Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

H2-Histamine receptor blocking agents metiamide and cimetidine were assessed in seven patients with Zollinger-Ellison syndrome (serum gastrin greater than 300 microgram/ml, basal acid output greater than 15 meq/h, ratio of basal acid output to maximal acid output greater than 0.5). Intravenous or oral administration of the drugs lowered acid secretion by at least 70% in all cases. Subsequent treatment of six patients for 3 to 15 months (oral therapy) and one patient for 1 month (intravenous therapy) showed that the drugs abolished symptoms in all seven, abolished diarrhea in five, allowed ulcer healing in six, and were well tolerated without adverse effects in seven. No patient failed to respond to the drug, although one died from tumor progression and two required total gastrectomy for complex reasons. The results indicate that patients with Zollinger-Ellison syndrome can be managed medically and, in light of current mortality trends, gain little from the extra risks attending total gastrectomy.
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PMID:H2-Histamine receptor blocking agents in the Zollinger-Ellison syndrome. Experience in seven cases and implications for long-term therapy. 2 4

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.
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PMID:Growth factors and oncogenes in human gastrointestinal carcinomas. 215 13

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.
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PMID:Somatostatin analog: effects on hypergastrinemia and hypercalcitoninemia. 243 92

The advent of the histamine H2-receptor antagonists and the renewed interest in curative surgery in patients with gastrinoma have made the differentiation between benign and malignant tumors of critical importance. An analysis of 65 patients with gastrinoma followed for an average of 93 months revealed two distinct clinical groups: those with and those without hepatic tumors at initial examination or operation. Among the 14 patients with hepatic tumors, 12 had multiple liver metastases from pancreatic or duodenal primary tumors, and 2 had primary hepatic gastrinomas. Ten of the 14 patients (71 percent) died from tumor progression, and the total tumor-related mortality for this group was 79 percent. In contrast, only 1 of 15 patients (7 percent) with tumor in the lymph nodes died from a tumor-related cause (recurrent ulcer hemorrhage), and none died from tumor progression. Only a single patient with lymph node metastases at initial exploration went on to the development of liver metastases, which was found incidentally at autopsy 313 months later. Among 23 patients with either primary tumors only or no tumors found at laparotomy, there was only one tumor-related death and no deaths from tumor spread. Life-table analysis demonstrated a significantly decreased length of survival for patients with liver tumor compared with those without liver involvement. Multiple endocrine adenopathy syndrome was not a significant factor in survival. Serum gastrin levels were likewise nondiscriminatory. Six of 52 patients (12 percent), including three with tumor in the lymph nodes, were apparently cured by excision of all gastrinoma recognized at laparotomy. The cure rate was 23 percent for patients without multiple endocrine adenopathy syndrome or liver metastases. Hepatic metastases is a definitive marker for clinically malignant disease and portends a poor prognosis. Patients with gastrinoma confined to the lymph nodes uncommonly follow a malignant clinical course. Such patients have at least a 20 percent probability of surgical cure if they do not have multiple endocrine adenopathy syndrome.
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PMID:Benign and malignant gastrinoma. 285 72

We used an octapeptide analogue of somatostatin, SMS 201-995, in dosages ranging from 150 to 450 micrograms/d administered subcutaneously in three daily doses for 1 to 16 months, to treat 22 patients with advanced malignant islet cell carcinomas. Of the 22 patients, there were 9 with gastrinomas; 3 with glucagonomas; 4 with insulinomas; 1 with ectopic production of parathyroid hormone; and 3 with mixed syndromes. The only biochemical marker in 1 patient was pancreatic polypeptide, and 1 patient had no demonstrable peptide production from the tumor. In 14 patients, dramatic decreases in the levels of circulating peptides (insulin, vasoactive intestinal polypeptide, gastrin, and glucagon) have been accompanied by major alleviations of symptoms. Steatorrhea appears to be the most significant toxicity. This analogue of somatostatin may be appropriate for use as early therapy in patients who have symptoms from syndromes related to islet cell carcinomas but in whom there is no immediate threat from tumor progression.
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PMID:Treatment of metastatic islet cell carcinoma with a somatostatin analogue (SMS 201-995). 288 85

The stomachs from 40 patients operated on for gastric cancer and chronic ulcer were studied immunohistochemically using antibodies to CEA, galactosyl transferase, pepsinogens A and C, gastrin, alpha 1-antitrypsin. CEA and galactosyl transferase of the cancer parenchyma are shown to mark tumor progression. The ratio of alpha 1-antitrypsin to pepsinogens in gastric epithelium and cancer cells probably plays a role in ulcerogenesis of normal mucosa and tumor tissue. Gastrin in carcinoma tissue is both an ulcerogenesis factor and a marker of tumor progression, an unfavourable prognosis of gastric cancer.
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PMID:[Possible markers of the progression and ulcerogenesis of stomach cancer]. 798 72

Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene occur in most colorectal cancers and lead to activation of beta-catenin. Whereas several downstream targets of beta-catenin have been identified (c-myc, cyclin D1, PPARdelta), the precise functional significance of many of these targets has not been examined directly using genetic approaches. Previous studies have shown that the gene encoding the hormone gastrin is activated during colon cancer progression and the less-processed forms of gastrin are important colonic trophic factors. We show here that the gastrin gene is a downstream target of the beta-catenin/TCF-4 signaling pathway and that cotransfection of a constitutively active beta-catenin expression construct causes a threefold increase in gastrin promoter activity. APC(min-/+) mice overexpressing one of the alternatively processed forms of gastrin, glycine-extended gastrin, show a significant increase in polyp number. Gastrin-deficient APC(min-/+) mice, conversely, showed a marked decrease in polyp number and a significantly decreased polyp proliferation rate. Activation of gastrin by beta-catenin may therefore represent an early event in colorectal tumorigenesis and may contribute significantly toward neoplastic progression. The identification of gastrin as a functionally relevant downstream target of the beta-catenin signaling pathway provides a new target for therapeutic modalities in the treatment of colorectal cancer.
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PMID:Gastrin is a target of the beta-catenin/TCF-4 growth-signaling pathway in a model of intestinal polyposis. 1095 28

An immunohistochemical study of cyclooxygenase (COX)-2 expression in pancreatic endocrine tumors (PET) was carried out, and the expression of COX-2 was compared with pathological features, the expression of several markers (hormones, vascular endothelial growth factor, single-stranded DNA, and the Ki-67 labeling index [LI]). Twenty PET, including 10 metastasizing cases (tumor size: 3-8 cm) and 10 non-metastasizing cases (tumor size: 0.3-8 cm) were studied. Tumors with a high level of COX-2 expression were placed in the H group, and the remaining tumors were placed in the L group. The H group was comprised of 13 tumors: all 10 of the metastasizing cases and three of the non-metastasizing cases. There were significant differences in tumor size between the two groups (H group 46.5 mm; L group 0.9 mm). There were significant differences in the presence of the following histological criteria for malignancy: pleomorphism (H group 13/13; L group 1/7), mitotic activity (H group 2.9; L group 0) and/or angioinvasion (H group 13/13; L group 1/7); and there were also significant differences in the number of cases that expressed ectopic hormones (gastrin, vasoactive intestinal peptide, serotonin and calcitonin; H group 12/13; L group 2/7) and in the Ki-67 LI (H group 8.3%; L group 0.4%). The distribution of COX-2-positive cells tended to be similar to the distribution of Ki-67-positive cells. Our data show that COX-2 is frequently upregulated in malignant PET and that there is a close relationship between COX-2 expression and tumor progression/proliferative activity.
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PMID:Immunohistochemical analysis of cyclooxygenase (COX)-2 expression in pancreatic endocrine tumors: association with tumor progression and proliferation. 1188 29

MTI/G-Gly mice and hGAS mice, overexpressing glycine-extended gastrin (G-Gly) and progastrin, respectively, display colonic mucosa hyperplasia, hyperproliferation, and an increased susceptibility to intestinal neoplasia. Here, we have used these transgenic mice to analyze in vivo the modulation of intracellular signaling pathways that may be responsible for the proliferative effects of gastrin precursors. The expression, activation, and localization of signaling and cell-to-cell adhesion molecules were studied using immunofluorescence and Western blot techniques on colonic tissues derived from MTI/G-Gly, hGAS, or wild-type FVB/N mice. These analyses revealed an up-regulation of Src tyrosine kinase and related signaling pathways [phosphatidyl inositol 3'-kinase (PI3K)/Akt, Janus-activated kinase (JAK) 2, signal transducer and activator of transcription (STAT) 3, and extracellular-signal regulated kinases (ERK)] in both MTI/G-Gly and hGAS mice compared with the wild-type control animals as well as an overexpression of transforming growth factor-alpha (TGF-alpha). In contrast, overexpression of the gastrin precursors did not affect the activation status of STAT1 nor the expression and the distribution of adhesion proteins (focal adhesion kinase, cadherins, and catenins). We report for the first time that the transition from a normal colonic epithelium to a hyperproliferative epithelium in MTI/G-Gly and hGAS mice may be a consequence of the up-regulation of Src, PI3K/Akt, JAK2, STAT3, ERKs, and TGF-alpha. Deregulation of cell adhesion, a late event in tumor progression, does not occur in these transgenic models.
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PMID:Signaling pathways associated with colonic mucosa hyperproliferation in mice overexpressing gastrin precursors. 1580 77

While Wnt and Ras signaling pathways are activated during progression of colorectal cancers, many of their important downstream targets remain to be elucidated. The gastrin gene encodes for a family of peptide growth factors that are commonly upregulated in colorectal neoplasia. Previously, we showed that the Wnt signaling pathway moderately stimulates the gastrin promoter. To determine whether Ras signaling can cooperate with Wnt signaling in transcriptional regulation of gastrin gene expression, we have analyzed the response of murine gastrin promoter-reporter gene constructs to combinations of oncogenic stimulation in transient transfection assays. We found a strong (25- to 40-fold) synergistic stimulation of the gastrin promoter by the combination of oncogenic beta-catenin and K-ras overexpression. Deletion analysis localized the response element to an area between -140 and -110bp upstream in the murine gastrin promoter. Electrophoretic mobility shift assays detected a complex containing beta-catenin/TCF, AP1, and SMAD3/4 transcription factors that bound to a DNA element through AP1 and SMAD binding sites. Gastrin promoter activation could be further enhanced or suppressed by the co-expression of wild type SMAD4 or dominant negative mutant of SMAD4, respectively, and abrogated by the PI3K inhibitor, LY20004, but not by the MEK inhibitor, PD98059. Taken together, our data strongly suggest that oncogenic Wnt and Ras signaling pathways can synergistically induce gastrin expression, possibly contributing to neoplastic progression.
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PMID:Synergistic activation of the murine gastrin promoter by oncogenic Ras and beta-catenin involves SMAD recruitment. 1613


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