big-gastrin and Adenoma

In contrast to sessile serrated adenomas and traditional serrated adenomas which are associated with a significant cancer risk, the role of hyperplastic polyps (HP) in colorectal carcinogenesis as well as the molecular mechanisms underlying their development remain controversial and still need to be clarified. Several reports suggest that a subset of HP may represent precursor lesions of some colorectal cancers. However, biomarkers are needed to identify the subset of HP that may have a malignant potential. The hormone precursor, progastrin (PG) has been involved in colon carcinogenesis and is known to activate pro-oncogenic pathways such as the ERK or the STAT3 pathway. We therefore analyzed PG expression and the activation of these signaling factors in HP.. We retrospectively analyzed PG expression as well as the phosphorylation of ERK and STAT3 by immunohistochemistry in HP from 48 patients.. Mean percentages of epithelial cells positive for PG or phospho-ERK were respectively, 31% and 33% in HP and were significantly higher in these lesions compared to normal colon (3%, p=0.0021 and 7%, p=0.0008, respectively). We found a significant correlation between PG and phospho-ERK expression in HP with ERK activation significantly stronger in lesions with high progastrin expression (p=0.015). In contrast, STAT3 was not significantly activated in HP compared to normal colon and we did not observe a significant correlation with PG expression.. HP overexpressing PG that have the highest activation of the ERK pathway might reflect less latent lesions that might have a malignant potential.

Topics: Adenoma; Adult; Aged; Aged, 80 and over; Colonic Polyps; Extracellular Signal-Regulated MAP Kinases; Female; Gastrins; Humans; Hyperplasia; Intestinal Mucosa; Male; Middle Aged; Oncogene Proteins; Protein Precursors; Retrospective Studies; Risk Factors; Signal Transduction; STAT3 Transcription Factor

Aberrant activation of the beta-catenin/Tcf-4 transcriptional complex represents an initiating event for colorectal carcinogenesis, shifting the balance from differentiation toward proliferation in colonic crypts. Here, we assessed whether endogenous progastrin, encoded by a target gene of this complex, was in turn able to regulate beta-catenin/Tcf-4 activity in adenomatous polyposis coli (APC)-mutated cells, and we analyzed the impact of topical progastrin depletion on intestinal tumor growth in vivo.. Stable or transient RNA silencing of the GAST gene was induced in human tumor cells and in mice carrying a heterozygous Apc mutation (APCDelta14), which overexpress progastrin but not amidated or glycine-extended gastrin.. Depletion of endogenous progastrin production strongly decreased intestinal tumor growth in vivo through a marked inhibition of constitutive beta-catenin/Tcf-4 activity in tumor cells. This effect was mediated by the de novo expression of the inhibitor of beta-catenin and Tcf-4 (ICAT), resulting from a down-regulation of integrin-linked kinase in progastrin-depleted cells. Accordingly, ICAT down-regulation was correlated with progastrin overexpression and Tcf-4 target gene activation in human colorectal tumors, and ICAT repression was detected in the colon epithelium of tumor-prone, progastrin-overexpressing mice. In APCDelta14 mice, small interfering RNA-mediated progastrin depletion not only reduced intestinal tumor size and numbers, but also increased goblet cell lineage differentiation and cell apoptosis in the remaining adenomas.. Thus, depletion of endogenous progastrin inhibits the tumorigenicity of APC-mutated colorectal cancer cells in vivo by promoting ICAT expression, thereby counteracting Tcf-4 activity. Progastrin targeting strategies should provide an exciting prospect for the differentiation therapy of colorectal cancer.

Topics: Adaptor Proteins, Signal Transducing; Adenoma; Adenomatous Polyposis Coli; Animals; Apoptosis; beta Catenin; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Colorectal Neoplasms; Gastrins; Gene Expression Regulation, Neoplastic; Genes, APC; Humans; Mice; Mice, Nude; Phosphatidylinositol 3-Kinases; Protein Precursors; Random Allocation; Repressor Proteins; RNA, Small Interfering; Signal Transduction; TCF Transcription Factors; Transcription Factor 7-Like 2 Protein; Transcription Factors; Transcriptional Activation; Transplantation, Heterologous

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

Six patients were studied with pituitary adenomas and elevated concentrations of gastrin similar to those found in cases of benign antral gastrinoma syndrome. Chromatography of the serum using Sephadex-G50 revealed different molecular forms of gastrin according to the type of adenomas. In those cases of acromegaly and gonadotrophinoma, gastrin-34 and unsulphated gastrins constitute the predominant forms. In contrast, in cases of Cushing's disease, gastrin-17, sulphated as well as non-sulphated were the predominant types; the chromatographic pattern was similar to that observed in two patients with antral gastrinoma syndrome who acted as controls. These findings demonstrate that pituitary adenomas might secrete gastrin. Taking into account that gastrin-34 and unsulphated gastrins were the predominant forms in cases of acromegaly, gonadotrophinoma and non-functioning adenoma, it is assumed that those molecular forms are mainly produced in the anterior lobe of the hypophysis. Conversely, gastrin-17 was the principal molecular form in cases of Cushing's disease confirming the close relationship of the synthesis of gastrin and corticotrophin peptides. The cases with Cushing's disease exhibited a serum gastrin pattern similar to that observed in the two cases with antral syndrome in which the predominant immunoreactive form of gastrin in gastrin-17 exhibiting a degree of sulphation corresponding to that of antral gastrin. It is concluded that the circulating excess of gastrin originated in the pituitary tumour tissue and the molecular form varied with the type of pituitary adenoma.

Topics: Adenoma; Adult; Chromatography, Gel; Female; Gastrins; Humans; Male; Middle Aged; Pituitary Hormones; Pituitary Hormones, Anterior; Pituitary Neoplasms; Protein Precursors

To determine if gastrin in hyperparathyroid glands is true gastrin or artifact and to determine the frequency of gastrin in parathyroid glands, 20 parathyroid glands from 11 patients with hyperparathyroidism but without MEA were extracted and analyzed for gastrin. The parathyroid glands from 4 out of 11 patients had measurable gastrin immunoreactivity (10.7 + 6 pg/mg tissue). Column separation chromatography confirmed that this was true gastrin (40% G-34; 50% G-17). Immunohistochemistry with ABC (avidin biotin complex) immunoperoxidase confirmed the presence of gastrin in cytoplasmic vesicles in scattered parathyroid cells. True gastrin does exist in some cells in some patients with hyperparathyroidism.

Topics: Adenoma; APUD Cells; Gastrins; Humans; Hyperparathyroidism; Hyperplasia; Immunoenzyme Techniques; Parathyroid Glands; Parathyroid Neoplasms; Protein Precursors; Radioimmunoassay