gastrins and Carcinoma--Squamous-Cell

Topics: Animals; Carcinoma, Squamous Cell; Cell Line, Tumor; Female; Gastrins; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Receptor, Cholecystokinin B; Receptors, Peptide; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Minigastrin radiotracers, such as [(111)In-DOTA]MG0 ([(111)In-DOTA-DGlu(1)]minigastrin), have been considered for diagnostic imaging and radionuclide therapy of CCK2R-positive human tumors, such as medullary thyroid carcinoma. However, the high kidney retention assigned to the pentaGlu(2-6) repeat in the peptide sequence has compromised their clinical applicability. On the other hand, truncated des(Glu)(2-6)-analogs, such as [(111)In-DOTA]MG11 ([(111)In-DOTA-DGlu(10),desGlu(2-6)]minigastrin), despite their low renal uptake, show poor bioavailability and tumor targeting. [(111)In]CP04 ([(111)In-DOTA-DGlu(1-6)]minigastrin) acquired by Glu(2-6)/DGlu(2-6) substitution showed promising tumor-to-kidney ratios in rodents. In the present study, we compare the biological profiles of [(111)In]CP04, [(111)In-DOTA]MG11, and [(111)In-DOTA]MG0 during in situ neutral endopeptidase (NEP) inhibition, recently shown to improve the bioavailability of several peptide radiotracers. After coinjection of the NEP inhibitor, phosphoramidon (PA), the stability of [(111)In]CP04 and [(111)In-DOTA]MG0 in peripheral mouse blood increased, with an exceptional >14-fold improvement monitored for [(111)In-DOTA]MG11. In line with these findings, PA treatment increased the uptake of [(111)In]CP04 (8.5 ± 0.4%ID/g to 16.0 ± 2.3%ID/g) and [(111)In-DOTA]MG0 (11.9 ± 2.2%ID/g to 17.2 ± 0.9%ID/g) in A431-CCK2R(+) tumors at 4 hours postinjection, whereas the respective increase for [(111)In-DOTA]MG11 was >6-fold (2.5 ± 0.9%ID/g to 15.1 ± 1.7%ID/g). Interestingly, kidney uptake remained lowest for [(111)In-DOTA]MG11, but unfavorably increased by PA treatment for [(111)In-DOTA]MG0. Thus, overall, the most favorable in vivo profile was displayed by [(111)In-DOTA]MG11 during NEP inhibition, highlighting the need to validate this promising concept in the clinic.

Topics: Animals; Carcinoma, Squamous Cell; Gastrins; Glycopeptides; Humans; Mice; Mice, SCID; Neprilysin; Protease Inhibitors; Radionuclide Imaging; Radiopharmaceuticals; Tissue Distribution; Tumor Cells, Cultured

A promoting effect of gastrin on stimulating Barrett's oesophagus proliferation has been demonstrated, but whether it plays a regulating role for esophageal squamous cell carcinoma (ESCC) to date has not been fully investigated. The aim of this study is to examine the expressions of gastrin, gastrin precursors and gastrin/CCK-2 receptor in ESCC. Tissue specimen sections from 38 patients with ESSC obtained from a high incidence area of north China were assessed using immunohistochemistry for amidated gastrin, gastrin precursors (progastrin and glycine-extended gastrin) and gastrin/CCK-2 receptors. Their clinical histopathological significance was also analyzed. Of 38 ESCC, the immunoreactivities of gastrin, glycine-extended gastrin and progastrin were observed in 13.2% (5/38), 7.9% (3/38) and 23.68% (9/38) cases. The expression of progastrin was obviously higher than other gastrins, though not significantly (P > 0.05). In positive cases for gastrin or glycine-extended gastrin, the scores of positive tumor cell numbers were at a lower density (<10/abundant-distributed field). However, the scores of progastrin positive tumor cell density in five of nine positive cases were over 10/abundant-distributed field. The immunoreactivity of gastrin/CCK-2 receptor was also observed in 15.8% (6/38) ESCC cases. There was not significant correlation regarding immunohistochemical results with known histomorphological parameters i.e. gender, tumor location and TNM stages. Based on our current results, ESCC tumor cells could be a possible cellular source of gastrin precursors, which has been postulated to play a role in regulating the growth in some human tumor cells.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Esophageal Neoplasms; Female; Gastrins; Humans; Immunohistochemistry; Male; Middle Aged; Neoplasm Staging; Protein Precursors; Receptor, Cholecystokinin B

The less processed forms of gastrin have recently been shown to act as trophic factors for both normal and malignant colonic cells. Although incompletely processed forms of gastrin such as glycine-extended gastrin and progastrin are also expressed in human lung cancers, the clinical significance of this expression has not been addressed. Consequently, we investigated the effects of overexpression of glycine-extended gastrin in a mouse strain that is prone to developing lung cancer and also examined the expression of incompletely processed gastrins in primary human lung cancers. We found that transgenic overexpression of glycine-extended gastrin in FVB/N mice resulted in a significant increase in the prevalence and growth of bronchoalveolar carcinoma. In addition, a substantial subset of human lung cancers was found to express progastrin and/or glycine-extended gastrin. Overexpression of glycine-extended gastrin by human lung cancers was associated with a significantly decreased survival. Taken together, these results suggest that glycine-extended gastrin may play a role in the growth and progression of some human lung cancers.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Animals; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cell Division; Gastrins; Glycine; Humans; Lung Neoplasms; Mice; Mice, Transgenic; Middle Aged; Prognosis; Survival Analysis; Time Factors

Mechanisms by which premalignant Barrett's metaplasia (BM) progresses to esophageal adenocarcinoma are currently being sought. This study investigated the role played by the polypeptide hormone gastrin, specifically its antiapoptotic effects through activation of protein kinase B/Akt (PKB/Akt). In esophageal cell lines with low basal levels of activated PKB/Akt, phosphorylation could be induced by exogenous amidated gastrin. High basal levels of activated PKB/Akt were linked to endogenous gastrin expression and were reduced by treatment with a cholecystokinin-type 2 receptor (CCK-2R) antagonist. Expression of a constitutively active splice variant of the CCK-2R additionally increased basal activation of PKB/Akt. It is proposed that gastrin acting in an autocrine and endocrine manner via a CCK-2R isoform may activate PKB/Akt and that with expression of gastrin and CCK-2R isoforms increasing in BM samples, gastrin may aid progression of BM through amplification of antiapoptotic pathways. Evidence for this proposal was provided through the observed specific up-regulation of PKB/Akt in BM samples.

Topics: Adenocarcinoma; Apoptosis; Barrett Esophagus; Benzodiazepines; Carcinoma, Squamous Cell; Esophageal Neoplasms; Esophagus; Gastrins; Hormone Antagonists; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Receptor, Cholecystokinin B; Tumor Cells, Cultured

In our inbred strain of cotton rats (Sigmodon hispidus) 50% of the females develop spontaneous ECL cell-derived tumors in the acid-producing part of the stomach due to hypergastrinemia secondary to gastric hypoacidity. Although the mechanism behind the hypoacidity is unknown, the female cotton rat is an excellent model for studying ECL cell-related tumorigenesis. In this study we wanted to explore the malignancy potential of these tumors and the ability of a gastrin receptor antagonist (YF476) to prevent their development. First, nine hypergastrinemic female cotton rats (10 months of age) were diagnosed by laparotomy as having gastric tumors. They were killed 6 months later. Second, 18 female cotton rats (2 months of age) were dosed monthly for 6 months with YF476 (500 micro mol/kg body wt) by s.c. injection, while 21 age-matched animals received vehicle. Samples from each stomach were collected for histology, immunohistochemistry and northern blot analysis. The gastric tumors harbored cells with immunohistochemical features of ECL cells. The tumors were found at times to invade and penetrate the stomach wall and to metastasize to perigastric sites. ECL-derived tumor cells were discovered in peritoneal fluid. At death only 1 out of 18 animals given YF476 displayed carcinomas (invasive growth), compared with 7 out of 21 in the vehicle dosed control group (P = 0.048). The spontaneous gastric tumors in cotton rats derived from ECL cells. The tumors were able to penetrate the stomach wall and to metastasize by intracavital seeding. Gastrin receptor blockade lowered the incidence of such tumors. We propose that the tumors are ECL cell carcinomas and that gastrin is the driving force behind the transformation from normal to malignant ECL cells.

Topics: Animals; Blotting, Northern; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Enterochromaffin-like Cells; Female; Gastrins; Immunohistochemistry; Liver; Mucous Membrane; Neoplasm Metastasis; Rats; Receptor, Cholecystokinin B; RNA, Messenger; Sigmodontinae; Time Factors

To evaluate the value of detection of 4 tumor markers(CEA, CA125, gastrin, and NSE) for histological types in patients with lung cancer and to improve the predicted efficiency of tumor markers for distinguishing between small cell lung cancer(SCLC) and non-small cell lung cancer (NSCLC), these 4 tumor markers in serum were determined in 51 patients (21 cases with SCLC, 30 cases with NSCLC) with confirmed primary diagnosis of lung cancer of different histology by radioimmunoassay. Linear learning machine method, PRIMA method and KNN method were used to classify SCLC and NSCLC. The levels of gastrin and NSE in SCLC were apparently higher than those of gastrin and NSE in NSCLC, but the levels of CEA and CA125 in SCLC were significantly lower than those in NSCLC. Smoking had an effect on the levels of CEA and CA125, but had little effect on those of gastrin and NSE. The total accuracy of the three methods was over 85% in distinguishing SCLC from NSCLC. So combined detection of the four tumor markers in serum might be useful in the prediction of histological types in patients with lung cancer.

Topics: Adenocarcinoma; Aged; Biomarkers, Tumor; CA-125 Antigen; Carcinoembryonic Antigen; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Gastrins; Humans; Lung Neoplasms; Male; Middle Aged; Phosphopyruvate Hydratase

Progastrin-releasing peptide (proGRP) is a specific tumor marker in patients with small cell lung carcinoma (SCLC). It has been reported that serum proGRP levels rarely are elevated in patients with nonsmall cell lung carcinoma (NSCLC); the reported frequency is <3%. The purpose of this study was to examine the clinicopathologic features of NSCLC patients with high serum proGRP levels.. The authors measured serum proGRP levels with a TND-4 kit, a newly developed enzyme-linked immunoadsorbent assay, in 544 NSCLC and 206 SCLC patients. Pathologic features were examined using conventional hematoxylin and eosin staining and histochemical and immunohistochemical staining using polyclonal antibodies to proGRP, chromogranin A, calcitonin, and monoclonal antibody to the neural cell adhesion molecule (NCC-Lu-243).. The serum proGRP levels were elevated in 140 SCLC patients (68.0%) and in 23 NSCLC patients (4.2%). Seven of these 23 NSCLC patients had serum proGRP levels > or = 100 pg/mL. They included two patients with renal dysfunction, one patient diagnosed cytologically with adenocarcinoma without undergoing precise pathologic examination, two patients diagnosed histologically with squamous cell carcinoma with foci of small cell elements, and two patients diagnosed with large cell neuroendocrine carcinoma and poorly differentiated adenocarcinoma, respectively, which showed neuroendocrine differentiation on immunohistologic analysis. The remaining 16 NSCLC patients had serum proGRP levels < 70 pg/mL.. Nearly all NSCLC patients had serum proGRP levels < 100 pg/mL. However, if an NSCLC patient presents with a proGRP level > or = 100 pg/mL, the clinicopathologic features must be examined with regard to the small cell component, neuroendocrine differentiation, and renal dysfunction.

Topics: Adenocarcinoma; Adult; Aged; Biomarkers, Tumor; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Enzyme-Linked Immunosorbent Assay; Female; Gastrins; Humans; Lung Neoplasms; Male; Middle Aged; Protein Precursors; Renal Insufficiency

We surgically prepared a hypergastrinemia model in rats and studied the effects of hypergastrinemia on chemically induced carcinogenesis in the esophagus. Operations were performed on 5-week-old male Donryu rats as follows: (1) truncal vagotomy plus pyloroplasty (group V), (2) segmental gastrectomy plus pyloroplasty (group G), (3) antrectomy (group A), and (4) no operation (group C) as a control. From the age of 6 weeks, the animals were given 0.003% N-methyl- N-amylnitrosamine (MAN) solution as drinking water for 8 weeks. After 20 weeks of MAN administration, the animals were bled and killed. The average serum gastrin levels in groups V and G were significantly higher than those groups C or A. There were significant differences between C and V in the incidence of carcinoma, and between V and A in the incidence of carcinoma including severe dysplasia. The incidence of histologically identified lesions per animal was determined, and significant differences were observed between C and both V and G in the incidence of carcinoma including severe dysplasia. Furthermore, we also detected gastrin receptors in the esophageal lesions produced by the oral administration of MAN to rats. The results of the present study suggest that endogenous hypergastrinemia has a positive influence on chemically induced carcinogenesis in the rat esophagus.

Topics: Animals; Carcinogens; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Disease Models, Animal; Esophageal Neoplasms; Gastrins; Male; Nitrosamines; Precancerous Conditions; Rats; Rats, Inbred Strains; Receptors, Cholecystokinin

Peptic ulcers in the gastric tube replacing the resected esophagus develop silently and cause serious problems. In this study, the acidity of the gastric tube was examined by 24-hour pH monitoring to determine if the acidity of the gastric tube was sufficient to cause peptic ulcers.. The acidity of a gastric tube was evaluated by 24-hour pH monitoring of both the fundus and the antrum in 55 patients treated for carcinoma of the esophagus. The correlation between the fasting serum gastrin concentration and the intraluminal acidity of the completely vagotomized gastric tube was examined.. In the patients with high postoperative acidity in the fundus or the antrum (46 percent of the 41 patients examined), the intraluminal pH remained consistently low, even long after operative treatment. Significant correlations existed between the percentage of time that the pH remained below 3 preoperatively and postoperatively in both the fundus and the antrum (r = 0.4777, p = 0.0386, and r = 0.7597, p = 0.0002, respectively). The percentage did not decrease significantly postoperatively. A significantly negative correlation (r = -0.783401, p < 0.0001) was found between the fasting serum gastrin level and the proportion of time that the nocturnal pH in the antrum remained below 3.. Even long after esophagectomy, the pH of the gastric tube is low enough to cause peptic ulcers, especially in patients with high preoperative acidity. In these patients, the intraluminal pH in the antrum of the gastric tube correlates inversely with the fasting serum gastrin level.

Topics: Aged; Carcinoma, Squamous Cell; Esophageal Neoplasms; Esophagectomy; Esophagoplasty; Female; Gastric Acidity Determination; Gastrins; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Monitoring, Physiologic; Stomach

In this study, determination of gastrin concentration in bronchoalveolar lavage fluid and serum has been detected by radioimmunoassay in 30 cases of lung cancer and 24 cases of non-cancer pulmonary diseases. The results show that the gastrin concentration and its positive rate of lavage fluids from cancer lung are much higher than those from healthy lung and serum in lung cancer patients, and those from serum and both disease and healthy lung in non-cancer pulmonary disease patients (P less than 0.01). The gastrin ratio of lavage fluids from cancer lung to serum is also significantly higher than the ratio of lavage fluid from healthy lung to serum and all the ratios in the non-cancer pulmonary disease group. These results suggest that there is a high gastrin concentration in local tissue of lung cancer, which is signified by the high concentration of gastrin and its high positive rate in lavage fluids from the lung with cancer. Therefore, the gastrin determination in lavage fluids and gastrin ratio of lavage fluids to serum are more reliable in the differential diagnosis of benign from malignant pulmonary diseases than gastrin determination of serum alone.

Topics: Adenocarcinoma; Adult; Aged; Bronchoalveolar Lavage Fluid; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Gastrins; Humans; Lung Diseases; Lung Neoplasms; Male; Middle Aged

Serial changes in serum gastrin level were detected by radioimmunoassay in 58 lung cancer patients before and after operation. In comparing these tests with those of 40 cases of noncancerous thoracic lesions and 151 normal adults, the serum gastrin from lung cancer patients is significantly higher than that of noncancerous thoracic lesions and normal individuals (P less than 0.01). The gastrin level is closely related to stage of cancer, size of primary tumor, presence of lymph node metastasis, and type of histological classification. The serum gastrin was found to decrease gradually after the removal of the tumor and to return to normal on the 14th postoperative day. Those patients whose serum gastrin level can return to normal on the 14th postoperative day will have a good prognosis; if not, their prognosis will be very poor. These results suggest that serum from patients with lung cancer contains a high concentration of gastrin that can help differentiate benign from malignant thoracic lesions and evaluate prognosis of patients with lung cancer. Therefore, the cause of high serum gastrin in patients with lung cancer is likely due to the gastrin-producing property of the lung cancer cells.

Topics: Adenocarcinoma; Adult; Aged; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Gastrin-Releasing Peptide; Gastrins; Humans; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Peptides; Postoperative Period; Prognosis; Thoracic Diseases

Elevated plasma gastrin levels have been found in patients with colorectal cancer. We measured fasting serum gastrin levels in control subjects (n = 12), patients with gastric cancer (n = 43), and patients with carcinoma of the esophagus (n = 55). Serum gastrin levels were significantly higher in patients with gastric cancer compared to normal controls (P less than 0.005) and those with esophageal cancer (P less than 0.05). This information may add to our understanding of the pathogenesis of gastric cancer.

Topics: Carcinoma, Squamous Cell; Esophageal Neoplasms; Gastrins; Humans; Pepsinogens; Stomach Neoplasms

Functions of the stomach placed in the posterior mediastinum after esophagectomy were studied in 20 esophageal carcinoma patients. Seven were long-term survivors who lived more than 5 years after operation, and five of them showed normal fasting serum gastrin levels and good or fair gastric acid secretion. Of 13 patients who had their operations within 3 years before the study, 11 showed high fasting serum gastrin levels and poor gastric acid secretion. The hepatobiliary and alimentary scintigrams with double isotopes demonstrated a time lag between the excretion of the food from the stomach and the excretion of bile into the bowels, regardless of the postoperative periods. Absorption of vitamin B12 was normal in patients who lived more than 2 years after operation. The intraluminal pressure and pH studies in long-term survivors showed that our operative technique, the posterior invagination esophagogastrostomy, was effective in preventing a gastroesophageal reflux in the anastomosis.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Esophageal Neoplasms; Esophagogastric Junction; Esophagoscopy; Esophagus; Female; Gastric Acid; Gastric Emptying; Gastrins; Humans; Intestinal Absorption; Liver; Male; Middle Aged; Radionuclide Imaging; Stomach; Thorax; Vitamin B 12

Sixty-eight endometrial carcinomas were examined histochemically and immunohistochemically for the presence of amine-containing or neurohormonal peptide-containing cells, particularly in relation to argyrophil cells. Argyrophil cells, detected in 43 of the 68 endometrial carcinomas by the Grimelius method, were subgrouped into two types according to the distribution of argyrophil granules and the shape of the tumor cells. Type I was found in 7 tumors and type II in 39; 3 tumors contained both cell types. The argyrophilia of type II cells was diminished in varying degrees in some tumors by diastase digestion, although it was unchanged in type I argyrophil cells. Indoleamine was detected by the formaldehyde-induced fluorescence method in type I argyrophil cells of four carcinomas. Immunohistochemically, somatostatin-reactive cells were found in two well-differentiated adenocarcinomas with argyrophilia; many of these cells corresponded to some of the type I argyrophil cells, although some were non-argyrophilic. Two adenosquamous cell carcinomas with type II argyrophil cells also contained cells that were immunoreactive with antisera against gastrin; however, they were non-argyrophilic.

Topics: Adenocarcinoma; Adult; Carcinoma, Squamous Cell; Enterochromaffin Cells; Female; Fluorescence; Gastrins; Histocytochemistry; Hormones; Humans; Immunoenzyme Techniques; Middle Aged; Somatostatin; Uterine Neoplasms

Tyrosine phosphorylation seems to be a key event in the control of cellular growth. Several viral transforming proteins, including the src protein of Rous sarcoma virus, the p120 protein of Abelson leukaemia virus and the middle T antigen of polyoma virus, are phosphorylated by associated tyrosine kinases. The levels of kinase activity correlate with the transforming efficiency of the virus. The receptors for epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and insulin are also phosphorylated by associated tyrosine kinase activities, which are stimulated by EGF, PDGF and insulin, respectively. The EGF-stimulated kinase and the src protein share similar substrate specificity for tyrosines immediately C-terminal to a sequence of acidic amino acids. Such a sequence is also found adjacent to the phosphotyrosine of middle T antigen, and in the homologous region of the hormone gastrin, adjacent to a tyrosine which is sulphated in approximately half the gastrin isolated from gastric mucosa. Reports that gastrin acts as a growth factor for cells of the gastrointestinal tract suggested that phosphorylation of this tyrosine might be physiologically more relevant than sulphation. We report here that synthetic human gastrin 17 is phosphorylated by the EGF-stimulated tyrosine kinase of A431 cell membranes. The Km values of 53-87 and 223-547 microM obtained in the presence and absence of EGF, respectively, are the lowest reported so far for this enzyme.

Topics: Carcinoma, Squamous Cell; Cell Line; Cell Membrane; Chromatography, High Pressure Liquid; Epidermal Growth Factor; Gastrins; Humans; Phosphorylation; Protein Kinases; Protein-Tyrosine Kinases

Topics: Amino Acid Sequence; Carcinoma, Squamous Cell; Cell Line; Cell Membrane; Gastrins; Humans; Kinetics; Peptide Fragments; Phosphorylation; Protein Kinases; Protein-Tyrosine Kinases