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T Lehy

Publications and source records attributed to T Lehy.

At least 37 records · Page 2Linked to original sources
PubMed1996

Transforming growth factor-alpha in vivo stimulates epithelial cell proliferation in digestive tissues of suckling rats.

BACKGROUND: The role that exogenous transforming growth factor-alpha (TGF-alpha) may exert on cell proliferation in vivo is poorly understood. AIM: To investigate the effect of rat TGF-alpha on epithelial cell proliferation in all suckling rat digestive tissues and to compare it with that of rat epidermal growth factor (EGF). ANIMAL AND METHODS: TGF-alpha and EGF were given three times daily either subcutaneously (10 or 20 micrograms/kg) or intraperitoneally (100 micrograms/kg) to rats from the ninth postnatal day. Cell proliferation was assessed through 5-bromo- 2-deoxyuridine incorporation and estimation of labelling indices. RESULTS: For both growth factors, the highest dose given for only two days significantly increased stomach and intestinal weights compared with controls (p < 0.05 to p < 0.001). The proliferative responded depended on the dose given, colonic mucosa being the most sensitive whereas oxyntic mucosa remained unresponsive. TGF-alpha was as potent as EGF in stimulating epithelial cell proliferation in antral, duodenal, and colonic mucosae. However, EGF was more active on oesophageal and jejunal cell proliferation whereas TGF-alpha was more active on pancreatic exocrine cell proliferation and the differences between the two growth factor treated groups were significant. CONCLUSIONS: These results prove for the first time the stimulating effect in vivo of exogenous rat TGF-alpha on epithelial cell proliferation in rat digestive tissues during the developmental period and support a functional role for TGF-alpha at that time.

Animals↗
PubMed1996

[Expression of hepatocyte growth factor and its receptor, C-Met in human digestive tissues and different gastric and colonic cancer cell lines].

OBJECTIVES AND METHODS: Hepatocyte growth factor (HGF) and its receptor c-Met exert mitogene and motogene activities in digestive tissues. The aim of the study was a) to detect and localize these proteins in adult human digestive mucosae, liver and pancreas, using western immunoblotting and immunohistochemistry with anti-HGF and c-Met antibodies and b) to identify the receptor in three digestive cancer cell lines. RESULTS: HGF and c-Met were detected by the two techniques used in esophagus, fundus, antrum, duodenum, cecum, colon and rectum where they were localized in epithelial and sometimes lamina propria cells. HGF and c-Met were also present in hepatocytes, and c-Met in pancreatic endocrine cells. c-Met was identified in human gastric HGT-1 and rat colon DHD/K12 cancer cells. HGF (40 ng/mL) scattered colonies formed by these cells as well as human T84 colon cancer cells. CONCLUSIONS: Our findings demonstrate the presence of HGF and c-Met in all human digestive tissues and are compatible with the implication of HGF in metastatic processes of digestive cancers.

Adult↗
PubMed1995

Developmental expression of transforming growth factor-alpha in the upper digestive tract and pancreas of the rat.

This study was designed to examine the developmental expression and the localization of the transforming growth factor alpha (TGF-alpha) in the upper gastrointestinal tract and pancreas of the rat. Immunohistochemical techniques using an antibody against rat TGF-alpha were performed on the stomach, duodenum and pancreas of fetuses (19 to 21 days of gestation), of pups during the suckling period (days 0 to 13 postpartum) and after weaning (day 25 postpartum) and of adults. The temporal appearance of TGF alpha varied depending on the tissues. In the antral mucosa it likely appeared before 19 days of gestation. In this tissue, the immunostaining was intense from 20 days of gestation and did not decline after birth. In the duodenum, the TGF alpha immunoreactivity was definitely present with a high intensity at 20 days of gestation in villi, crypts and Brünner's glands and there after became irregular. In the fundic mucosa, TGF alpha expression was weak but clearly-established at 21 days of gestation, at least in parietal cells, and regularly increased after birth. In the pancreas, it appeared only after birth and solely in the exocrine gland. The TGF alpha immunoreactivity displayed as age progressed, first a granular pattern apparently confined in the supranuclear, i.e., Golgi area, then a diffuse cytoplasmic pattern. These findings suggest that TGF alpha may have a functional role during the developmental process of the digestive system.

Aging↗
PubMed1994

Developmental expression of transforming growth factor-alpha and epidermal growth factor receptor proteins in the human pancreas and digestive tract.

This study was designed to localize transforming growth factor alpha (TGF-alpha) and epidermal growth factor receptor (EGFR) expression in the developing human gastrointestinal tract and pancreas. Immunohistochemical techniques using specific antibodies against human TGF-alpha and EGFR were performed on digestive tissues of fetuses from 9 to 10 to 24 weeks of gestation, children and adults. In fetuses, TGF-alpha and EGFR proteins were expressed in all epithelial tissues studied with a good correlation and from an age as early as 9 to 10 weeks of gestation, except for TGF-alpha in the esophagus. The strongest TGF-alpha immunostaining was noted in the stomach and the proximal colon. Unexpectedly, immunoreactive gut endocrine cells were observed with the two antibodies used. Relatively numerous in fetuses, they decreased in number with age and were rare in adults particularly along the colon. Enteroglucagonsecreting cells were shown to express TGF-alpha, while some gastrin, somatostatin and pancreatic glucagon cells were immunostained with EGFR antibodies. The presence of TGF-alpha and its receptor in digestive tract epithelium and pancreatic tissues early in fetal life suggests a functional role for TGF-alpha during the developmental process of the digestive system. We demonstrate that TGF-alpha is also produced by endocrine cells and might have an additional mode of action other than paracrine, at least during fetal life.

Adult↗
PubMed1993

Octreotide (SMS 201-995) inhibits the growth of colon peritoneal carcinomatosis in BDIX rats.

In order to assess the effect of octreotide, a somatostatin analogue, on the growth of colon peritoneal carcinomatosis, 20 BDIX rats were injected i.p. with 1 x 10(6) colon cancer cells (DHD/K12 tumor cell line) and received octreotide, 65 micrograms/kg s.c. every 12 h (n = 10) or saline (n = 10) for 42 days, starting 3 days after tumor cell injection. Animals were killed at the end of the treatment. The mean volume of ascites was lower in the octreotide group (33.7 +/- 7.6 ml), than in the control group (67.5 +/- 16.3 ml; P < 0.05). The extent of peritoneal carcinomatosis (in five classes according to a previously published classification) was lower in the octreotide group (P < 0.05). Cell proliferation, using the BrdU technique, was markedly inhibited by octreotide (labeling index of tumor cells: 17.0 +/- 0.6% vs. 26.3 +/- 2.2% in controls, P < 0.001). No significant decrease in labeling index was observed in normal colonic mucosa. Two subtypes of somatostatin receptors were found in all tumors, using the 30F3 monoclonal antireceptor antibody. KD and Bmax values were not significantly different in the octreotide and control groups: high affinity, low capacity receptors (KD = 1.4 x 10(-10) M and 0.7 x 10(-10) M, respectively; Bmax = 3.8 and 2.9 pmol/mg protein, respectively); low affinity, high capacity receptors (KD = 1 +/- 0.2 x 10(-9) M and 5.5 +/- 0.05 x 10(-10) M, respectively; Bmax = 27.8 +/- 0.1 and 22.8 +/- 0.05 pmol/mg protein, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1993

Gastric endocrine cell evolution in patients with Zollinger-Ellison syndrome. Influence of gastrinoma growth and long-term omeprazole treatment.

Evolution of gastrinoma tumoral mass, fasting serum gastrin concentrations, and gastric endocrine cells has been analyzed in 21 patients with the Zollinger-Ellison syndrome committed to long-term omeprazole treatment (up to 7.75 years, median 37 months). Gastrinoma growth was seen in eight patients. Significant increase in serum gastrin was only observed in the group of patients with gastrinoma growth. Fundic argyrophil cell densities were correlated with serum gastrin (r' = 0.68, P = 0.002). Argyrophil and antral gastrin cell densities significantly increased during the survey, but increases were greater in the group with gastrinoma growth (respectively, +136% and +131%) than in the other group (respectively, +34% and +43%). Progression in the degree of argyrophil cell hyperplasia, noted qualitatively, was observed in 11 patients. Fundic carcinoids developed in three of these 11 patients, all three having multiple endocrine neoplasia type 1 (MEN 1). Positive linear individual correlations (r > or = 0.85) between argyrophil cell densities and corresponding durations of omeprazole treatment were found in nine of the 10 patients studied at least three times and who had a clear-cut increase in those cell densities. Thus, increase in serum gastrin and fundic argyrophil cell densities appeared closely associated with gastrinoma growth; however, duration of drug-induced hypochlorhydria may also affect cell proliferation.

APUD Cells↗
PubMed1993

Chronic endogenous hypergastrinemia in humans: evidence for a mitogenic effect on the colonic mucosa.

BACKGROUND: Information concerning the influence that gastrin may exert on the colon is fragmentary and somewhat controversial. This study analyzed the effect of chronic endogenous hypergastrinemia on cell proliferation and tumor occurrence in the human colonic mucosa. METHODS: Twenty-three consecutive hypergastrinemic patients presenting with the Zollinger-Ellison syndrome and 18 normogastrinemic subjects were studied. All had fasting serum gastrin determination, colonoscopy, and cell kinetic measurement in two colonic sites using in vitro 5'-bromodeoxyuridine incorporation. RESULTS: Macroscopic tumors, one endocrine and five adenomas, were found in 5 of 23 hypergastrinemic patients, without apparent relationship with the level of gastrin. The labeling indices were significantly higher in hypergastrinemic than in normogastrinemic individuals in the right and left colon, (P < 0.002 to P < 0.001) without resulting in colonic cell hyperplasia. There was no correlation between labeling indices and serum gastrin concentrations or duration of hypergastrinemia. The DNA labeling distribution along the crypt was normal in the two groups, without expansion of the proliferative zone towards the surface. CONCLUSIONS: These results showed for the first time that long-lasting endogenous hypergastrinemia is accompanied by increased in vivo cell proliferation in the human colonic mucosa. However, the prevalence of adenomas (17.4%) in patients, all more than 50 years old, may not be different from that in the general population.

Adenoma↗
PubMed1993

Is the multiple endocrine neoplasia type 1 gene a suppressor for fundic argyrophil tumors in the Zollinger-Ellison syndrome?

In the Zollinger-Ellison syndrome, fundic argyrophil carcinoid tumors have been described only in the small genetically defined subgroup of patients who have the multiple endocrine neoplasia type 1 syndrome (MEN-1). Allelic losses on 11q13, on which MEN-1 gene has been localized, have been noted in parathyroid and pancreatic tumors of patients with MEN-1, suggesting that the MEN-1 gene could act as a recessive tumor suppressor gene. One fundic argyrophil carcinoid tumor from a patient with the Zollinger-Ellison syndrome and MEN-1 was studied. Loss of heterozygosity in the tumor DNA at loci close to MEN-1 locus was looked for using Southern technique with six DNA probes. Segregation of alleles was examined in relatives. In the tumor DNA, we found the loss of one allele with PYGM, the closest probe to the MEN-1 locus. The allele lost in the tumor had been transmitted by the unaffected parent. This suggests that in patients with the Zollinger-Ellison syndrome and MEN-1, the promotion of fundic argyrophil carcinoid tumors results from the inactivation of the two copies of MEN-1 gene and that fundic argyrophil carcinoid tumors may be included in the spectrum of MEN-1-related tumors.

Adult↗
PubMed1993

Clinical, anatomical, and evolutive features of patients with the Zollinger-Ellison syndrome combined with type I multiple endocrine neoplasia.

The clinical evolution of type I multiple endocrine neoplasia (MEN I) was studied in 45 patients among a consecutive series of 172 with Zollinger-Ellison syndrome (ZES). These 172 patients were seen in our hospital between 1959 and 1989. Diarrhea was half as frequent in ZES-MEN I as in sporadic ZES cases. At diagnosis, mean basal acid output and serum gastrin levels in MEN I patients (28.8 +/- 6.6 mmol/h and 587 +/- 487 pg/ml, respectively) were not different from those observed in the others with sporadic ZES. Laparotomy was performed in all 36 patients with no diffuse liver involvement to attempt the removal of gastrinomas. Twenty-nine patients had adenomas, located in the pancreas in 21, in the duodenal wall in 3, and in both in 5. Adenomas were multiple in 23 cases (78%). No tumor was found in seven patients. Twenty-nine of the 36 operated patients were tumor-free after surgery; 7 died in the postoperative period between 1959 and 1970. Median follow-up of the 38 other patients was 95 months (range 17-278 months). Among the 24 patients without residual tumor at discharge (group I), biological and/or morphological evidence of a persistent or recurrent source of gastrin was obtained in 22. Among the 14 patients with residual tumor (group II), an increase in tumor size was seen in 5 after a median of 27 months (range 9-36 months), while no change occurred in 9 after 54 months (3-100 months). Actuarial survival curves were not different, either in group I versus group II patients (67 and 72% at 5-year follow-up, respectively) or in MEN I versus sporadic ZES patients. Apparently, complete resection of primary tumor did not reduce the incidence of subsequent liver metastases. In all, 21 of the 45 patients had malignant gastrinomas (47%), consisting of liver metastases in 14 (31%), metastatic lymph nodes in 11 (24%), and lung metastases in 2 (4%). Monitoring of fundic argyrophil cells disclosed hyperplasia in 13 of the 14 MEN I patients (92%), and 5 had invasive carcinoid tumors. Taken together, these results prompt us to recommend that in ZES-MEN I patients, surgery should be avoided and oxyntic mucosa regularly monitored.

Adolescent↗
PubMed1993

Long-term treatment with octreotide in patients with the Zollinger-Ellison syndrome.

This study reports the effects of 4 and 5-year treatment with octreotide (200 micrograms sc bid) in the Zollinger-Ellison syndrome (ZES). No symptoms related to acid hypersecretion were observed in the four patients throughout the study, and upper GI endoscopy was normal. Basal acid output (BAO) measured 12 h after injection, was below 10 mmol h-1 in three to four patients and previous ranitidine treatment was discontinued. In the fourth case (pretreatment BAO value: 115 mmol h-1), BAO progressively decreased to 42 mmol h-1 after 5 years of octreotide treatment. At the end of the study, serum gastrin levels were 58.5% (30-68) of the pretreatment values and two patients had normal gastrin levels. Peak acid output (PAO) decreased markedly after 2, 4 and 5 years, by 68% (35-89) suggesting that octreotide had exerted an antitrophic effect on parietal cell mass. Diffuse hyperplasia of fundic argyrophil cells present in two patients before octreotide, decreased during the treatment. Mean argyrophil cell density for all patients was not significantly modified. Antral gastrin-cell density was in the normal range. No long-term side effect of octreotide treatment was observed. Although octreotide may not be considered as a substitute for benzimidazoles in the treatment of ZES, its specific properties may be of therapeutic benefit in some ZES patients.

Adult↗
PubMed1993

Gastric endocrine cell proliferation and fundic argyrophil carcinoid tumors in patients with the Zollinger-Ellison syndrome.

The Zollinger-Ellison syndrome (ZES) is characterized by hyperchlorhydria due to sustained hypergastrinemia of tumoral origin. In ZES, as in all pathological and experimental conditions associated with chronic hypergastrinemia, endocrine argyrophil cells, particularly enterochromaffin-like cells, proliferate in the fundic mucosa. In patients with ZES, fundic argyrophil carcinoids only develop in those patients who also have multiple endocrine neoplasia type 1. The authors review factors which might influence fundic argyrophil cell proliferation in the ZES. Clinical characteristics of the patients with fundic argyrophil carcinoid tumors as well as pathology and the putative mechanisms of development of these tumors are described.

Animals↗
PubMed1992

Influence of multiple endocrine neoplasia type 1 on gastric endocrine cells in patients with the Zollinger-Ellison syndrome.

The influences of multiple endocrine neoplasia type 1 (MEN 1), hypergastrinaemia, age, and sex on gastric endocrine cell densities were studied in 48 patients with the Zollinger-Ellison syndrome of either the sporadic type (n = 31) or associated with MEN 1 (n = 17). The mean fundic argyrophil cell density was higher in women (p < 0.05). It showed no appreciable difference between young and old women but it declined with age in men. The mean argyrophil cell density, when adjusted for sex, was higher (+48.5%, p = 0.06) in patients with Zollinger-Ellison syndrome associated with MEN 1 than in those with sporadic type disease. This measurement was not significantly different between the two groups of patients when antisecretory treatments were considered. In patients with sporadic type disease, fundic argyrophil cells showed a normal pattern (16%) or diffuse (71%) or linear (13%) hyperplasia. In patients with MEN 1 diffuse and linear hyperplasia were of the same order (53% and 47%). Furthermore, fundic argyrophil endocrine tumours developed in five of 17-that is, 29.5% of patients with associated MEN 1 while none was seen in patients with sporadic type disease. These tumours showed an exclusive or prominent enterochromaffin like cell population. Antral gastrin and somatostatin cell densities and fasting serum gastrin concentrations were similar in the two groups of patients with Zollinger-Ellison syndrome. Whatever the underlying mechanism for carcinoidosis, the risk of developing fundic enterochromaffin like cell tumours in Zollinger-Ellison syndrome patients who present with MEN 1 is probably higher than was initially estimated and suggests that regular follow up of these patients is necessary.

Adolescent↗
PubMed1992

Detection of gastrin mRNA in human antral mucosa and digestive endocrine tumors by in situ hybridization: a correlative study with immunocytochemistry and electron microscopy.

In gastrinomas, as well as in other endocrine tumors whose hormone overproduction is responsible for clinical syndromes, antibodies against the bioactive form(s) of hormones can fail to detect immunoreactivity. Moreover, tumor secretory granule morphology may fail to allow tumor type identification. The use of anti-pre-pro-gastrin antibodies has been proposed as an alternative to identify gastrinomas. The aim of the present study was to demonstrate that in situ detection of gastrin mRNA may represent another possibility. A 35S-labeled cDNA probe encoding the human gastrin pre-pro-hormone was used to localize gastrin gene transcripts in antral mucosa and digestive endocrine tumors from patients with a Zollinger-Ellison syndrome characterized by high serum gastrin levels. In situ hybridization was combined with light and electron microscopic immunostaining of the bioactive gastrin 17/34 form and morphological study of secretory granules. Gastrin mRNAs were detected in antral gastrin cells and in a variable proportion of tumor cells in all endocrine tumor studied. Transcript expression correlated well with immunohistochemical staining and granule ultrastructure for most of the tumors, and provided crucial evidence for identifying as gastrinomas two tumors with weak immunoreactivity and poorly granulated cells. Our data show that in situ hybridization is a sensitive method for gastrin mRNA detection and represents a valuable tool for the identification of gastrinomas.

Digestive System Neoplasms↗
PubMed1991

Effect of the histamine-1 antagonist astemizole alone or with omeprazole on rat gastric mucosa.

The stimulation of acid secretion by gastrin may in the rat be explained solely by gastrin-induced histamine release. This study was done to examine whether histamine could mediate the general trophic effect of gastrin on the oxyntic mucosa, by using a long-acting selective histamine-1 antagonist (astemizole) alone or with omeprazole-induced hypergastrinaemia for 90 days in female Sprague-Dawley rats. At day 90, isolated vascularly perfused rat stomachs were prepared to study maximal gastrin- and histamine-stimulated acid and pepsinogen outputs and maximal gastrin-stimulated histamine release. Oxyntic mucosa morphometry, mucosal histamine and pepsinogen contents, and plasma gastrin and histamine levels were also determined. For the first time, omeprazole has been found to inhibit gastric emptying and to increase plasma histamine. As compared with controls, astemizole alone did not influence plasma gastrin, increased plasma histamine in only some rats, and gave a slight increase in all other variables. Together with omeprazole, it further increased variables already stimulated by omeprazole. Thus, mucosal thickness, histamine concentration, and chief-cell density in oxyntic mucosa were significantly higher in astemizole/omeprazole-treated rats than in omeprazole-treated rats. Gastrin-stimulated histamine release was increased in both astemizole- and omeprazole-treated rats. For all rats plasma histamine was significantly correlated with plasma gastrin and with numerical fundic argyrophil cell density. In conclusion, the present study confirms the trophic effect of gastrin and shows a slight trophic effect of astemizole on the oxyntic mucosa. It also shows that plasma histamine may reflect the argyrophil cell density in the oxyntic mucosa and that omeprazole inhibits gastric emptying.

Animals↗