vasoactive-intestinal-peptide and Thyroid-Neoplasms

Multiple Endocrine Neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary cancer syndrome presented mostly by tumours of the parathyroids, endocrine pancreas and anterior pituitary, and characterised by a very high penetrance and an equal sex distribution. It occurs in approximately one in 30,000 individuals. Two different forms, sporadic and familial, have been described. The sporadic form presents with two of the three principal MEN1-related endocrine tumours (parathyroid adenomas, entero-pancreatic tumours and pituitary tumours) within a single patient, while the familial form consists of a MEN1 case with at least one first degree relative showing one of the endocrine characterising tumours. Other endocrine and non-endocrine lesions, such as adrenal cortical tumours, carcinoids of the bronchi, gastrointestinal tract and thymus, lipomas, angiofibromas, collagenomas have been described. The responsible gene, MEN1, maps on chromosome 11q13 and encodes a 610 aminoacid nuclear protein, menin, with no sequence homology to other known human proteins. MEN1 syndrome is caused by inactivating mutations of the MEN1 tumour suppressor gene. This gene is probably involved in the regulation of several cell functions such as DNA replication and repair and transcriptional machinery. The combination of clinical and genetic investigations, together with the improving of molecular genetics knowledge of the syndrome, helps in the clinical management of patients. Treatment consists of surgery and/or drug therapy, often in association with radiotherapy or chemotherapy. Currently, DNA testing allows the early identification of germline mutations in asymptomatic gene carriers, to whom routine surveillance (regular biochemical and/or radiological screenings to detect the development of MEN1-associated tumours and lesions) is recommended.

Topics: Adolescent; Adrenal Cortex Neoplasms; Adult; Aged; Aged, 80 and over; Angiofibroma; Carcinoid Tumor; Child; Facial Neoplasms; Female; Gastrinoma; Genetic Testing; Humans; Insulinoma; Lipoma; Male; Meningioma; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Parathyroid Neoplasms; Pituitary Neoplasms; Prolactinoma; Proto-Oncogene Proteins; Thyroid Neoplasms; Vasoactive Intestinal Peptide; Young Adult

Histopathological and experimental observations indicate that tumors composed wholly or in part of neuroendocrine elements may arise in tissues derived from ectoderm (including neuroectoderm), mesoderm, and endoderm. These tumors frequently exhibit multidirectional differentiation as manifested by multihormonality and by the presence of morphological features indicative of divergent differentiation both in vivo and in vitro. The existence of stem cells, plasticity of differentiated cells, microenvironmental influences, and random events are factors which might all interact to determine the characteristics of any particular tumor. The production of characteristic regulatory peptide products in association with tumors of specific histological subtypes and with other neuroendocrine markers suggests mechanisms for nonrandom activation of multiple genes common to neuroendocrine-programmed cells. Future studies applying new molecular biological techniques to intact tissues and to in vitro models may help to clarify the mechanisms that regulate the expression of the neuroendocrine phenotype in normal and neoplastic states.

Topics: Adrenal Gland Neoplasms; Animals; Apudoma; Calcitonin; Carcinoid Tumor; Cricetinae; Female; Gastrins; Hormones, Ectopic; Humans; Neurotensin; Ovarian Neoplasms; Pancreatic Neoplasms; Pheochromocytoma; Rats; Somatostatin; Thyroid Neoplasms; Uterine Neoplasms; Vasoactive Intestinal Peptide

As sensitive radioimmunoassays for the detection of polypeptide hormones are developed, the exciting discovery of a diffusely distributed system of interrelated endocrine cells has begun a new era of endocrinology. This system, although anatomically disassociated, is bound together by a number of common features such as its biosynthetic mechanism, histochemical and ultrastructural features, and embryologic origin (Table I). The most prominent feature, however, is their biosynthetic pathways for hormone production, from which the acronym APUD has been derived. These are the capacity for Amine Precursor Uptake such as DOPA and then subsequent Decarboxylation, resulting in the synthesis of bioactive amines or polypeptide hormones. Hyperplasias or neoplasms of these cells are defined as apudomas. In the last ten years a great deal of research has rapidly altered the original concepts of this system, especially in terms of its embryologic origin, physiologic interrelationships, classification, as well as the addition of many new APUD cell members. These will be reviewed, and the origin, diagnosis, and treatment of each recognized apudoma will be synthesized in light of its membership within the APUD system.

Topics: Adenoma, Islet Cell; APUD Cells; Apudoma; Carcinoid Tumor; Carcinoma; Endocrine Glands; Humans; Neural Crest; Neuroblastoma; Paraganglioma; Pheochromocytoma; Pituitary Neoplasms; Somatostatin; Thyroid Neoplasms; Vasoactive Intestinal Peptide

Although serum calcitonin and CEA are sensitive indicators for the presence of medullary thyroid carcinoma (MTC), the localization of tumor sites may be very difficult. In an approach to localize MTC lesions we performed comparative in vivo studies in 12 patients with primary MTC and in 4 patients with suspected recurrent MTC using 123I-VIP (150 MBq/1 microgram) and 111In-DTPA-D-Phe-1-octreotide (111In-OCT; 150 MBq/1 microgram). Despite elevated calcitonin values in all patients with suspected recurrent or metastatic lesions, both ultrasound and computed tomography (CT) were unable to localize a tumor site. 111In-OCT localized the primary tumor in the thyroid gland in 7 of 11 patients (63.5%). In 2 of 4 patients (50%) with suspected recurrent MTC, pathological uptake of 111In-OCT in the mediastinum or liver was demonstrable. In none of the 11 patients did 123I-VIP-receptor scanning indicate primary, recurrent, or metastatic tumor lesions. In vitro binding studies showed an absence of high-affinity VIP receptors in MTC tissue, whereas high-affinity 111In-OCT receptors were present in 4 of 6, and low-affinity 123I-VIP as well as 111In-OCT receptors were present in 6 of 6 MTC tissue samples. We conclude that somatostatin receptor scanning using 111In-OCT may visualize primary MTC, but it has only a low sensitivity in the detection of recurrent disease. The 123I-VIP-receptor scan is not helpful in the localization diagnosis of primary or recurrent MTC.

Topics: Adult; Aged; Carcinoma, Medullary; Female; Humans; Indium Radioisotopes; Iodine Radioisotopes; Male; Middle Aged; Octreotide; Pentetic Acid; Radionuclide Imaging; Receptors, Somatostatin; Thyroid Neoplasms; Vasoactive Intestinal Peptide

Somatostatin modulates several renal tubular cell functions, including gluconeogenesis and proliferation. In this study, we demonstrate that cultured human proximal tubular epithelial cells (PTEC) express somatostatin. We also demonstrate positive and negative regulation of PTEC somatostatin production. We found that PTEC derived from 14 different human donors consistently expressed somatostatin mRNA and/or peptide as detected by RT-PCR and enzyme-linked immunoassay. Furthermore, Northern blot analysis revealed that PTEC express the same size mRNA transcript (750 nucleotides) as human thyroid carcinoma (TT) cells. The PTEC mitogens, epidermal growth factor(EGF) and hydrocortisone, inhibit PTEC somatostatin secretion, whereas forskolin (a direct stimulator of adenylate cyclase) and fetal bovine serum stimulate secretion. These findings raise the possibility that renal-derived somatostatin modulates tubular cell function in an autocrine/paracrine manner. Manipulation of this pathway may lead to novel methods with which to alter tubular cell proliferation and function in vivo.

Topics: Blotting, Northern; Cells, Cultured; Culture Media, Conditioned; Epithelial Cells; Humans; Kidney Tubules, Proximal; Neoplasm Proteins; Neuropeptide Y; Polymerase Chain Reaction; Protein Biosynthesis; RNA, Messenger; Somatostatin; Thyroid Neoplasms; Vasoactive Intestinal Peptide

Hypercalcitoninemia in gastroenteropancreatic tumors associated with calcitonin immunoreactivity is rare.. We report here two patients in whom pancreatic neuroendocrine tumors both contained and secreted immunoreactive calcitonin. Both patients experienced elevated basal calcitonin immunoreactivity.. The peak responses of immunoreactive calcitonin occurred 5 minutes after pentagastrin administration in these two patients and were 30% and 180% above basal concentrations corresponding to peak increments of 0.39 and 8.78 ng/ml, respectively. The immunoreactive calcitonin response to pentagastrin in these two patients was not significantly different from that seen among five patients with medullary carcinoma of the thyroid gland.. It does not appear that immunoreactive calcitonin responses to pentagastrin stimulation will discriminate between patients with medullary carcinoma of the thyroid gland and those with nonfamilial, gastroenteropancreatic neuroendocrine tumors that express calcitonin immunoreactivity. In patients with secretory diarrhea and/or flushing, an elevated level of immunoreactive calcitonin, in the absence of a thyroid mass in the neck, may herald the presence of a gastroenteropancreatic neuroendocrine tumor.

Topics: Adenoma, Islet Cell; Aged; Calcitonin; Female; Humans; Liver Neoplasms; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Pancreatic Polypeptide; Pentagastrin; Stomach Neoplasms; Thyroid Neoplasms; Vasoactive Intestinal Peptide

The concentrations of immunoreactive (IR) corticotropin-releasing hormone (CRH) in 218 neuroendocrine tumors were determined by CRH radioimmunoassay. The tumors examined were 86 pancreatic endocrine tumors (PET), 22 neuroblastic tumors (NBT), 26 carcinoid tumors (CA), 24 pheochromocytomas (PHEO), 40 small cell lung carcinomas (SCLC) and 20 medullary thyroid carcinomas (MTC). IR-CRH was detectable in 21 neuroendocrine tumors (10 PET, four NBT, three CA, two PHEO and two SCLC) at levels of 10-2,700 ng/g wet weight (9.6%). The 21 patients with these CRH-producing tumors showed no clinical symptoms suggestive of Cushing's syndrome. The levels of plasma IR-CRH extracted by immunoaffinity chromatography were < 7.5 pg/ml in five normal subjects and a patient with a neuroblastic tumor containing 55 ng/g wet weight IR-CRH, but in a patient with a thymic carcinoid tumor containing 1,000 ng/g wet weight IR-CRH, the plasma level was elevated to 180 pg/ml. This patient did not have Cushing's syndrome nor an elevated plasma adrenocorticotropic hormone (ACTH) level. The concentrations of nine peptides (growth hormone-releasing hormone, somatostatin, ACTH, calcitonin, gastrin-releasing peptide, glucagon, vasoactive intestinal peptide, neuropeptide tyrosine and pancreatic polypeptide) were determined in extracts of the 21 IR-CRH-producing tumors. Some of these peptides were frequently found to be produced concomitantly with CRH. The results indicate IR-CRH to be produced by various neuroendocrine tumors, but Cushing's syndrome, due to the CRH, to be very rare. The results also show that CRH-producing tumors produce multiple hormones.

Topics: Adenoma, Islet Cell; Adrenal Gland Neoplasms; Adrenocorticotropic Hormone; Bombesin; Calcitonin; Carcinoid Tumor; Carcinoma, Small Cell; Chromatography, Gel; Corticotropin-Releasing Hormone; Gastrin-Releasing Peptide; Gastrins; Humans; Hypothalamus; Lung Neoplasms; Neoplasms; Neuroblastoma; Pancreatic Neoplasms; Peptides; Pheochromocytoma; Somatostatin; Thyroid Neoplasms; Vasoactive Intestinal Peptide

Recent investigations suggest that although thyroid-stimulating hormone (TSH) is the major regulator of thyroid gland function, it is not the only hormone that regulates the thyroid gland. Another factor regulating thyroid gland function is vasoactive intestinal polypeptide (VIP), which is present in nerves that innervate thyroid blood vessels and follicles. Previous studies have documented that VIP stimulates adenylate cyclase (AC) activity in cultured normal and hyperplastic (Graves) thyroid tissue, thus increasing intracellular cyclic AMP concentration. To our knowledge, however, there is no information concerning the effect of VIP on neoplastic thyroid tissue. Therefore we studied the effect of VIP on normal and neoplastic human thyroid tissue from 10 patients (follicular adenomas, 4; follicular carcinomas, 3; and papillary carcinomas, 3). Adenylate cyclase activity was measured in a 8000 g membrane preparation in the basal state and when incubated with VIP, TSH, and both. VIP increased AC activity in normal tissue and tumor in a dose-dependent manner, with maximal stimulation at 10(-6) mol/L (p less than 0.05). In normal tissue, 10(-6) mol/L VIP and a maximally stimulating concentration of TSH (300 mU/ml) stimulated AC to the same degree. In tumors, although both TSH and VIP increased AC activity, the response to TSH was greater (p less than 0.01). VIP and TSH had an additive effect in normal tissue (p less than 0.05), whereas in tumors the AC response to VIP and TSH was the same as with TSH alone (p = 0.66). This study documents that VIP is a potent stimulator of adenylate cyclase in both normal and neoplastic human thyroid tissues. The magnitude of this effect is similar to that produced by TSH, which implies that VIP plays a physiologically important role in the regulation of the secretion and growth of normal and neoplastic thyroid tissues.

Topics: Adenocarcinoma; Adenoma; Adenylyl Cyclases; Carcinoma, Papillary; Cyclic AMP; Humans; Thyroid Gland; Thyroid Neoplasms; Thyrotropin; Vasoactive Intestinal Peptide

In 12 patients treated 2 to 58 months previously for medullary carcinoma of the thyroid, basal serum concentrations of calcitonin, gastrin, vasoactive intestinal polypeptide, glucagon, insulin, and pancreatic polypeptide were measured in search of any correlation between these and the clinical course of the disease. All patients had elevated serum calcitonin levels indicating present disease. One patient had increased serum concentrations of several hormones. Another had achlorhydria and high serum gastrin levels. No relationship between calcitonin and gastro-intestinal polypeptides was found in 11 patients. No correlations were found between serum levels of polypeptides and the occurrence of diarrhoea in 5 patients. It is concluded that gastro-intestinal polypeptides, which are produced by other apudomas, are not secreted in more than normal concentrations under basal conditions, by the majority of patients previously treated for medullary carcinoma of the thyroid.

Topics: Adolescent; Adult; Aged; Calcitonin; Carcinoma; Diarrhea; Female; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Glucagon; Humans; Insulin; Male; Middle Aged; Thyroid Neoplasms; Vasoactive Intestinal Peptide

Topics: Achlorhydria; APUD Cells; Apudoma; Carcinoid Tumor; Carcinoma; Cholecystokinin; Diarrhea; Endocrine System Diseases; Humans; Hypokalemia; Malignant Carcinoid Syndrome; Neoplasms; Pancreatic Diseases; Paraganglioma; Paraneoplastic Endocrine Syndromes; Peptides; Prostaglandins E; Somatostatin; Syndrome; Thyroid Neoplasms; Vasoactive Intestinal Peptide

Levels of vasoactive intestinal polypeptide (VIP) were measured by radioimmunoassay in plasma or tissue from thirty-five patients with watery diarrhoea, and in plasma of twenty-five normal controls. Plasma levels were between 0.6 and 11.0 ng/ml in thirty-one of the thirty-three patients in whom it was measured and too low to measure (less than 200 pg/ml) in the other two. Peptide levels were less than 200 pg/ml in twenty-three of the controls, but higher in the remaining two. All tissues from patients were "rich" in VIP (10 ng to 35 microgram per g). The aetiologic diagnoses included pancreatic islet-cell adenoma or adenocarcinoma, islet-cell hyperplasia, bronchogenic carcinoma, pheochromocytoma, ganglioneuroblastoma, medullary thyroid carcinoma, and retroperitoneal histiocytoma. The findings support the conclusions that: (1) VIP is a likely mediator of the water-diarrhoea syndrome; (2) the syndrome may result from a variety of tumours; (3) this or a related peptide hormone may be secreted by these tumours; and (4) these tumours may have a common embryonic origin.

Topics: Adrenal Gland Neoplasms; Adrenal Medulla; APUD Cells; Diarrhea; Gastrointestinal Hormones; Humans; Lung Neoplasms; Pancreatic Neoplasms; Radioimmunoassay; Thyroid Neoplasms; Vasoactive Intestinal Peptide