gastrins and Carcinoma

Gastric cancer has reduced prevalence, but poor prognoses. To improve treatment, better knowledge of carcinogenesis and cells of origin should be sought. Stomach cancers are typically localized to one of the three mucosae; cardial, oxyntic and antral. Moreover, not only the stem cell, but the ECL cell may proliferate and give rise to tumours. According to Laurén, the classification of gastric carcinomas seems to reflect biological important differences and possible different cell of origin since the two subtypes, intestinal and diffuse, do not transform into the other and show different epidemiology. The stem cell probably gives rise to the intestinal type, whereas the ECL cell may be important in the diffuse type. Elevation of gastrin may be the carcinogenic factor for

Topics: Carcinogenesis; Carcinoma; Cell Proliferation; Gastric Mucosa; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Stomach Neoplasms

Inhibitors of gastric acid secretion are efficient drugs in the treatment of acid-related diseases. However, by reducing gastric acidity, hypergastrinemia develops. Gastrin regulates its target cell, the enterochromaffin (ECL) cell, both functionally and tropicaly. Long-term hypergastrinemia in whatever species studied, has been shown to induce tumors originating from the ECL cell. In man, at least 10 years of hypergastrinemia, accompanied by high or reduced gastric acidity is necessary to induce ECL cell carcinoids. There are reports indicating development of ECL cell carcinoids after long-term treatment with proton pump inhibitors. Moreover, the ECL cell may give rise to gastric carcinomas of diffuse type, which have increased during the last decades. Furthermore, most of the carcinomas developing in patients with long-lasting hypergastrinemia are of ECL cell origin. Therefore, long-lasting iatrogenic hypergastrinemia induced by potent inhibitors of acid secretion may be expected to increase the occurrence of gastric carcinomas in the future.

Topics: Anti-Ulcer Agents; Carcinoma; Drug Administration Schedule; Enterochromaffin Cells; Gastric Acid; Gastrins; Humans; Stomach Neoplasms

An important role for beta-catenin pathways in colorectal carcinogenesis was first suggested by the protein's association with adenomatous polyposis coli (APC) protein, and by evidence of dysregulation of beta-catenin protein expression at all stages of the adenoma-carcinoma sequence. Recent studies have, however, shown that yet more components of colorectal carcinogenesis are linked to beta-catenin pathways. Pro-oncogenic factors that also release beta-catenin from the adherens complex and/or encourage translocation to the nucleus include ras, epidermal growth factor (EGF), c-erbB-2, PKC-betaII, MUC1, and PPAR-gamma, whereas anti-oncogenic factors that also inhibit nuclear beta-catenin signaling include transforming growth factor (TGF)-beta, retinoic acid, and vitamin D. Association of nuclear beta-catenin with the T cell factor (TCF)/lymphoid enhancer factor (LEF) family of transcription factors promotes the expression of several compounds that have important roles in the development and progression of colorectal carcinoma, namely: c-myc, cyclin D1, gastrin, cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-7, urokinase-type plasminogen activator receptor (aPAR), CD44 proteins, and P-glycoprotein. Finally, genetic aberrations of several components of the beta-catenin pathways, eg, Frizzled (Frz), AXIN, and TCF-4, may potentially contribute to colorectal carcinogenesis. In discussing the above interactions, this review demonstrates that beta-catenin represents a key molecule in the development of colorectal carcinoma.

Topics: Adenoma; Adenomatous Polyposis Coli Protein; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; beta Catenin; Calcium-Calmodulin-Dependent Protein Kinases; Carcinoma; Colorectal Neoplasms; Cyclin D1; Cyclooxygenase 2; Cytoskeletal Proteins; Gastrins; Glycogen Synthase Kinase 3; Humans; Hyaluronan Receptors; Intestinal Mucosa; Isoenzymes; Matrix Metalloproteinase 7; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Proto-Oncogene Proteins; Receptors, Cell Surface; Receptors, Urokinase Plasminogen Activator; Signal Transduction; Trans-Activators

Multi-autocrine loops of the epidermal growth factor (EGF), transforming growth factor alpha (TGF alpha), platelet-derived growth factor (PDGF) and TGF beta system are expressed in human gastrointestinal carcinomas. In esophageal and gastric carcinomas, they evidently play an important role in tumor progression. Gastrin, one of the major gut hormones, may also act as an autocrine growth factor for gastric and colonic carcinomas. The HST1 and INT-2 genes, belonging to the fibroblast growth factor gene family, are coamplified in approximately 50% of primary tumors and in all the metastatic tumors of esophageal carcinoma. TGF alpha and EGF are the ligands of the tumor cells that overexpress EGF receptor in esophageal carcinomas. The synchronous expression of EGF and its receptor, as well as TGF alpha and ras p21, is evidently correlated with the depth of tumor invasion, metastasis and prognosis of gastric carcinomas. Amplification of c-erbB-2 and EGF receptor genes has been observed in many metastatic sites of gastric carcinomas regardless of histological type. In addition to TGF alpha and EGF, TGF beta and PDGF A chain produced by tumor cells may stimulate collagen synthesis not only by fibroblasts but also by tumor cells themselves, resulting in extensive progression and diffuse fibrosis of scirrhous gastric carcinomas. Moreover, TGF alpha or EGF and estrogen may also play a cooperative role in the development of scirrhous gastric carcinoma. In colorectal carcinoma, it has been shown that the accumulation of several alterations in ras genes and p53 genes is most important for the conversion of adenoma to carcinoma. Critical genetic changes, including activation of oncogenes, mutation and deletion of tumor suppressor genes and disturbances in transcriptional regulatory sequences, may bring about aberrant expression of growth factors and their receptors in gastrointestinal carcinomas. The understanding of the significance of EGF-related growth factors in tumor progression provides a framework for a biological approach to the therapy of human gastrointestinal carcinomas. 8-Cl-cAMP, which inhibits expression of oncogenes and TGF alpha, may be useful not only for cancer therapy but also for the study of cell differentiation.

Topics: Carcinoma; ErbB Receptors; Gastrins; Gastrointestinal Neoplasms; Gene Expression; Growth Substances; Humans; Proto-Oncogenes; Receptors, Cell Surface; Receptors, Platelet-Derived Growth Factor; Transforming Growth Factors

Topics: Acetylcholine; Anemia, Pernicious; Atrophy; Calcium; Carcinoma; Catecholamines; Circadian Rhythm; Duodenal Ulcer; Gastric Juice; Gastric Mucosa; Gastrins; Gastritis; Gastrointestinal Diseases; Hormones, Ectopic; Humans; Ligation; Pancreatic Ducts; Secretin; Stimulation, Chemical; Stomach Diseases; Stomach Neoplasms; Stomach Ulcer; Zollinger-Ellison Syndrome

Topics: Adult; Aged; Anemia, Pernicious; Carcinoma; Clinical Trials as Topic; Duodenal Ulcer; Female; Gastric Juice; Gastrins; Hernia, Diaphragmatic; Histamine; Humans; Male; Middle Aged; Secretory Rate; Stomach; Stomach Neoplasms; Stomach Ulcer

Multidrug resistance (MDR) is one of the major reasons for the failure of chemotherapy-based gastric carcinoma (GC) treatments, hence, biologically based therapies are urgently needed. Gastrin (GAS), a key gastrointestinal (GI) hormone, was found to be involved in tumor formation, progression, and metastasis. In this study, quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical staining analysis revealed a high level of expression of GAS in drug-insensitive GC tissues (P<0.01) and similar results were revealed in GC cell lines SGC7901 and its multidrug-resistant variants SGC7901/VCR and SGC7901/ADR. We constructed a eukaryotic expression vector pCDNA3.1(+)/GAS for GAS overexpression and recombinant lentiviral vectors for specific siRNA (siGAS). Transfection of pCDNA3.1(+)/GAS increased (P<0.05) while transfection of siGAS (P<0.05) and co-treated with paclitaxel (TAX) and vincristine (VCR) combination (TAX-VCR) decreased (P<0.01) the cell viability of SGC7901, SGC7901/VCR and SGC7901/ADR. Apoptosis rates of SGC7901/VCR and SGC7901/ADR were reduced by pCDNA3.1(+)/GAS and increased by siGAS (P<0.05). The apoptosis rates of SGC7901/VCR, SGC7901/ADR and SGC7901 were all upregulated (P<0.01) when cells were co-treated with a combination of siGAS and TAX-VCR. Additionally, siGAS significantly downregulated the expression of Bcl-2 and multidrug-resistant associate protein (MRP1) and P-glycoprotein (Pgp) (P<0.05) in SGC7901/VCR and SGC7901/ADR cells. Moreover, GAS overexpression in SGC7901 cells significantly inhibited p27Kip1 expression but increased phosphorylation levels of p27Kip1 on Thr (187) and Ser (10) sites (P<0.05), as well as increasing nuclear accumulation of S-phase kinase-associated protein 2 (Skp2) and cytoplasmic accumulation of the Kip1 ubiquitination-promoting complex (KPC) (P<0.05). Silencing of Skp2 blocked the promoting effects of pCDNA3.1(+)/GAS on viability, the expression of MRP1 and Pgp and the inhibitory effects of pCDNA3.1(+)/GAS on apoptosis. In conclusion, we suggest that GAS contributes to the emergence of MDR of SGC7901 cells via the degradation of p27Kip1.

Topics: Aged; Camptothecin; Carcinoma; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p27; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Fluorouracil; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Irinotecan; Male; Middle Aged; Multidrug Resistance-Associated Proteins; Phosphorylation; Proteolysis; RNA, Small Interfering; S-Phase Kinase-Associated Proteins; Stomach Neoplasms

Proton pump inhibitors (PPIs) are routinely used for control of upper gastrointestinal disorders, often with long-term application. However, there has been some concern about the long-term safety and the possibility of cancer induction and development of neuroendocrine tumors (NET) in the stomach. We therefore analyzed the influence of PPI use on tumor development histologically, immunohistochemically, and serologically in the glandular stomachs of Helicobacter pylori (Hp)-infected and uninfected Mongolian gerbils (MGs). 53 MGs were divided into 6 groups: Hp+25PPI, Hp+5PPI, Hp, 25PPI, 5PPI, and controls. The high-dose Hp+25PPI and 25PPI groups received the PPI (lansoprazole) at 25mg/kg/day, and the low-dose Hp+5PPI and 5PPI groups were given 5mg/kg/day. After 50 or 100 weeks, animals were sacrificed humanely, and the glandular stomach samples were evaluated histologically and phenotypically, using antibodies against chromogranin A (CgA), gastrin and gastric inhibitory polypeptide (GIP). Serum gastrin levels were also examined. NETs occurred in the Hp+25PPI, Hp+5PPI, Hp, and 25PPI groups, but there was no synergistic effect between Hp-infection and high-dose PPI administration. Serum gastrin was increased statistically by Hp infection and high-dose PPI administration, but not influenced by the low-dose. The NETs featured expression of CgA, but not gastrin or GIP. In conclusions, PPI at low dose had no influence on development of carcinomas and NETs in the Hp-infected and uninfected glandular MG stomach, suggesting clinical safety. However, PPI at high dose increased NET development and serum gastrin in the MG model.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Animals; Carcinoma; Cell Transformation, Neoplastic; Chromogranin A; Gastric Inhibitory Polypeptide; Gastrins; Gerbillinae; Helicobacter Infections; Helicobacter pylori; Lansoprazole; Male; Neoplasms, Glandular and Epithelial; Neuroendocrine Tumors; Proton Pump Inhibitors; Stomach Neoplasms

Expression of gastrin and cholecystokinin 2 (CCK(2)) receptor splice variants (CCK(2)R and CCK(2i4sv)R) are upregulated in human colonic adenomas where they are thought to contribute to tumor growth and progression. To determine the effects of ectopic CCK(2) receptor variant expression on colonic epithelial cell growth in vitro and in vivo, we employed the non-tumorigenic colonic epithelial cell line, NCM356. Receptor expression was induced using a retroviral expression vector containing cDNAs for either CCK(2i4sv)R or CCK(2)R. RT-PCR and intracellular Ca(2+) ([Ca(2+)](i)) imaging of RIE/CCK(2)R cells treated with conditioned media (CM) from NCM356 revealed that NCM356 cells express gastrin mRNA and secrete endogenous, biologically active peptide. NCM356 cells expressing either CCK(2)R or CCK(2i4sv)R (71 and 81 fmol/mg, respectively) grew faster in vitro, and exhibited an increase in basal levels of phosphorylated ERK (pERK), compared with vector. CCK(2) receptor selective antagonist, YM022, partially inhibited the growth of both receptor-expressing NCM356 cells, but not the control cells. Inhibitors of mitogen activated protein kinase pathway (MEK/ERK) or protein kinase C (PKC) isozymes partially inhibited the elevated levels of basal pERK and in vitro growth of receptor-expressing cells. Vector-NCM356 cells did not form tumors in nude mice, whereas, either CCK(2) receptor-expressing cells formed large tumors. Autocrine activation CCK(2) receptor variants are sufficient to increase in vitro growth and tumorigenicity of non-transformed NCM356 colon epithelial cells through a pathway involving PKC and the MEK/ERK axis. These findings support the hypothesis that expression of gastrin and its receptors in human colonic adenomas contributes to tumor growth and progression.

Topics: Adenoma; Animals; Calcium; Carcinoma; Cell Culture Techniques; Cell Division; Colon; Colorectal Neoplasms; Disease Progression; DNA Primers; Gastrins; Genetic Variation; Humans; Intestinal Mucosa; Mice; Mutation; Neoplasm Staging; Receptor, Cholecystokinin B; Reverse Transcriptase Polymerase Chain Reaction

Female Japanese cotton rats become hypoacidic and hypergastrinaemic from age 2 months and later develop gastric carcinomas in the oxyntic mucosa. Previous studies have demonstrated that carcinogenesis can be halted by a gastrin receptor antagonist and that carcinomas can be induced by a histamine-2 receptor antagonist or partial corpectomy, both of which induce hypergastrinaemia. The aim of the present study was to examine the effect of antrectomy in female cotton rats.. The animals were either antrectomized (Group 1) or sham-operated (Group 2) 2 months after detection of hypergastrinaemia and terminated 4 months after operation. A third group was antrectomized at age 2 months while still normo-acidic (Group 3) and terminated 6 months after operation.. Antrectomy after 2 months of hypergastrinaemia prevented the development of carcinoma compared with in sham-operated animals, whereas some of the animals that were antrectomized at 2 months of age also developed carcinomas. In Groups 1 and 2 as well as in animals developing carcinomas in Group 3, there was marked hyperplasia of neuroendocrine cells in the oxyntic mucosa expressing chromogranin A, vesicular monoamine transporter (VMAT)-2, ghrelin and somatostatin. Gastrin-positive cells were found adjacent to neoplastic areas in the oxyntic mucosa.. The removal of antral gastrin by antrectomy halts carcinogenesis in cotton rats, but other mechanisms may also play a role.

Topics: Animals; Carcinoma; Disease Models, Animal; Female; Gastrectomy; Gastrins; Hormones; Pyloric Antrum; Sigmodontinae; Stomach Neoplasms

Topics: Blood-Brain Barrier; Brain Neoplasms; Breast Neoplasms; Carcinoma; Cytokines; Gastrins; Gastrointestinal Neoplasms; Helicobacter Infections; Humans; Lung Neoplasms; Mast Cells; Neoplasm Metastasis; Stress, Physiological

The role of enterochromaffin-like (ECL) cells in gastric carcinogenesis is not fully understood. Spontaneous tumours developing in hypergastrinemic female cotton rats have an adenocarcinoma phenotype, but numerous cells in the dysplastic mucosa as well as in the carcinomas are positive for neuroendocrine markers. In the present study of female cotton rats with 2 and 8 months' hypergastrinemia, the oxyntic mucosa of the stomach was examined histologically and immunolabelled for histidine decarboxylase (HDC) and pancreastatin, and hyperplastic and neoplastic ECL cells were evaluated by electron microscopy. These animals developed hyperplasia of the oxyntic mucosa in general and of the ECL cells in particular after 2 months and dysplasia and carcinomas after 8 months. The immunoreactivity of the ECL cells in the oxyntic mucosa was increased at 2 months and declined at 8 months. These histological changes were associated with progressive loss of secretory vesicles and granules in ECL cells. We suggest that ECL cells in hypergastrinemic cotton rats dedifferentiate with time and that the gastric carcinomas may develop from ECL cells.

Topics: Animals; Carcinoma; Cell Transformation, Neoplastic; Chromogranin A; Enterochromaffin-like Cells; Female; Gastrins; Histidine Decarboxylase; Hyperplasia; Pancreatic Hormones; Parietal Cells, Gastric; Rats; Sigmodontinae; Stomach Neoplasms

Among inbred female cotton rats (Sigmodon hispidus) 25-50% of the animals develop spontaneous gastric carcinomas; the corresponding figure for male cotton rats is approximately 1%. Animals with carcinomas have hypergastrinaemia and gastric hypo-anacidity and the tumours are derived from enterochromaffin-like (ECL) cells. The mechanism behind the hypo-anacidity is unknown. Carcinomas are found in all female cotton rats with hypergastrinaemia lasting more than 4 months and this represents an excellent animal model for studying gastric carcinogenesis. In this study, the somatostatin analogue octreotide was given to female cotton rats to prevent carcinoma development caused by hypergastrinaemia. Twelve female cotton rats were given monthly injections of long-acting octreotide (5 mg i.m.) for 6 months. A control group of 20 animals was not given injections. Of the 20 control animals, 13 developed hypergastrinaemia and histologically invasive carcinomas or dysplasia. Of the 12 animals in the octreotide group, five developed hypergastrinaemia. None of these five animals developed histological cancer (P<0.05), whereas three had dysplasia. However, octreotide did not affect plasma gastrin concentration or antral gastrin mRNA abundance significantly. Dysplasia of the oxyntic mucosa in hypergastrinaemic animals was accompanied by a marked increase in chromogranin A-immunoreactive cells and cells positive for Sevier-Munger staining. The malignant tissue also contained groups of cells with Sevier-Munger staining. In conclusion, octreotide prevented ECL cell carcinomas in hypergastrinaemic cotton rats without lowering the gastrin concentration.

Topics: Animals; Antineoplastic Agents, Hormonal; Carcinoma; Chromogranin A; Chromogranins; Enterochromaffin-like Cells; Female; Gastrins; Immunochemistry; Octreotide; Parietal Cells, Gastric; Rats; RNA, Messenger; Sigmodontinae; Stomach Neoplasms

Among inbred female cotton rats (Sigmodon hispidus) 25%-50% of the animals develop spontaneous gastric carcinomas, whereas males have an incidence of less than 1%. The carcinomas are enterochromaffin-like (ECL)-cell derived. Animals with gastric carcinomas also have hypergastrinaemia and gastric hypoacidity, but the mechanism behind the hypoacidity is unknown. Carcinomas have been found in all female cotton rats with spontaneous hypergastrinaemia lasting more than 4 months, and a gastrin receptor antagonist prevents the development of carcinoma. The purpose of the present study was to investigate whether induced hypergastrinaemia in male cotton rats would also result in carcinomas.. Hypergastrinaemia was induced by partial corpectomy of male cotton rats, aiming at removal of 80%-90% of the corpus. A control group was sham-operated.. All partially corpectomized animals developed persistent hypergastrinaemia. Six months after the operation, 9 out of 13 partially corpectomized animals developed gastric cancer. In the dysplastic mucosa surrounding the tumours there was an increase in chromogranin A immunoreactive cells, where numerous cells also were stained using the Sevier-Munger technique. Tumour tissue also contained cells that were chromogranin A positive and stained by Sevier-Munger.. ECL-cell carcinomas can be induced in male cotton rats by partial corpectomy. This supports a previous statement that spontaneous carcinomas in female cotton rats are caused by gastric hypoacidity and hypergastrinaemia. In hypergastrinaemic animals, ECL-cell carcinomas develop independently of gender within a relatively short period of time, and cotton rats therefore represent an interesting model for studying gastric carcinogenesis.

Topics: Animals; Biopsy, Needle; Carcinoma; Disease Models, Animal; Enterochromaffin-like Cells; Gastrectomy; Gastrins; Hydrogen-Ion Concentration; Immunohistochemistry; Male; Probability; Rats; Sensitivity and Specificity; Sigmodontinae; Statistics, Nonparametric; Stomach Neoplasms

We describe a patient with multiple endocrine neoplasia type 1 characterized by the simultaneous occurrence of parathyroid cancer, parathyroid adenomas, and pancreatic gastrinoma, who presented with an episode of acute hypercalcemia. The rapid parathyroid hormone assay provided a basis for the diagnosis of parathyroid hyperfunction. Mediastinal metastasis of the parathyroid carcinoma was found at autopsy. However, the staining of pancreatic and gastric tissue for parathyroid hormone-related protein does not make it possible to exclude completely the contribution of this peptide in mediating the hypercalcemia. To our knowledge, this is the first reported case of parathyroid carcinoma as part of the multiple endocrine neoplasia type 1 syndrome.

Topics: Acute Disease; Adenoma; Adult; Carcinoma; Fatal Outcome; Gastrinoma; Gastrins; Humans; Hypercalcemia; Hyperparathyroidism; Male; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Parathyroid Hormone; Parathyroid Neoplasms

The relationship between plasma gastrin levels and colorectal cancer is controversial. When confounding factors which increase plasma gastrin levels are taken into account, it has been shown that gastrin levels are not elevated in patients with colorectal cancer. However, these studies only measured amidated gastrin. Total gastrin (which includes unprocessed, partially processed, and mature forms of gastrin) has been shown to be elevated in patients with colorectal cancer.. The aim of this study was to determine whether fasting plasma levels of progastrin, amidated gastrin, or glycine extended gastrin are elevated in patients with colorectal cancer or colorectal polyps compared with controls.. Progastrin, amidated gastrin, and glycine extended gastrin were estimated by radioimmunoassay using the following antibodies: L289, 109-21, and L2. Blood samples were analysed for Helicobacter pylori by an enzyme linked immunosorbent assay.. Median progastrin levels were significantly higher in the cancer group (27.5 pmol/l) than in the polyp (< or =15 pmol/l) or control (< or =15 pmol/l) group (p=0.0001 There was no difference in median levels of amidated gastrin between groups. Median levels of amidated gastrin were significantly higher in H pylori positive patients (19 pmol/l) than in H pylori negative patients (8 pmol/l) (p=0.0022). Median plasma progastrin levels were significantly higher for moderately dysplastic polyps (38 pmol/l) compared with mildly dysplastic (15 pmol/l) and severely dysplastic (15 pmol/l) polyps (p=0.05).. Plasma levels of progastrin, but not amidated gastrin or glycine extended gastrin, are significantly elevated in patients with colorectal cancer compared with those with colorectal polyps or controls, irrespective of their H pylori status. We conclude that measuring plasma progastrin levels in patients with colorectal cancer is warranted.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Bacterial; Biomarkers, Tumor; Carcinoma; Case-Control Studies; Colonic Polyps; Colorectal Neoplasms; Female; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Protein Precursors

Processing intermediates of preprogastrin (gly-gastrin and progastrin), termed nonamidated gastrins, are mitogenic for several cell types including colonic epithelial cells. However, presently it is not known if nonamidated gastrins play a role in colon carcinogenesis and if the effects are similar to those of amidated gastrins.. Colon carcinogenesis in response to azoxymethane (AOM) was examined in transgenic mice overexpressing either progastrin (hGAS) or amidated gastrin (INS-GAS), compared with that in wild-type (WT) mice.. In AOM-treated groups, the total number of tumors per colon was significantly higher in hGAS (4.8+/-0.34) than INS-GAS (3.0+/-0.16) and WT (2.7+/-0.35) mice. Total numbers of adenocarcinomas and adenomas per animal colon were also significantly higher in hGAS than INS-GAS and WT mice. The size of the tumors was greater in hGAS mice, resulting in a significantly higher tumor burden per mouse in the hGAS mice than INS-GAS and WT mice. Although >90% of the tumors were located in the distal half of the colon in INS-GAS and WT mice, a significant number (42%) were present at the proximal end of the colon in hGAS mice.. The results suggest that the risk for developing colon carcinomas and adenomas in response to AOM is significantly increased in mice expressing high levels of progastrin, but not amidated gastrins.

Topics: Adenoma; Amides; Animals; Azoxymethane; Carcinogens; Carcinoma; Colonic Neoplasms; Gastrins; Incidence; Mice; Mice, Transgenic; Neoplasms, Multiple Primary; Protein Precursors; Reference Values; Survival Analysis

Gastrin and the cholecystokinin type B/gastrin receptor (CCKBR) have been shown to be expressed in colorectal adenocarcinoma. Both exogenous and autocrine gastrin have been demonstrated to stimulate growth of colorectal cancer but it is not known if gastrin affects the growth of colonic polyps. The purpose of this study was to determine if gastrin and CCKBR are expressed in human colonic polyps and to determine at which stage of progression this occurs.. A range of human colonic polyps was assessed for gastrin and CCKBR gene and protein expression.. Normal colonic mucosa did not express gastrin or CCKBR. Gastrin and CCKBR reverse transcription-polymerase chain reaction products were detected and verified by specific hybridisation with an oligo probe on Southern blots. Gastrin and CCKBR were expressed in 78% and 81% of polyps, respectively. Both genes were coexpressed in 97% of cases. Immunohistochemistry identified progastrin in 91%, glycine extended gastrin 17 in 80%, and amidated gastrin 17 in only 47% of polyps. CCKBR was present in 96% of polyps. Expression of gastrin and CCKBR was seen in all histological types and sizes of polyps.. This study is the first to show widespread expression of both gastrin and its receptor in colorectal polyps. Their activation occurs early in the adenoma-carcinoma sequence. Gastrin may promote progression through the adenoma-carcinoma sequence.

Topics: Adenoma; Aged; Carcinoma; Colonic Neoplasms; Colonic Polyps; Disease Progression; Female; Gastrins; Humans; Immunohistochemistry; Male; Middle Aged; Neoplasm Proteins; Precancerous Conditions; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Reverse Transcriptase Polymerase Chain Reaction

Our recent studies using comparative genomic hybridization showed that gain or amplification at the 17q12-q21 region is very common in the intestinal type of gastric cancer. Here, we describe a fluorescence in situ hybridization study with gastrin (GAS)-specific and ERBB2-specific probes on ten specimens of gastric carcinoma that, by using comparative genomic hybridization, showed 1) DNA copy number gain or amplification at 17q12-q21, a region known to harbor the GAS and ERBB2 genes (four cases); 2) gain of the entire chromosome 17 (three cases); or 3) normal copy number of chromosome 17 (three cases). GAS and ERBB2 protein expression was studied by Western immunoblotting from gastric cancer cell lines with or without gain at 17q12-q21 as well as a breast cancer cell line with ERBB2 amplification. Our results showed that simultaneous amplification of both GAS and ERBB2 was four- to ninefold in the tumors with the 17q12-q21 amplification. Both genes were amplified in the same nuclei, and the hybridization signals were localized to the same region of the nucleus. Overexpression of GAS and ERBB2 was observed by Western immunoblotting only in the gastric cancer cell line with gain at 17q12-q21. The ERBB2 amplification is also a recurrent change in breast cancer. To investigate whether the GAS amplification is unique in gastric cancer, fluorescence in situ hybridization analysis was performed on 40 breast cancer cell lines. The ERBB2 amplification was observed in 11 cell lines, but none of the lines showed the GAS amplification. This indicates that the formation of an amplicon, in which both the GAS and the ERBB2 genes are amplified, might be unique in gastric cancer, especially in its intestinal type, and that simultaneous amplification of both genes is important to the tumorigenesis of intestinal gastric cancer. We demonstrate here for the first time that a gene of a physiological hormone is amplified in tumors that originate from cells that normally secrete the hormone.

Topics: Breast Neoplasms; Carcinoma; Chromosomes, Human, Pair 17; Gastrins; Gastrointestinal Neoplasms; Gene Amplification; Humans; In Situ Hybridization, Fluorescence; Receptor, ErbB-2; Tumor Cells, Cultured

Endocytosis of gastrin was studied in a number of gastrin-receptor-expressing cell lines by confocal laser scanning microscopy (CLSM) with the aid of a biologically active fluorescent derivative, rhodamine green heptagastrin. Rapid clustering (within 4-7 min) and internalization of fluorescent ligand upon binding at room temperature and 37 degrees C were observed in the rat pancreatic acinar carcinoma cell line AR42J, human gastric carcinomas AGS-P and SIIA, human colon carcinomas HCT116 and HT29, and in NIH/3T3 cells transfected with human and rat gastrin/cholecystokinin-B receptor cDNA. Internalization was inhibited by hypertonic medium. Fluorescent heptagastrin and transferrin colocalized in the same endocytic vesicles at different stages of internalization suggesting that endocytosis occurred predominantly through a clathrin-dependent mechanism. At 37 degrees C partial colocalization with the lysosomal marker neutral red was detected by CLSM, implying that internalized gastrin accumulated in the lysosomes. Immunoelectron microscopy studies with antibodies against gastrin revealed the presence of the internalized hormone in multivesicular vesicles and endosomes. Almost no hormone was detected in lysosomes with the antibodies to gastrin, suggesting that the degradation of the peptide is rapid in those vesicles. Continuous accumulation of fluorescent label was observed by CLSM in the presence of the protein synthesis inhibitor cycloheximide, suggesting that the gastrin receptor is recycled back to the cell membrane after hormone delivery to intracellular compartments. An estimated average recycling time for the receptor molecules was 1 h in NIH/3T3 cells.

Topics: 3T3 Cells; Animals; Carcinoma; Carcinoma, Acinar Cell; Coated Pits, Cell-Membrane; Cycloheximide; Endocytosis; Gastrins; Gastrointestinal Neoplasms; Humans; Lysosomes; Mice; Microscopy, Confocal; Microscopy, Immunoelectron; Neoplasm Proteins; Pancreatic Neoplasms; Protein Synthesis Inhibitors; Rats; Receptors, Cholecystokinin; Recombinant Proteins; Transfection; Transferrin; Tumor Cells, Cultured

The effect of endogenous hypergastrinemia on growth of human colon carcinoma is not known. Our aim was to study the growth of human colon carcinoma in an animal model with endogenous hypergastrinemia.. Human colon carcinoma was transplanted to the colon of 40 athymic rats. Of these, 25 underwent gastric fundectomy to accomplish endogenous hypergastrinemia, and 15 were sham operated to serve as controls. The duration of the study was 8 weeks. During the last week, 12 fundectomized animals received a gastrin (cholecystokinin B) receptor antagonist. Metaphase arrest index, local invasion, and distant spread of the tumor were investigated. Expression of gastrin and cholecystokinin B receptor messenger RNA was examined by reverse-transcription polymerase chain reaction.. Tumor spread by direct extension outside the colon was observed in all animals, and liver metastases were observed in 10 of the 25 fundectomized animals. Sham-operated animals showed none of these features. The metaphase arrest index of the tumor did not differ between fundectomized animals given the cholecystokinin B receptor antagonist and sham-operated animals, whereas it was significantly increased in fundectomized animals not given the antagonist. The tumor expressed both gastrin and cholecystokinin B receptor messenger RNA.. The results indicate that endogenous hypergastrinemia may promote proliferation and spread of human colon carcinoma expressing cholecystokinin B receptor.

Topics: Aged; Animals; Carcinoma; Colonic Neoplasms; Female; Gastric Fundus; Gastrins; Humans; Liver Neoplasms; Male; Neoplasm Transplantation; Rats; Rats, Inbred Lew; Rats, Nude; Receptors, Cholecystokinin

Topics: Adenoma; Adrenal Gland Neoplasms; Adrenocortical Hyperfunction; Aged; Carcinoma; Carcinoma, Papillary; Female; Gastrins; Humans; Hypercalcemia; Hypothyroidism; Multiple Endocrine Neoplasia; Pituitary Neoplasms; Thyroid Neoplasms

Gastrin has a trophic effect on the mucosa of the gastrointestinal tract and seems to have the potential for promoting colonic cancerogenesis through a chronic stimulation of the epithelial proliferation. Plasma gastrin has been reported to be elevated in patients with colorectal neoplasms. The aim of the present study was to verify this observation. Presurgical serum levels of gastrin were compared between 49 patients with colorectal neoplasms and 47 controls hospitalized for other surgical lesions. Results show significantly higher gastrin levels of case group than controls: 72.72 + 85.41 vs. 46.79 + 24.09 pg/ml (p < 0.05), and provide support for the hypothesis of a gastrin-stimulated neoplastic growth enhancing at the same time the potential therapeutic role of reducing gastrin secretion.

Topics: Adenoma; Adult; Aged; Aged, 80 and over; Carcinoma; Colorectal Neoplasms; Female; Gastrins; Humans; Male; Middle Aged; Radioimmunoassay

Inhibition of colon carcinoma cell growth by the nonselective gastrin/cholecystokinin (CCK) receptor antagonists proglumide and benzotript provided evidence that gastrin functions as an autocrine growth factor. However, the molecular properties of the receptor mediating the antagonist effects have not been identified. A 78-kDa gastrin-binding protein (GBP), the sequence of which is related to the family of enzymes possessing enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase activities, has been previously purified from porcine gastric mucosal membranes. I now report that covalent cross-linking of 125I-labeled [Nle15]gastrin2,17 to the 78-kDa GBP is inhibited by crotonyl-CoA and by acetoacetyl-CoA. Gastrin, CCK, and their analogues also inhibit cross-linking, and the spectrum of analogue affinities correlates better with the values previously reported for binding to the gastrin/CCK-C receptor than with the values reported for binding to either the CCK-A or the gastrin/CCK-B receptor. Cross-linking is also inhibited by proglumide and benzotript, but no inhibition is seen with either the CCK-A receptor-selective antagonist L364,718 or the gastrin/CCK-B receptor-selective antagonist L365,260. The affinities of antagonists for the GBP correlate well with their affinities for the gastrin/CCK-C receptor and with their potencies for inhibition of colon carcinoma cell growth. I conclude that the 78-kDa gastrin-binding protein is (i) a member of the hydratase/dehydrogenase family of fatty acid oxidation enzymes, (ii) the gastrin/CCK-C receptor, and (iii) the target for the antiproliferative action of two gastrin/CCK receptor antagonists.

Topics: 3-Hydroxyacyl CoA Dehydrogenases; Acyl Coenzyme A; Animals; Carcinoma; Carrier Proteins; Colonic Neoplasms; Enoyl-CoA Hydratase; Gastrins; Humans; Mitochondrial Trifunctional Protein; Multienzyme Complexes; Protein Binding; Receptors, Cholecystokinin; Swine

This report describes an immunohistopathologic analysis characterizing the incidence, pattern of distribution, and hormonal content of neuroendocrine (NE) cells in human benign prostate and prostatic adenocarcinoma.. Formaldehyde-fixed, paraffin-embedded material from 15 benign prostates, 31 primary prostatic adenocarcinomas, 16 metastatic lesions, 21 primary tumors treated with short-course diethylstilbestrol (DES), and 10 specimens from hormone-refractory patients were examined. NE cells were identified using silver histochemistry and a panel of immunohistochemical NE markers (chromogranin-A, serotonin, neuron-specific enolase), and specific peptide hormone antibodies.. NE cells were identified in all benign prostates. NE cells were identified in 77% of primary untreated adenocarcinomas with no significant differences with respect to pathologic stage. NE cells were found isolated and dispersed in the tumor, composing the minority of malignant cells. Double-labeling and serial section immunohistochemistry demonstrated the coexpression of prostate-specific antigen (PSA) in NE cells. In addition to serotonin, some tumors expressed multiple hormone immunoreactivities. NE cells were identified in 56% of metastatic deposits, with a similar pattern of distribution. In DES-treated cases, NE cells were found consistently in the adjacent benign epithelium, whereas 52% of tumors contained NE cells. Hormone-refractory tumors contained NE cells in 60% of cases.. This analysis demonstrates that a significant proportion of primary and metastatic prostatic adenocarcinomas contain a subpopulation of NE cells, the expression of which does not appear to be suppressed with androgen ablation and does not correlate with pathologic stage. Furthermore, NE cells coexpress PSA, suggesting a common precursor cell of origin. The elaboration of biogenic amines and neuropeptides suggests that NE cells dispersed in prostatic carcinoma may play a paracrine growth-regulatory role.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Basement Membrane; Calcitonin; Carcinoma; Cell Differentiation; Chromogranin A; Chromogranins; Cytoplasm; Diethylstilbestrol; Gastrin-Releasing Peptide; Gastrins; Humans; Keratins; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Neurosecretory Systems; Peptides; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Seminal Vesicles; Serotonin; Staining and Labeling; Thyrotropin

Female Syrian golden hamsters with N-nitroso-bis (2-oxopropyl) amine (BOP)-induced pancreatic cancers were treated for 2 months with bombesin/gastrin-releasing peptide (GRP) antagonist D-Tpi6,Leu13 psi(CH2NH)Leu14 bombesin(6-14) (RC-3095). Bombesin and GRP(14-27) were also administered alone and in combination with the antagonist RC-3095. RC-3095 exerted a dose-dependent inhibitory effect on growth of pancreatic cancers. The number of animals with pancreatic cancers was significantly lower in the group treated with 60 micrograms/day of RC-3095 and the weight of tumorous pancreata was reduced. Administration of bombesin or GRP alone did not stimulate the growth of pancreatic tumors and, in fact, had a slightly suppressive effect on cancers which was significant only in Experiment I. Bombesin and GRP (14-27) given together with RC-3095 did not nullify the inhibitory effect of the antagonist on pancreatic cancer growth. Actually, a greater inhibition of pancreatic tumors was observed after administration of RC-3095 together with bombesin or GRP, than with RC-3095 alone. The mechanism of action of bombesin, GRP, and bombesin antagonists on pancreatic cancers appears to be complex. The inhibitory effect of bombesin antagonists on pancreatic cancer growth was accompanied by a decrease in the binding capacity of EGF receptors in tumor membranes. Administration of bombesin also caused a down-regulation of EGF receptors and the greatest decrease in binding capacity of EGF receptors was observed after treatment with RC-3095 in combination with GRP. Inhibition of pancreatic cancer can thus be tentatively explained by some common pathways in the action of bombesin, GRP and their antagonists, that could be mediated by interference with EGF-receptor mechanisms.

Topics: Animals; Body Weight; Bombesin; Carcinoma; Cricetinae; Dose-Response Relationship, Drug; Down-Regulation; Epidermal Growth Factor; ErbB Receptors; Female; Gastrin-Releasing Peptide; Gastrins; Growth Hormone; Insulin-Like Growth Factor I; Mesocricetus; Nitrosamines; Pancreatic Neoplasms; Peptide Fragments; Peptides; Receptors, Bombesin; Receptors, Neurotransmitter

Topics: Adenocarcinoma; Animals; Antigens, Viral, Tumor; Carcinoma; Gastrinoma; Gastrins; Genetic Engineering; Hyperplasia; Liver Neoplasms; Mice; Mice, Transgenic; Pancreatic Neoplasms; Pyloric Antrum; Stomach Neoplasms

One hundred and twenty-eight cases of gastric carcinoma were examined with immunohistochemical technic for carcinoembryonic antigen (CEA), human chorionic gonadotropin (HCG), serotonin, gastrin and lysozyme. CEA were observed in 105 cases. Twenty-four cases were positive for HCG, 53 cases for serotonin, 31 cases for gastrin, 89 cases for lysozyme. Sixty-nine cases exhibited more than two hormones or one hormone and lysozyme simultaneously in different cells of the same tumor. Ultrastructurally, sometimes three types of secretory granules were noticed. The electron dense granules in the lysozyme-containing tumor cells were similar to those of Paneth's cells in intestinal metaplasia. The positive rates of the above three hormones, lysozyme and multi-marker expression in diffuse type carcinoma were higher than those in intestinal type, and 42/44 cases of the diffuse type carcinoma were histologically undifferentiated carcinomas or signet-ring cell carcinomas. Lymph node metastasis occurred more frequently in those carcinomas with hormone or lysozyme positivity. These findings suggest that these neoplastic endocrine cells and Paneth's cells have originated from multipotential differentiation of neoplastic stem cells in the stomach, reflecting the state of the gene activity in the tumor cells.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Carcinoembryonic Antigen; Carcinoma; Chorionic Gonadotropin; Gastrins; Humans; Immunohistochemistry; Lymphatic Metastasis; Muramidase; Neoplasm Staging; Serotonin; Stomach Neoplasms

Topics: Adult; Aged; Aged, 80 and over; Carcinoma; Colonic Neoplasms; Female; Gastrins; Humans; Male; Middle Aged; Postoperative Care; Preoperative Care; Prospective Studies; Rectal Neoplasms; Reference Values; Time Factors

The effects of the opioid receptor agonists methionine-enkephalin (Met-ENK) and leucine-enkephalin (Leu-ENK) on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine were investigated in Wistar rats. After 25 weeks of oral treatment with the carcinogen, the rats received subcutaneous injections of Met-ENK (20 micrograms/kg) or Leu-ENK (20 micrograms/kg) once every 2 days. The prolonged administrations of Met-ENK and Leu-ENK significantly increased the incidence of gastric cancers in week 52. Treatments with these opioid receptor agonists significantly increased the labeling index of the antral mucosa. These findings indicate that opioids enhance gastric carcinogenesis and suggest that their effects may be related to their influence on increasing proliferation of the antral epithelial cells.

Topics: Animals; Carcinoma; Cell Division; Drug Synergism; Enkephalin, Leucine; Enkephalin, Methionine; Gastric Mucosa; Gastrins; Hydrogen-Ion Concentration; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach Neoplasms

Gastrin may play a role in gastric carcinogenesis, as indicated by an increased frequency of gastric carcinomas in patients with pernicious anaemia and the fact some human gastric cancer cell lines carry the gastrin receptor. Recently, it has been shown that the acid-stimulatory effect of gastrin may be solely mediated by histamine release from the enterochromaffin-like (ECL) cell, on which gastrin has a specific trophic effect. We therefore found it of interest to examine human gastric carcinomas for the presence of ECL tumour cells by using silver staining and chromogranin immunohistochemistry. We found evidence of ECL cell-derived tumour cells in 40% of the diffuse gastric carcinomas but no such tumour cells in the intestinal type of gastric carcinoma. This may suggest that diffuse gastric carcinomas, like malignant gastric tumours of the mastomys, are in fact malignant ECLomas.

Topics: Carcinoma; Enterochromaffin Cells; Gastric Mucosa; Gastrins; Humans; Receptors, Cholecystokinin; Staining and Labeling; Stomach; Stomach Neoplasms

Forty-five patients with metastatic neuroendocrine tumors were treated with a regimen of etoposide 130 mg/m2/d for 3 days plus cisplatin 45 mg/m2/d on days 2 and 3. Both drugs were given by continuous intravenous infusion. Among 27 patients with well-differentiated carcinoid tumors or islet cell carcinomas, only two partial objective tumor regressions were observed (7%). Among 18 patients prospectively classified as having anaplastic neuroendocrine carcinomas, however, there were nine partial regressions and three complete regressions, an overall regression rate of 67%. For anaplastic disease, the median duration of regression was 8 months (range to 21 months). Tumor response was unrelated to primary site, endocrine hyperfunction, or prior therapy experience. The median survival of all patients with anaplastic tumors was 19 months; this seemed favorable when considering the small experiences with these rare tumors reported in the literature. Toxicity, which was severe for most patients, consisted primarily of vomiting, leukopenia, thrombocytopenia, anemia, alopecia, and neuropathy. The anaplastic neuroendocrine tumor is strongly responsive to therapy with combined etoposide and cisplatin. Patients with undifferentiated carcinomas, originating in typical neuroendocrine tumor sites (small and large bowel, pancreas, and stomach) or of unknown origin, who have consistent histologic findings by light microscopy should be evaluated for this possibility with appropriate immune staining or electron microscopy.

Topics: Adenoma, Islet Cell; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoid Tumor; Carcinoma; Cisplatin; Etoposide; Female; Gastrins; Glucagon; Humans; Hydroxyindoleacetic Acid; Male; Middle Aged; Pancreatic Neoplasms; Prospective Studies; Remission Induction; Survival Rate

Topics: Carcinoma; Gastrins; Humans; Stomach Neoplasms

The trophic effect of gastrin in the intestine has been shown. Fasting gastrin levels of patients with adenomatous polyps or adenocarcinoma and in control subjects were determined (n = 141). The mean value of fasting gastrin of control subjects (n = 75) was 47.1 pg/ml +/- 17.8, of patients with adenomatous polyps (n = 49) 49.8 pg/ml +/- 20.7, of patients with carcinoma (n = 17) 50.1 pg/ml +/- 23.3. Neither in the group of patients with adenomatous polyps nor in the group of patients with carcinoma, fasting gastrin levels were elevated compared to control subjects. Our study indicates that there is no significant difference in fasting gastrin between either group (control subjects, colon polyps and carcinoma).

Topics: Aged; Carcinoma; Colonic Polyps; Colorectal Neoplasms; Fasting; Female; Gastrins; Humans; Male; Middle Aged

The expression of gastrin/cholecystokinin (CCK) peptides and their precursors was examined in 16 medullary carcinomas of the human thyroid. Measurements with libraries of sequence-specific radioimmunoassays before and after enzymatic cleavage of extracts and chromatographic fractions showed that the carcinomas contained 1.7 pmol carboxyamidated CCK/g tissue (median; range 0.6-21.8 pmol/g), 0.9 pmol glycine-extended precursor/g (median; range less than 0.2-2.3 pmol/g) and 2.3 pmol further COOH-terminal-extended proCCK/g (median; range 0.9-6.2 pmol/g). Neither carboxyamidated gastrins nor any progastrins could be measured. Gel and reverse-phase chromatography revealed only small molecular forms, i.e. greater than 90% of the amidated immunoreactivity eluted like non-sulphated CCK-8 or CCK-7. The results show that human medullary thyroid carcinomas synthesize CCK peptides. The predominance of non-sulphated CCK is unusual. Taken together with earlier observations from dogs and pigs, our results raise the possibility that small non-sulphated CCK peptides modulate thyroid C-cell secretion in an autocrine manner.

Topics: Amino Acid Sequence; Carcinoma; Cholecystokinin; Chromatography, Gel; Chromatography, High Pressure Liquid; Gastrins; Humans; Molecular Sequence Data; Peptide Fragments; Protein Precursors; Radioimmunoassay; Thyroid Neoplasms

7 gastrinomes and 1 gastrin-producer complex carcinoma-carcinoid tumor were examined by light and electron microscopical-method and by immunohistochemical method. In six cases, the tumor was in the pancreas or in the wall of duodenum; in two cases its localisation was of extra-gastroenteropancreatic (liver, lymph node). All patients developed Zollinger-Ellison syndrome, three patients bled and one had diarrhea. One patient had other tumors, besides gastrinome, which were characteristic of MEN-I syndrome. By immunohistochemical methods all tumors proved to be gastrin and neuron-specific-enolase positive. In four cases somatostatin positivity, in some cases glucagon, pancreatic polypeptide, S-100 protein, keratin and carcinoembryonal antigen positivity were detected. Relation could not be detected between other polypeptide hormones, produced besides gastrin, and biological behaviour of tumor and clinical symptoms.

Topics: Carcinoid Tumor; Carcinoma; Duodenal Neoplasms; Gastrins; Humans; Pancreatic Neoplasms; Stomach Neoplasms; Zollinger-Ellison Syndrome

The effects of somatostatin on the incidence, number, and histological type of gastric cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine were investigated in Wistar rats. Rats received alternate-day s.c. injections of 100 or 200 micrograms/kg body weight of somatostatin in depot form after 25 weeks of p.o. treatment with the carcinogen. Prolonged administration of somatostatin at both dosages significantly increased the incidence and number of gastric cancers of the glandular stomach in Week 52. Furthermore, somatostatin at 200 micrograms/kg caused a significant increase in the incidence of gastric cancers penetrating the muscle layer or deeper layers. However, somatostatin at both dosages did not influence their histological appearance. Histologically, somatostatin at both dosages significantly elevated the labeling index of gastric cancers but not of the antral mucosa and significantly reduced the gastrin levels. These findings indicate that somatostatin enhances gastric carcinogenesis after N-methyl-N'-nitro-N-nitrosoguanidine treatment and that this effect may be related to its effect in increasing proliferation of gastric cancers and decreasing serum gastrin level.

Topics: Animals; Carcinoma; Cell Division; Gastric Mucosa; Gastrins; Hydrogen-Ion Concentration; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Rats; Rats, Inbred Strains; Somatostatin; Stomach Neoplasms

The effects of cysteamine (2-aminoethanethiol hydrochloride) on the incidence, number and histology of colon tumors induced by azoxymethane (AOM), and on the norepinephrine concentration in the colon wall tissue and the labelling indices of colon mucosa and colon cancers were investigated in Wistar rats. Rats received 10 weekly injections of 7.4 mg/kg body weight of AOM and alternate-day subcutaneous injections of 25 mg/kg of cysteamine in 0.9% NaCl solution until the end of the experiment. At week 40, prolonged administration of cysteamine significantly reduced the incidence and number of colon tumors. Histologically, the adenocarcinomas that did develop in rats treated with cysteamine exhibited high mucin-producing activity. Administration of cysteamine caused significant decreases in the norepinephrine concentration in colon tissue and in the labelling indices of colon mucosa and cancers. Our findings indicate that cysteamine inhibits the development of colon tumors. This action may be related to its effect in decreasing norepinephrine concentration in the colon wall tissues and subsequently in decreasing proliferation of colon cancer cells.

Topics: Adenocarcinoma; Adenoma; Animals; Azoxymethane; Carcinoma; Cell Division; Colon; Colonic Neoplasms; Cysteamine; Gastrins; Male; Norepinephrine; Rats; Rats, Inbred Strains

The growth-regulating effects of pentagastrin, gastrin and the gastrin-receptor antagonist proglumide were investigated in three established cell lines derived from human colorectal carcinomas in vitro and after transplantation into nude mice. In vitro a significant increase of cell growth in the SW 403 cell line incubated with pentagastrin or gastrin was observed. In the Lovo cell line this effect was only detected after synchronization of cell growth. Pentagastrin and gastrin had no effect on the growth of the Ls 174 T cell line. Proglumide reduced cell proliferation in all three cell lines as well as in the L929S cell line derived from fibroblasts, which served as control. After transplantation into nude mice all tumor cell lines increased, Lovo and Ls 174 T as undifferentiated tumor, SW 403 as differentiated. Pentagastrin increased and proglumide decreased growth in SW 403 tumors, whereas no effect was observed on Ls 174 T and Lovo tumors. We therefore conclude that growth of some colorectal carcinomas is regulated by gastrin, but that the effect of proglumide is unspecific rather than related to blockage of gastrin receptors. The growth-regulating effect of gastrin could be due to tumor differentiation.

Topics: Animals; Carcinoembryonic Antigen; Carcinoma; Cell Division; Colorectal Neoplasms; Gastrins; Glutamine; Humans; Mice; Pentagastrin; Proglumide; Receptors, Cholecystokinin; Tumor Cells, Cultured

Eight patients with stomach cancer are described who had also a striking glandular hyperplasia of the fundic mucosa adjacent and remote from the tumor. Five of the eight patients were young women (30 to 37 years of age). The tumors were poorly differentiated carcinomas and six of the eight patients have died of their disease. None of the patients had clinical evidence of endocrine dysfunction including the Zollinger-Ellison syndrome. Immunohistochemistry revealed cells with endocrine differentiation in five of eight tumors, and in two tumors gastrin producing cells were found. Five of seven patients showed increased numbers of antral G-cells. In two patients numerous endocrine (chromogranin-positive) cells were present in the fundic mucosa, specific products of which could not be identified with the antigens tested. No satisfactory explanation exists for this coincidence and its apparent predominance in young female patients. It may be that endocrine substances are responsible for this fundic hyperplasia and that they may also act as promotors of tumor growth.

Topics: Adult; Carcinoma; Female; Gastric Fundus; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Immunohistochemistry; Male; Middle Aged; Sex Factors; Stomach Neoplasms

One hundred patients with gastric carcinoma resected surgically were studied by PAP immunoperoxidase and ultrastructural method. It was found that the tumor cells were positive for gastrin, serotonin, somatostatin as well as argyrophil particles in 19 patients. In these 19 patients, the quantity of endocrine tumor cells surpassed half of its total cancer cells in 4, leading to a separate entity of neuroendocrine gastric carcinoma. The authors hope to introduce this new subtype into the classification of gastric carcinoma. Among the 100 cases, 50 patients with undifferentiated carcinomas contained the NE cells in 16 (32%), the remains for high differentiated adenocarcinomas had the NE cells in 3 (6%) only. It was suggested that the appearance of NE tumor cells was closely correlated to differentiation of gastric carcinoma. This study theoretically demonstrated the heterogenicity of gastric carcinoma and supported the theory that different kinds of tumor cells (endocrine and nonendocrine) may have a common origin and are derived from the endoembryogenetic immature precursor cells.

Topics: Adenocarcinoma; Carcinoma; Gastrins; Humans; Immunohistochemistry; Neurosecretion; Serotonin; Somatostatin; Stomach Neoplasms

Serum concentration of gastrin determined by radioimmunoassay in 90 consecutive patients who underwent colonoscopy, and serum levels of gastrin in patients with colorectal neoplasia and controls were compared. Based on clinical history, findings of colonoscopy, and pathologic examinations of biopsies, 80 patients were considered eligible for the study. Serum levels of gastrin in 36 controls were 54.1 +/- 13.1 pg/ml and did not differ from serum levels of gastrin in 44 patients with colorectal neoplasia. There was also no significant difference in serum levels of gastrin among 28 patients with adenomas and 16 patients with carcinoma. The present study disclosed that carcinogenesis of the colon and rectum was not associated with hypergastrinemia.

Topics: Adenoma; Carcinoma; Colorectal Neoplasms; Female; Gastrins; Humans; Male; Middle Aged

Human gastrin-releasing peptide (GRP) mRNA was detected in the tumor tissues of medullary thyroid carcinomas and small cell lung carcinomas using synthetic oligodeoxyribonucleotides as hybridization probes. The amount of GRP mRNA was estimated by radiodensitometric hybridization assay. A good correlation was found between the amount of GRP mRNA and the concentration of immunoreactive GRP in the tumor tissues.

Topics: Carcinoma; Carcinoma, Small Cell; Densitometry; Gastrin-Releasing Peptide; Gastrins; Humans; Immunologic Techniques; Lung Neoplasms; Nucleic Acid Hybridization; Oligodeoxyribonucleotides; Peptides; Radioimmunoassay; RNA, Messenger; Thyroid Neoplasms

The heterogeneity of gastrin-containing G cells present in human gastric mucosa has been examined immunohistochemically. Calcitonin gene-related peptide (CGRP), calcitonin and human chorionic gonadotropin (hCG)-immunoreactivity were detected in about 500, 20 and 10 cells pro 1,000 G cells, respectively, these findings supporting the "one cell, multi-hormone theory". Gastrin, calcitonin immunoreactive tumor cells were demonstrated in 13%, 3% of the antral adenocarcinomas and 17% and 10% of antral endocrine tumors, but they were not found in fundic adenocarcinomas and endocrine tumors. Cell hybridization between the tumor cell and the G-cell might be a possible mechanism for the occurrence of gastric and calcitonin in the gastric tumors. HCG-immunoreactive tumor cells were detected in 27% of antral adenocarcinomas, and in 24% of the fundic adenocarcinomas, and the production of hCG by gastric tumor cells might be based on the gene expression during carcinogenesis, regardless of the tumor localization.

Topics: Adenocarcinoma; Calcitonin; Calcitonin Gene-Related Peptide; Carcinoma; Chorionic Gonadotropin; Duodenal Ulcer; Gastric Mucosa; Gastrins; Humans; Immunochemistry; Neuropeptides; Pyloric Antrum; Stomach Neoplasms

A somatostatin analog (SMS 201-995) was used to treat symptomatic patients with a residual tumor burden of gastrinoma or medullary thyroid carcinoma and pathologic elevations of circulating marker peptides associated with these neuroendocrine tumors. Possible inhibitory effects of the analog on marker peptides, patients' symptoms, or tumor progression were studied in a dose-response protocol and during several months of self-injection of SMS 201-995. Both patients reported remarkable relief of secretory diarrhea and other symptoms, and serum gastrin was successfully suppressed by increasing doses of the analog. However, no effect was seen in reduction of hypercalcitoninemia. Morphologic imaging of residual tumor showed no progression of medullary thyroid carcinoma during treatment and, in the case of hepatic gastrinoma metastases, remarkable tumor regression was confirmed. No toxicity or glucose intolerance was experienced. Somatostatin analog shows promise for palliative management of endocrinologic symptoms due to neuroendocrine tumors, and an inhibitory effect can be measured in some but not all peptide markers. Further evidence of its negative trophic effect on tumor blood flow may suggest an antineoplastic potential, as well as palliative use of this new treatment.

Topics: Adult; Antineoplastic Agents; Calcitonin; Carcinoma; Dose-Response Relationship, Drug; Drug Evaluation; Female; Gastrins; Humans; Male; Octreotide; Palliative Care; Postoperative Care; Somatostatin; Thyroid Neoplasms; Zollinger-Ellison Syndrome

Topics: Animals; Carcinoma; Gastrins; Gastrointestinal Hormones; Gastrointestinal Neoplasms; Humans; Neoplasms, Hormone-Dependent; Pancreatic Neoplasms; Pentagastrin; Receptors, Cell Surface

The effects of synthetic [Asu1,7]-eel calcitonin (0.5 MRC unit/kg body weight intravenously for 30 min) on circulating levels of human calcitonin, calcium and gastrin were investigated in five patients with medullary carcinoma of the thyroid. Blood samples were obtained before and 15, 30, 60, 90, 120 and 180 min after commencement of infusion of [Asu1,7]-eel calcitonin. Plasma levels of human calcitonin were measured by radioimmunoassay. Cross-reactivity with [Asu1,7]-eel calcitonin in this assay was negligible. On infusion of [Asu1,7]-eel calcitonin, the mean plasma level of human calcitonin decreased significantly to 71.0 +/- 8.7% of the basal level (mean +/- SEM, P less than 0.05) after 30 min and 68.4 +/- 25.4% of the basal level (P less than 0.05) after 60 min. The serum calcium level also decreased significantly, but lagged behind the decrease of human calcitonin, being 95.1 +/- 0.7% of the basal level (P less than 0.01) at 120 min and 94.8 +/- 0.6% of the basal level (P less than 0.02) at 180 min. The mean plasma gastrin level did not change significantly on infusion of [Asu1,7]-eel calcitonin. In pooled data for all times, the percentage change in human calcitonin was not significantly correlated with either the percentage change in calcium (r = -0.25, P greater than 0.1) or the percentage change in gastrin (r = -0.38, P greater than 0.1).

Topics: Adolescent; Adult; Aged; Animals; Calcitonin; Calcium; Carcinoma; Eels; Female; Gastrins; Humans; Male; Thyroid Neoplasms

Twenty medullary carcinomas of the thyroid gland were examined for the presence of immunoreactive calcitonin, thyroglobulin, glucagon, keratin, gastrin/CCK, carcinoembryonic antibody (CEA), insulin, serotonin, adreno-corticotropic hormone (ACTH), prostatic acid phosphatase, and somatostatin using the immunoperoxidase peroxidase-antiperoxidase technique. In addition, they were stained with mucicarmine, alcian blue/periodic acid-Schiff (PAS), Grimelius, Congo red, crystal violet, and Fontana-Masson stains. Calcitonin-immunoreactive cells were absent in one tumor and present in 19 tumors (95%). Thyroglobulin was present in seven tumors (35%). Twenty tumors contained CEA-immunoreactive cells (100%). Fourteen cases were immunoreactive to serotonin (70%) and 12 were positive for somatostatin (60%). Glucagon- and gastrin/CCK-immunoreactive cells were found in two cases each (10%). Four tumors (20%) contained ACTH-immunoreactive cells and three cases (15%) were positive for prostatic acid phosphatase. Five cases (25%) contained keratin-immunoreactive cells. One case was immunoreactive to insulin (5%). Grimelius-positive cells were present in 19 of the cases (95%). Mucin-containing cells were present in 65% of the cases. The validity of the immunocytochemical localizations was tested by specific absorption of each antibody with the corresponding antigen. The demonstration of immunoreactivity for multiple antigens in each of the 20 cases suggests that the origin of medullary thyroid carcinomas is from a neuroendocrine cell potentially capable of producing numerous hormone substances. In addition, as the neoplastic cells in 35% of the tumors contained hormonal substances as well as thyroglobulin, it is suggested that papillary or follicular tumors mixed with a neuroendocrine component exist more commonly than previously suspected. Finally, psammoma bodies might be present in pure medullary carcinoma of the thyroid gland.

Topics: Acid Phosphatase; Adrenocorticotropic Hormone; Aged; Calcitonin; Carcinoembryonic Antigen; Carcinoma; Female; Gastrins; Glucagon; Humans; Lymphatic Metastasis; Male; Middle Aged; Mitosis; Serotonin; Somatostatin; Staining and Labeling; Thyroglobulin; Thyroid Neoplasms

In eight of 10 patients with Zollinger-Ellison syndrome resection of all visible tumor tissue was combined with gastrectomy. The results in this group of patients, as in other series reported in the literature, suggest that excision of gastrinoma by partial pancreatectomy or enucleation can be combined safely with gastrectomy. Perhaps excision of tumor is preferable in the management of patients with solitary tumor who do not have the multiple endocrine neoplasia syndrome. We await further follow-up studies and experience with additional patients before judging this thesis of tumor resection with gastric preservation.

Topics: Adenoma; Adult; Aged; Carcinoma; Female; Gastrectomy; Gastric Acid; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatectomy; Zollinger-Ellison Syndrome

A human gastric carcinoma cell line TMK-1 was established in vitro by the soft agar method from SC-6-JCK, a poorly differentiated adenocarcinoma xenotransplanted in nude mice. TMK-1 cells had a doubling time of approximately 35 hr and showed carcinoembryonic antigen (CEA), alpha 1-antitrypsin and secretory component immunoreactivity. Ultrastructurally, the tumor cells were characterized by numerous mitochondria, tubulovesicles and intracytoplasmic canaliculi filled with abundant microvilli. The growth of TMK-1 cells was promoted by 10nM human gastrin (G-17), 2 microM tetragastrin or 2 microM pentagastrin, among which human gastrin showed the most effective growth promotion. Moreover, incorporation of [3H]thymidine into TMK-1 cells was stimulated by gastrin in a dose-dependent manner. The content of cyclic adenosine 3',5'-monophosphate (cAMP) in TMK-1 cells was increased by gastrin treatment but decreased to the control level within 10 min. cAMP-dependent protein kinase was also activated by gastrin administration.

Topics: Carcinoma; Cell Cycle; Cell Line; Cyclic AMP; DNA, Neoplasm; Dose-Response Relationship, Drug; Gastrins; Humans; Microscopy, Electron; Protein Kinases; Stomach Neoplasms; Time Factors

Gastrin-releasing peptide, the mammalian counterpart of amphibian bombesin, has been found to be present in high concentration by radioimmunoassay in eight histologically confirmed medullary thyroid carcinomas and to be undetectable in postmortem normal thyroid tissue. Chromatographic analysis of the tumor extracts by gel permeation revealed two major peaks of gastrin-releasing peptide-like immunoreactivity (GRP-LI). However, reverse-phase high-pressure liquid chromatography demonstrated three immunoreactive peaks of GRP-LI. None of these immunoreactive peaks was coeluted with synthetic porcine GRP or amphibian bombesin, but one of the peaks exactly emerged in the position of neuromedin C (C-terminal decapeptide of GRP). Sections from nine primary or secondary tumours were immunostained for GRP using a peroxidase/anti-peroxidase technic. All the medullary thyroid carcinomas were shown to contain GRP-LI, specifically localized to the tumor cells. This immunoreactivity is elevated in plasma from some patients with this malignancy, raising the possibility that it may be used as an additional tumor marker.

Topics: Carcinoma; Chromatography, Gel; Chromatography, High Pressure Liquid; Gastrin-Releasing Peptide; Gastrins; Humans; Immunochemistry; Peptides; Radioimmunoassay; Thyroid Gland; Thyroid Neoplasms

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

Glicentin-containing cells (Glic. cells) in intestinal metaplasia, adenoma and carcinoma of the stomach were examined using immuno-histochemical techniques. Glic. cells first occurred in the gastric mucosa of the transitional area between metaplastic and intact gastric glands. They frequently showed hyperplasia or micronoduli in the budding area of the deeper metaplastic glands, but in completely intestinalized mucosa these endocrine cells decreased remarkably. Gastric adenomas with mild dysplasia had a good number of glicentin-immunoreactive cells which were located in the deeper adenoma glands. Gastrin- and somatostatin-positive cells were also detected in the adenomas. The incidence of glicentin-positive tumor cells was significantly higher in well differentiated adenocarcinoma than in poorly differentiated adenocarcinoma. Among the seven cases of scirrhous argyrophil cell carcinoma, three showed glicentin- and glucagon-immunoreactivity in the same area of the tumor. These findings suggest that the selective increase of Glic. cells in intestinal metaplasia may be closely related to the development of gastric adenoma. Glicentin positive tumor cells in gastric carcinomas can be regarded to be an expression of intestinal or fetal markers.

Topics: Adenoma; Carcinoma; Gastrins; Glucagon; Growth Hormone-Releasing Hormone; Hormones, Ectopic; Humans; Intestinal Mucosa; Intestines; Metaplasia; Proglucagon; Protein Precursors; Stomach Neoplasms

The effects of gastrointestinal hormones on gastric carcinomas were examined in vitro and in vivo. In five of seventeen cases of human gastric carcinomas, the uptake of 14C-leucine into the tumor tissue in organ culture was enhanced by 10 micrograms/ml of gastrin. Also, in four of thirteen cases of human gastric carcinomas, the production of 14C-labelled proteins in medium was increased by gastrin. All the cases in which protein synthesis was enhanced by gastrin were histologically poorly differentiated adenocarcinomas. The effects of gastrin and secretin on the growth of gastric carcinoma, which was serially transplanted in athymic mice, were examined. The doubling time of the tumor was 7.1 days. The doubling time was shortened to 4.1 days by daily administration of 250 micrograms/kg of gastrin. This topic effect of gastrin on gastric carcinoma was inhibited by 100 U/kg of secretin. These results showed that the growth and protein synthesis of gastrointestinal tumor may be regulated by gastrointestinal hormones.

Topics: Adenocarcinoma; Animals; Carcinoma; Cell Division; Gastrins; Humans; Leucine; Mice; Mice, Nude; Neoplasm Proteins; Neoplasm Transplantation; Secretin; Stomach Neoplasms

The case of a patient with small-cell carcinoma of the lung, bone marrow metastases, and hypertrophic pulmonary osteoarthropathy is reported. Normal growth hormone serum concentrations contrasted with significant increases in ACTH, beta-MSH, calcitonin, and gastrin. A hormonal etiology has previously been suggested for hypertrophic pulmonary osteoarthropathy. Our findings indicate that the hormone responsible for hypertrophic pulmonary osteoarthropathy may be an APUD polypeptidic substance, that differs from immunoreactive GH but is related to somatomammotropins.

Topics: Adrenocorticotropic Hormone; Aged; Calcitonin; Carcinoma; Gastrins; Humans; Lung Neoplasms; Male; Melanocyte-Stimulating Hormones; Osteoarthropathy, Secondary Hypertrophic

Rats transplanted with medullary thyroid carcinoma (MTC) were divided into 3 groups which received for 34 weeks diets with low (0.09%), medium (0.40%) or high (1.80%) calcium content with a calcium/phosphate ratio 2:1. After 6 weeks the different calcium regimens produced corresponding variations in serum calcium and inverse changes in serum magnesium. No alterations in serum proteins were observed. Serum immunoreactive calcitonin (iCT) was unaltered until week 28 of the experiment, but thereafter increased rapidly by about 4-fold. No difference in serum iCT was observed between the 3 groups at any time. Immunoreactive serum gastrin was reduced in rats on medium and low calcium diet compared to those on a high calcium diet. After 28 weeks, when serum iCT was rising, gastrin values fell in rats on high calcium diet to levels approaching those in the other groups. With increased serum iCT (weeks 28-34) serum gastrin concentrations were low and equal in the 3 groups despite different serum calcium concentrations. Electronmicroscopic examination of tumors from the various diet groups did not reveal significant ultrastructural differences.. low, medium and high calcium intake gave corresponding changes in serum calcium. Diet-induced hypercalcaemia was not normalized by elevated serum iCT. In contrast, serum immunoreactive gastrin maintained by high calcium diet was suppressed by hypercalcitonaemia.

Topics: Animals; Calcitonin; Calcium; Calcium, Dietary; Carcinoma; Cytoplasmic Granules; Female; Gastrins; Neoplasm Transplantation; Neoplasms, Experimental; Rats; Thyroid Neoplasms

In 3 patients with medullary thyroid carcinoma, plasma calcitonin levels showed 3 distinct peaks associated with a simultaneous rise in plasma gastrin after each meal. It is suggested that endogenous gastrin secreted following food intake stimulated the calcitonin secretion from the tumor. The peak of the plasma calcitonin secretion after the evening meal was less prominent than that for breakfast or lunch, while no significant differences were observed in peak values in plasma gastrin after each meal. The reason for this discrepancy remains to be clarified.

Topics: Adult; Aged; Calcitonin; Carcinoma; Circadian Rhythm; Eating; Female; Gastrins; Humans; Thyroid Neoplasms

Insulin, proinsulin, glucagon and gastrin were determined in extracts of tumors of 27 patients with pancreatic islet cell neoplasia of pancreas, in one patient with nesidioblastosis, in extracts of uninvolved portions of the pancreas in 11 of the tumor patients and of 15 control pancreases. Mean insulin concentration in solitary adenomas and in adenomas of patients with adenomatosis was higher than in control pancreases; however, in all but 1 patient the insulin concentration in neoplastic islet tissue was lower than in islet tissue of control pancreas, assuming islet volume is 1% of pancreas. The percentage of proinsulin was elevated in 52% of tumors. Adenoma insulin content correlated with increments of plasma insulin after tolbutamide administration. Insulin and proinsulin concentrations in pancreas uninvolved by tumor were not suppressed. Fasting plasma glucagon was elevated in patients with islet cell adenomatosis and in patients with islet cell carcinoma some of whom had multiple endocrine adenomatosis. The mean concentration of glucagon in tumors was lower than in control pancreases. Elevated concentration of gastrin was found in some adenomas. The data indicate: 1) insulin-secreting islet cell tumors have decreased storage capacity for insulin, 2) elevated concentration of proinsulin in tumors may be due to decreased capacity to store insulin and in some to decreased conversion of proinsulin to insulin as well, 3) tolbutamide stimulates the exaggerated release of a relatively constant fraction of insulin stored in adenomas. 4) solitary adenomas may contain excess amounts of pancreatic hormones in addition to insulin, 5) elevated plasma glucagon in patients with organic hyperinsulinism may indicate malignancy, microadenomatosis or multiple endocrine adenoma syndrome, and 6) chronic hyperinsulinism and hypoglycemia due to adenoma do not suppress insulin and proinsulin content of uninvolved pancreas.

Topics: Adenoma; Adenoma, Islet Cell; Adolescent; Adult; Aged; Antigen-Antibody Reactions; Carcinoma; Female; Gastrins; Glucagon; Humans; Hyperinsulinism; Insulin; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreas; Pancreatic Hormones; Proinsulin; Tolbutamide

Topics: Adenoma; Adult; Aged; Carcinoma; Cell Differentiation; Female; Fluorescent Antibody Technique; Gastric Mucosa; Gastrins; Humans; Male; Middle Aged; Stomach Neoplasms

The number of distribution and the numbers of G cells in the antropyloric region of the rabbit stomach were mapped employing immunoperoxidase localization and morphometric quantitation and compared to similar analyses in hypercalcemic rabbits bearing the VX2 carcinoma. In normal animals, G cells were confined to the lower third of the antropyloric mucosa, where they were randomyly distributed within the mucosal glands. In contrast, tumor-bearing animals showed an extension of these cells into the middle third of the antropyloric mucosa. The absolute counts of G cells in control rabbits were 5.3 +/- 0.78 (mean +/- SE) per unit area, while those in hypercalcemic tumor-bearing rabbits were 11.9 +/- 0.46, a statistically significant increase. It is concluded that rabbits bearing VX2 carcinoma have G-cell hyperplasia.

Topics: Animals; Carcinoma; Cell Count; Female; Gastric Mucosa; Gastrins; Hypercalcemia; Hyperplasia; Immunoenzyme Techniques; Neoplasms, Experimental; Pyloric Antrum; Rabbits

Rats transplanted with medullary thyroid carcinoma (MCT) were followed with radio-immuno assay of serum calcitonin (iCT) using antisera to human CT and I125 labelled calcitonin-M. From the 4th month after transplantation, serum from the tumour rats contained iCT in concentrations 8-10 fold higher than serum from the control rats. The tumour cells had retained their ability to react on pentagastrin and calcium injections with increased CT release. It was further shown that the tumour bearing rats had elevated basal gastrin concentratkons in serum. While calcium injection lead to a rise in the serum gastrin concentration in the control group, the adverse effect was seen in the tumour bearing rats. The morphological features and the responsiveness of the rat tumour cells to physiological secretagogues make this tumour a suitable animal model for the study of interactions between CT and gastro-intestinal factors. It is suggested that the gastrin response to calcium might be of interest also in the diagnosis of human MCT.

Topics: Animals; Calcitonin; Calcium; Carcinoma; Female; Gastric Juice; Gastrins; Neoplasm Transplantation; Neoplasms, Experimental; Pentagastrin; Rats; Secretory Rate; Thyroid Neoplasms; Time Factors

Angiographic findings in one giant cell carcinoma, one cystadenocarcinoma, one poorly vascularized mucinous cystadenocarcinoma, as well as in two avascular (gastrin- and glucagon-producing) islet-cell tumors of the pancreas are described. Two hypervascularized islet-cell tumors are presented for comparison and a case of tumorous chronic pancreatitis in a child is reported because ot its rarity. The aggressiveness of the giant cell carcinoma of the pancreas was demonstrated by its expansive growth. In the case of cystadenocarcinoma angiography revealed the tumor with hepatic metastases not diagnosed at explorative laparotomy. The relative hypovascularity in the case of mucinous cystadenocarcinoma was unusual. Both avascular islet-cell tumors simulated a pancreatic pseudocyst and the final diagnosis was made only by immunoassay. Chronic pancreatitis in a child presented with marked hypervascularization.

Topics: Adenoma, Islet Cell; Adult; Aged; Angiography; Carcinoma; Celiac Artery; Chronic Disease; Contrast Media; Cystadenoma; Diagnosis, Differential; Female; Gastrins; Glucagon; Hepatic Artery; Humans; Male; Middle Aged; Pancreatic Cyst; Pancreatic Neoplasms; Pancreatitis; Zollinger-Ellison Syndrome

Plasma hCT levels were less than 50 pg/ml in 50 normal subjects. In 16 patients with medullary carcinoma of the thyroid (MCT), plasma hCT levels were distinctively elevated and they fell significantly after total thyroidectomy, but in 11 of them plasma levels were still high, indicating the presence of metastases. In 74 patients with the other types of malignancy, plasma hCT levels were found to be high in 9 cases (3 oat cell carcinoma of the lung, 4 malignant carcinoids, one malignant pheochromocytoma and one acute myelocytic leukemia). Except for the leukemic case, all these tumors were derived from neural crest. In 12 patients with primary hyperparathyroidism, plasma hCT levels were less than 20 pg/ml. In 13 hypoparathyroid patients, two with pseudohypoparathyroidism and one with pseudoidiopathic hypoparathyroidism, plasma hCT levels were slightly elevated. Some patients with uremia had elevated plasma hCT levels, but there was no relation between plasma levels of hCT and those of PTH, urea nitrogen or creatinine. In response to Ca (4.5 mg/kg/10 min) or tetragastrin (4 mug/kg/5 min) infusion, a marked increase in plasma hCT was observed in all patients with MCT, but not in normal subjects. In 5 hypoparathyroid patients, a significant increase to both stimuli was also observed in all cases. Two patients with pseudopseudohypoparathyroidism responded to the Ca load. These results indicate that the determination of plasma hCT levels especially after a short Ca or tetragastrin infusion is important to study various pathological conditions.

Topics: Calcitonin; Calcium; Carcinoma; Carcinoma, Small Cell; Cross Reactions; Dose-Response Relationship, Drug; Gastrins; Humans; Hyperparathyroidism; Infusions, Parenteral; Lung Neoplasms; Thyroid Neoplasms; Thyroidectomy

We have compared the effects of oral and intravenous ethanol on the secretion of both thyrocalcitonin and gastrin in five patients with medullary carcinoma of the thyroid. Ethanol caused a moderate rise in plasma thyrocalcitonin to 316% +/- 343% of baseline when given intravenously and to 197% +/- 106% of baseline when given orally. Only oral ethanol caused a measurable rise in serum gastrin levels. Serum calcium did not change significantly from baseline during either oral or intravenous administration. The results suggest that stimulation of thyrocalcitonin secretion by ethanol is not secondary to increased secretion of gastrin nor to the induction of hypercalcemia. Neither oral nor intravenous ethanol appears to be as effective as intravenous pentagastrin in testing for the presence of medullary carcinoma.

Topics: Administration, Oral; Calcitonin; Carcinoma; Ethanol; Female; Gastrins; Humans; Injections, Intravenous; Male; Middle Aged; Pentagastrin; Thyroid Gland; Thyroid Neoplasms

Topics: Carcinoma; Female; Gastric Juice; Gastric Mucosa; Gastrins; Humans; Iodine Isotopes; Male; Middle Aged; Radioimmunoassay; Secretory Rate; Stomach Neoplasms

Topics: Adolescent; Adult; Aged; Animals; Calcitonin; Carcinoma; Chickens; Depression, Chemical; Female; Gastrins; Guinea Pigs; Humans; Immune Sera; Iodine Isotopes; Male; Middle Aged; Radioimmunoassay; Stimulation, Chemical; Thyroid Neoplasms; Zollinger-Ellison Syndrome

Thirty specimens of stomach, duodenum, and jejunum, removed at operation, were examined by optical microscopical, cytochemical, and electron microscopical techniques. The overall distribution of four types of endocrine polypeptide cell in the stomach, and three in the intestine, was determined. The seven cell types are described by names and letters belonging to a scheme for nomenclature agreed upon at the 1969 Wiesbaden conference on gastrointestinal hormones. The gastrin-secreting G cell was the only cell for which firm identification with a known hormone was possible. Although there was wide variation in the distribution of the various cells, from one case to another, striking differences were nevertheless observable, with respect to the G cell, between antra from carcinoma and from ulcer cases.

Topics: Bile Duct Neoplasms; Carcinoma; Duodenal Ulcer; Duodenum; Fluorescent Antibody Technique; Gastric Mucosa; Gastrins; Gastrointestinal Hormones; Humans; Jejunum; Microscopy; Microscopy, Electron; Peptides; Placenta; Stomach; Stomach Neoplasms

Topics: Adult; Carcinoma; Computers; Female; Gastric Acidity Determination; Gastric Juice; Gastrins; Gastritis; Humans; Male; Middle Aged; Peptides; Pyrazoles; Statistics as Topic; Stimulation, Chemical; Stomach Neoplasms; Stomach Ulcer

Topics: Aged; Blood Glucose; Bronchial Neoplasms; Carcinoma; Coronary Disease; Gastrins; Humans; Insulin; Liver Cirrhosis; Middle Aged; Osteochondritis; Peptides

Topics: Adenocarcinoma, Scirrhous; Carcinoma; Cats; Duodenal Ulcer; Duodenum; Gastric Mucosa; Gastrins; Histamine; Physiology; Stomach Neoplasms; Stomach Ulcer