gastrins and Peritoneal-Neoplasms

Peritoneal metastasis is a major cause of recurrence of gastric cancer and integrins are key molecules involved in gastric cancer cells attachment to the peritoneum. The peptide hormone, gastrin, initially identified for its role in gastric acid secretion is also a growth factor for gastric mucosa. Gastrin has also been shown to contribute to gastric cancers progression. Here, we provide the first evidence that gastrin increases the adhesion of gastric cancer cells. Gastrin treatment induces the expression of α2 integrin subunit through a mechanism that involves the ERK pathway. We also observed in response to gastrin an increase in the amount of α2 integrin associated with β1subunit. In addition, gastrin-stimulated cell adhesion was blocked with an anti-α2β1 integrin neutralizing antibody. We also show that gastrin activates the integrin pathway via the phosphorylation of β1 integrin by a Src family kinase. This mechanism may contribute to the enhancement of cell adhesion observed in response to gastrin since we found an inhibition of gastrin-mediated cell adhesion when cells were treated with a Src inhibitor. By regulating one of the key step of the metastatic process gastrin might contribute to increase the aggressive behaviour of human gastric tumours.

Topics: Cell Adhesion; Cell Line, Tumor; Gastrins; Humans; Integrin alpha2beta1; MAP Kinase Signaling System; Neoplasm Metastasis; Peritoneal Neoplasms; Peritoneum; Phosphorylation; Signal Transduction; Stomach Neoplasms

In comparison to somatostatin receptor scintigraphy, gastrin receptor scintigraphy using 111In-DTPA-minigastrin (MG0) showed added value in diagnosing neuroendocrine tumors. We investigated whether the 68Ga-labeled gastrin analogue DOTA-MG0 is suited for positron emission tomography (PET), which could improve image quality. Targeting of cholecystokinin-2 (CCK2)/gastrin receptor-positive tumor cells with DOTA-MG0 labeled with either 111In or 68Ga in vitro was investigated using the AR42J rat tumor cell line. Biodistribution was examined in BALB/c nude mice with a subcutaneous AR42J tumor. In vivo PET imaging was performed using a preclinical PET-computed tomographic scanner. DOTA-MG0 showed high receptor affinity in vitro. Biodistribution studies revealed high tumor uptake of 68Ga-DOTA-MG0: 4.4 ± 1.3 %ID/g at 1 hour postinjection. Coadministration of an excess unlabeled peptide blocked the tumor uptake (0.7 ± 0.1 %ID/g), indicating CCK2/gastrin receptor-mediated uptake (p  =  .0005). The biodistribution of 68Ga-DOTA-MG0 was similar to that of 111In-DOTA-MG0. Subcutaneous and intraperitoneal tumors were clearly visualized by small-animal PET imaging with 5 MBq 68Ga-DOTA-MG0. 111In- and 68Ga-labeled DOTA-MG0 specifically accumulate in CCK2/gastrin receptor-positive AR42J tumors with similar biodistribution apart from the kidneys. AR42J tumors were clearly visualized by microPET. Therefore, 68Ga-DOTA-MG0 is a promising tracer for PET imaging of CCK2/gastrin receptor-positive tumors in humans.

Topics: Animals; Binding, Competitive; Cell Line, Tumor; Cholecystokinin; Chromatography, High Pressure Liquid; Coordination Complexes; Drug Screening Assays, Antitumor; Gastrins; Inhibitory Concentration 50; Male; Mice; Mice, Nude; Neoplasms; Peritoneal Neoplasms; Positron-Emission Tomography; Rats; Receptor, Cholecystokinin B; Subcutaneous Tissue; Tissue Distribution

The effects of combined administration of bombesin (40 micrograms/kg body weight) and the ornithine decarboxylase (ODC) inhibitor, 1,3-diaminopropane (DAP), on the development of large and small intestinal tumors and the incidence of their metastasis to the peritoneum induced by azoxymethane (AOM, 7.4 mg/kg body weight), the ODC activity of the intestinal wall, and the labeling index of the intestinal mucosa and tumor were investigated in inbred Wistar rats. Rats received weekly s.c. injections of AOM for 10 weeks, s.c. injections of bombesin every other day, and drinking water containing DAP (2.5 g/l) until the end of the experiment at week 40. Administration of bombesin significantly increased the incidence of intestinal tumors at week 40. It had no influence on the location, size, histological features or depth of involvement of intestinal adenocarcinomas, but significantly increased the incidence of their metastasis to the peritoneum. It also resulted in a significant increase in the intestinal ODC activity and labeling index. Administration of DAP with bombesin significantly reduced the enhancement of intestinal carcinogenesis by bombesin. Although the combined use of DAP with bombesin had little or no influence on the location, size, histological features, or depth of involvement of intestinal cancers, the incidence of their metastasis was significantly reduced. DAP significantly attenuated bombesin enhancement of the intestinal ODC activity and labeling index. These findings indicate that ODC inhibition attenuated the enhancement of intestinal carcinogenesis and metastasis to the peritoneum.

Topics: Adenocarcinoma; Animals; Azoxymethane; Body Weight; Bombesin; Cell Division; Diamines; Drug Synergism; Gastrins; Intestinal Mucosa; Intestinal Neoplasms; Male; Neoplasm Metastasis; Ornithine Decarboxylase Inhibitors; Peritoneal Neoplasms; Rats; Rats, Wistar

The authors report the case of a 48 years old man presenting a pancreatic islet cell carcinoma (gastrinoma) with liver, nodes and peritoneal metastases, associated with an elevated alpha-fetoprotein (AFP) concentration. Incomplete remission was first obtained with a chemotherapy using Streptozotocin combined with 5-Fluorouracil, in association with a Somatostatin analogue (SMS 201-995). But when relapses occur, another chemotherapy was not so effective. Serum gastrin and AFP levels had the same evolution and appear to have the same interest to follow the course of the disease.

Topics: alpha-Fetoproteins; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Fatal Outcome; Fluorouracil; Gastrinoma; Gastrins; Humans; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Octreotide; Pancreatic Neoplasms; Peritoneal Neoplasms; Remission Induction; Streptozocin

A 37-year-old man with a primary mesenteric gastrinoma is reported. A parathyroid adenoma had been removed 13 years ago. Six years earlier the patient underwent an emergency distal gastrectomy because of massive bleeding from a duodenal ulcer. Two months later stomal ulcers developed associated with hypergastrinemia. No gastrinoma was detected and total gastrectomy was performed. The fasting plasma level of gastrin was stable in the range from 580 to 920 pg/ml for the following 5 years. However, the level was found to abruptly increase to 4125 pg/ml. The level increased progressively to 11383 pg/ml within 1 year. A gastrinoma was identified in the jejunal mesenterium, and it was completely removed. After surgery the plasma level of gastrin decreased below the limit of the assay, and the paradoxical response to secretin was no longer observed.

Topics: Adult; Gastrins; Humans; Laparotomy; Male; Mesenteric Arteries; Mesentery; Peritoneal Neoplasms; Radiography; Zollinger-Ellison Syndrome

Topics: Adult; Calcium; Follow-Up Studies; Gastrectomy; Gastrins; Hepatic Artery; Humans; Ligation; Liver Neoplasms; Lymph Node Excision; Lymphatic Metastasis; Male; Mesentery; Middle Aged; Neoplasm Metastasis; Peritoneal Neoplasms; Radiography; Radionuclide Imaging; Streptozocin; Zollinger-Ellison Syndrome