 patients and genetic screening leads to accurate risk evaluation in families and consequently a preventive treatment of MTC and adrenal neoplasms. Recent discoveries on MEN syndromes and related familial endocrine disorders have a major clinical impact and allow a better understanding of the physiological pathways involved in familial as well as in sporadic endocrine tumor pathogenesis.

ISSN:1663-2818    

DOI:10.1159/000185465

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Multiple endocrine neoplasia type 1 (MEN 1) is characterized by the combined occurrence, to variable degree, of hyperparathyroidism (HPT) (85.7% of cases according to the French Registry of GENEM 1), tumors of the endocrine pancreas (49.6%), pituitary adenomas (38.4%) and, less frequently, adrenal tumors (9.6%) and neuroendocrine tumors (5.8%). Currently, diagnosis of MEN 1 is done in the fourth decade of life, but familial screening (using genetic tools whose diagnostic accuracy approaches 100%) has lowered the age of diagnosis. Screening for MEN 1 in a patient harboring an apparently sporadic tumor will depend on the endocrine gland involved. Extensive screening for MEN 1 in the presence of HPT will be conducted only when the familial history is suggestive, when parathyroid glands are hyper-plastic or when multiple parathyroid adenomas have been found at surgery. All patients with an endocrine pancreas tumor need to be investigated for the presence of other endocrine lesions of MEN 1. Extensive screening for MEN 1 is only recommended when a patient with a pituitary tumor or an adrenal tumor has a familial history suggestive of MEN 1. Otherwise regular measurement of blood calcium and PTH levels seem sufficient. Extensive screening for endocrine lesions when MEN 1 is suspected involves hormone measurements and imaging procedures. For the diagnosis of HPT, calcemia and PTH 1-84 must be measured. In the absence of clinical symptoms, basal measurement of serum gastrin, glucose, insulin, glucagon, VIP, somatostatin and pancreatic polypeptide levels are combined with abdominal ultrasonography. When symptoms suggest the Zollinger-Ellison syndrome, the secretin stimulation test is recommended. The diagnosis of a pituitary tumor is made by pituitary imaging and selected hormone assays (mainly PRL). To detect an adrenal tumor, CT scan is recommended, combined with serum potassium, urinary free cortisol and androgen measurement. When the diagnosis of MEN 1 is made, clinical and hormonal follow-up (once a year) and imaging surveillance (every 3-5 years) may be sufficient to detect new other endocrinopathies (unless suggestive clinical symptoms arise). Surgical management of each endocrine lesion must be done by skilled surgeons according to therapeutic protocols which have been discussed in detail.Genetic screening is an integral part of familial screening which may be conducted in collateral and in the offspring of MEN 1 patients. Obviously ethical principles (informed consent, etc.) must be respected. As it is now possible to detect presymptomatic gene carriers with a high degree of accuracy, follow-up is needed to make appropriate management decisions. The marked anxiety provoked by screening in an overtly asymptomatic healthy subject must not be underestimated. Conversely, a negative genetic diagnosis helps to reassure the subject and avoid repetitive and costly follow-up.

ISSN:1663-2818    

DOI:10.1159/000185466

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Multiple endocrine neoplasia type 2 (MEN-2) is an inherited multiglandular disease with age-related penetrance and variable expression. The prognosis of MEN-2 is linked to the carcinological evolution of medullary thyroid cancer (MTC), which depends mainly on the stage of discovery, and to the incidents related to pheochromocytomas. This emphasizes the need for early diagnosis and management of MEN-2. Since 1993, mutations evidenced on the proto-oncogene RET have allowed subjects at risk to be identified, thus leading to a three-step management of these patients. (1) For all the potentially affected members of a MEN-2 family, screening by molecular genetics of the ret gene enables one to identify the subjects at risk who bear the mutation. When no mutation is observed, a linkage analysis study may be proposed. (2) In the subjects at risk, early screening for the various types of endocrine lesions may then start in childhood and be performed using specific biological markers of MTC, pheochromocytoma and primary hyperparathyroidism, and particularly, basal and pentagastrin-stimulated calcitonin measurement, which is known to be the most sensitive marker for the monitoring of MTC. (3) This step of biological investigations enables the earliest possible treatment of any endocrine lesion detected before it is expressed clinically, thus improving the prognosis of MEN-2. When genetic screening cannot be performed, only annual clinical and biological monitoring remain available in all members of a family affected with MEN-2.

ISSN:1663-2818    

DOI:10.1159/000185467

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Pituitary adenomas are differentiated tumors expressing their appropriate mature hormone. Tumoral cells sometimes present with a defective physiological inhibitory or stimulatory control, resulting in paradoxical responses or nonresponsiveness to regulatory neurohormones. These abnormalities can be explained by defects at the intracellular transduction mechanism level. Knowledge of these defective pathways has made progress in the understanding of the pathogenesis of pituitary adenomas possible. The discovery of mutations of Gsα named gsp oncogenes in 40% of human somatotropinomas represents one of the most important advances in this field. Other molecular alterations were identified but are rare and sporadic and the pathogenesis of pituitary adenomas remains largely unknown.Abnormal transduction mechanisms may also result in a variable sensitivity of tumors to pharmacological therapy. The dopamine agonist, bromocriptine, is able to normalize blood PRL levels and to reduce tumor size in the majority of patients with prolactinoma, but is ineffective in 8-15% of them. Under physiological conditions, PRL secretion is under the tonic inhibitory control of dopamine which binds D2 receptors negatively coupled to adenylyl cyclase. Several defects in the dopaminergic transduction pathways participate in this bromocriptine resistance. The mean D2-binding site density is decreased to 50% as compared to responsive tumors. This loss of D2 receptors can account for a lower transcription level of its gene and is accompanied by modifications in the messenger alternative splicing; the D2 short isoform receptor expression decreases preferentially. A reduction in Gi2α protein expression is also observed and is correlated to that of the D2 receptor. Finally, the pituitary-specific transcription factor Pit-1 expression is affected. A highly significant correlation was seen between the D2 receptor mRNA and Pit-1 mRNA levels. These defects observed on many levels of the dopaminergic transduction cascade may be the first steps in the loss of the functional features of differentiated tumors toward more proliferative tumor

ISSN:1663-2818    

DOI:10.1159/000185468

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Although hypothalamic neurohormones were originally identified on the basis of their ability to influence hormone release from the target cells, it is at present clear that these agents are involved in the control of several biological processes that include cell proliferation and differentiation as well as hyperplasia and neoplastic transformation. Hypothalamic neurohormones bind specific receptors belonging to the G-protein-coupled receptor superfamily to generate intracellular effectors, in particular cAMP and calcium. Several in vivo and in vitro studies suggest the presence of functional and/or structural alterations in the receptor/effector molecules involved in the transduction of hypothalamic neurohormone action in the pituitary. The present study reports the frequent presence in pituitary tumors of cellular alterations that result in amplification of stimulatory signals, particularly activation of the cAMP-dependent pathway, and reduction of inhibitory inputs, both events having possible implications in tumor formation and/or progression.

ISSN:1663-2818    

DOI:10.1159/000185469

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

We summarize here our data showing that various phenotypical characteristics distinguish prolactinoma cell lines obtained from responder and nonresponder patients, as defined by their responses to bromocriptine administration. Nonresponder cell lines have a higher degree of malignancy than responder cells and do not express D2 receptors for dopamine. Both cell lines express NGF receptors. Exposure of the most malignant nonresponder cell lines to NGF, both in vitro and when transplanted in vivo in nude mice, results in their differentiation into the responder phenotype reexpressing D2 receptors. Sequential administration of NGF and bromocriptine thus may be a promising therapy for patients refractory to bromocriptine.

ISSN:1663-2818    

DOI:10.1159/000185470

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Activation of the cAMP pathway from the cell surface to the nucleus plays a major role in somatotroph differentiation and growth. This pathway is regulated mainly by the antagonistic hypothalamic hormones GHRH and somatostatin. Several pituitary-specific, as well as ubiquitous, expressed genes are regulated by cAMP in GH-secreting cells. Among them are the GH, GHF-1/Pit-1, c-fos and GHRH-receptor genes. Protein kinase A phosphorylation of Ser133 of the transcription factor cAMP-responsive element binding protein (CREB), seems to play a pivotal role in the activation of the cAMP pathway in normal and tumoral somatotrophs. The oncogenic activating mutations of the G-protein as subunit stimulate transcription and CREB phosphorylation in somatotroph cells. The implications of the nuclear targets of cAMP in the differentiation and growth of somatotrophs are discussed in this review.

ISSN:1663-2818    

DOI:10.1159/000185471

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

The anterior pituitary-specific transcription factor Pit-1 (also known as GHF-1) was initially identified and cloned as a transactivator of the GH and PRL genes, and later as a regulator of the TSHβ gene. Analysis of Pit-1 expression during mouse embryogenesis revealed that initiation of its expression correlates both temporally and spatially with activation of its target genes. Immunocytochemical studies revealed a high expression of Pit-1 protein in the nuclei of only three cell types: somatotropes, lactotropes and thyrotropes. The importance of Pit-1 as a regulator of the anterior pituitary development has been further demonstrated by the absence of somatotropes, lactotropes and thyrotropes in the pituitary glands of Pit-1-defective mice and humans. Since Pit-1 is required for both cell phenotype and proliferation, one may ask if this transcription factor might be associated with development of pituitary tumors. Several investigators have reported Pit-1 gene expression in human pituitary adenomas. These studies, while not in total agreement, show that pituitary tumorigenesis does not seem to be associated with a gross alteration of Pit-1 gene expression in humans. Pit-1 transcripts, identical in size and sequence to those observed in normal pituitary, were described in human GH-, PRL- and TSH-secreting pituitary adenomas and in most cases the presence of Pit-1 transcripts correlated with the localization of Pit-1 protein. The biological relevance of Pit-1 expression reported in some nonfunctioning adenomas remains to be clarified. As expression of the PRL and GH genes is ultimately confined to distinct lactotropic and somatotropic populations despite the presence of Pit-1 protein in both cell types, there must be additional mechanisms that control the cell-specific activation of the PRL and GH promoters. The Pit-1β isoform, raised through alternative splicing of exon 2 of the Pit-1 gene, is a more potent inducer of GH transcription than the major Pit-1 form. This form could, at least in part, account for the cell-specific activation of the PRL and GH genes. Pit-1β was invariably found present in all the tumors expressing the Pit-1 major form, no significant difference in the Pit-1 β/Pit-1 expression ratio being observed between tumors identified as pure GH- or PRL-producing tumors. This lack of selectivity together with its low level of expression is therefore not in favor of a key role for the β-isoform in the cell type-specific expression of the GH and PRL genes in humans. The failure of somatotropes, lactotropes and thyrotropes to proliferate in Pit-1-defective mice and humans indicates that Pit-1 might be competent to activate genes required for cell proliferation or survival of the three cell types. Recent data indeed suggest that Pit-1 may directly or indirectly regulate somatotropes and lactotropes through activation of the receptors for GRF and SRIF on the one hand, and dopamine on the other hand. Such regulatory mechanisms could contribute to the differentiation of the somatomammotropic lineage in fully differentiated somatotropic and lactotropic c

ISSN:1663-2818    

DOI:10.1159/000185472

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Pituitary corticotropic cells express a specific vasopressin receptor, called V1b or V3, through which vasopressin stimulates corticotropin secretion. We recently cloned a cDNA coding for this receptor and showed that it belongs to the G protein-coupled receptor family. V3 mRNA is readily detected by RT-PCR in normal human pituitaries and corticotropic pituitary adenomas but not in PRL or GH-secreting adenomas, thus demonstrating that, like POMC itself and the CRH receptor, V3 is a marker of the corticotropic phenotype. Nuclease protection experiments suggest that V3 is overexpressed in some corticotropic adenomas, and thus may play a role in tumor development by activating the phospholipase C-signalling pathway. In addition analysis of its expression in nonpituitary neuroendocrine tumors showed a striking association with carcinoids of the lung responsible for the ectopic ACTH syndrome.

ISSN:1663-2818    

DOI:10.1159/000185473

出版商:S. Karger AG    

年代:1997

数据来源: Karger