epidermal-growth-factor and Intestinal-Polyps

Two genes (MAT1A and MAT2A) encode for methionine adenosyltransferase, an essential enzyme responsible for S-adenosylmethionine (SAMe) biosynthesis. MAT1A is expressed in liver, whereas MAT2A is widely distributed. In liver, increased MAT2A expression is associated with growth, while SAMe inhibits MAT2A expression and growth. The role of MAT2A in colon cancer in unknown. The aims of this study were to examine whether MAT2A expression and SAMe and its metabolite methylthioadenosine (MTA) can modulate growth of colon cancer cells.. Studies were conducted using resected colon cancer specimens, polyps from Min mice, and human colon cancer cell lines RKO and HT-29. MAT2A expression was measured by real-time polymerase chain reaction and cell growth by the 3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide assay.. In 12 of 13 patients and all 9 polyps from Min mice, the MAT2A messenger RNA levels were 200%-340% of levels in adjacent normal tissues, respectively. Epidermal growth factor, insulin-like growth factor 1, and leptin increased growth and up-regulated MAT2A expression and MAT2A promoter activity in RKO and HT-29 cells. SAMe and MTA lowered the baseline expression of MAT2A and blocked the growth factor-mediated increase in MAT2A expression and growth in colon cancer cell lines. Importantly, the mitogenic effect of these growth factors was inhibited if MAT2A induction was prevented by RNA interference. SAMe and MTA supplementation in drinking water increased intestinal SAMe levels and lowered MAT2A expression.. Similar to the liver, up-regulation of MAT2A also provides a growth advantage and SAMe and MTA can block mitogenic signaling in colon cancer cells.

Topics: Adenosine; Aged; Animals; Cell Death; Cell Division; Colonic Neoplasms; Drug Interactions; Epidermal Growth Factor; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; HT29 Cells; Humans; Insulin-Like Growth Factor I; Intestinal Polyps; Leptin; Male; Methionine Adenosyltransferase; Mice; Mice, Inbred C57BL; Middle Aged; Mitogens; Polyamines; Promoter Regions, Genetic; S-Adenosylmethionine

Members of the protein kinase C (PKC) family of serine/threonine kinases play key regulatory roles in numerous cellular processes, including differentiation and proliferation. Of the 11 mammalian PKC isoforms known, several have been implicated in tumor development and progression. However, in most cases, isotype specificity is poorly defined, and even contrary functions for a single PKC have been reported mostly because appropriate molecular and genetic tools were missing to specifically assess the contribution of single PKC isoforms in vivo. In this report, we therefore used PKC genetic targeting to study the role of PKCalpha and PKCzeta in colorectal cancer. Both isoforms were found to be strongly down-regulated in intestinal tumors of ApcMin/+ mice. A deletion of PKCzeta did not affect tumorigenesis in this animal model. In contrast, PKCalpha-deficient ApcMin/+ mice developed more aggressive tumors and died significantly earlier than their PKCalpha-proficient littermates. Even without an additional Apc mutation, PKCalpha knockout mice showed an elevated tendency to develop spontaneous intestinal tumors. Transcriptional profiling revealed a role for this kinase in regulating epidermal growth factor receptor (EGFR) signaling and proposed a synergistic mechanism for EGFR/activator protein and WNT/APC pathways in mediating intestinal tumor development.

Topics: Animals; Betacellulin; Colorectal Neoplasms; Down-Regulation; Epidermal Growth Factor; ErbB Receptors; Gene Expression Profiling; Genes, jun; Intercellular Signaling Peptides and Proteins; Intestinal Polyps; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein Kinase C; Protein Kinase C-alpha; Signal Transduction; Transcription, Genetic

The etiology of adenomas in the stomach and duodenum in patients with familial adenomatous polyposis (FAP) is unknown. In this study the plasma concentration of epidermal growth factor (EGF), and other gastrointestinal polypeptides with a possible trophic effect on the gastrointestinal mucosa, was unchanged before and after meal stimulation. In 3 of 7 patients an increased EGF immunoreactivity was found in duodenal adenomas. This study has not indicated that regulatory peptides are involved in development of duodenal polyps in FAP, but suggests further studies to determine the role of EGF in FAP.

Topics: Adenoma; Adenomatous Polyposis Coli; Adult; Duodenal Neoplasms; Epidermal Growth Factor; Female; Gastrointestinal Hormones; Humans; Hyperplasia; Intestinal Mucosa; Intestinal Polyps; Male; Middle Aged; Peptides

Duodenal adenomas are a frequent extracolonic manifestation in patients with familial polyposis coli (FPC). Epidermal growth factor (EGF), a polypeptide that stimulates cellular growth and differentiation, is localized in Paneth cells in the small intestine. In two patients with FPC, we found EGF immunoreactivity in duodenal adenomas. Numerous EGF immunoreactive Paneth cells were localized, not as usually, in the bottom of the crypts, but scattered along the crypts alone or in clusters. We do not know whether EGF is involved in the development of duodenal polyps in FPC patients, or whether the present findings represent secondary changes in duodenal polyps.

Topics: Adenoma; Adenomatous Polyposis Coli; Adult; Duodenal Neoplasms; Duodenum; Epidermal Growth Factor; Female; Humans; Hyperplasia; Intestinal Mucosa; Intestinal Polyps; Male; Neoplasms, Multiple Primary

The purpose of the present study was to determine whether skin fibroblasts from individuals, either with an inherited predisposition to cancer or with genetic disorders usually associated with a high risk of cancer, can be oncogenically transformed in vitro by a tumor promoter alone. The effects of chronic and limited applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) on several properties that are associated with transformation were examined using skin fibroblasts from individuals with polyposis coli, a familial cancer syndrome, xeroderma pigmentosum, Fanconi's anemia, and trisomy 21. The results of this study show that TPA treatment induces similar changes on cellular morphology, growth rate, saturation density, epidermal growth factor binding, and cytoskeleton in fibroblasts from both normal and genetically predisposed individuals. None of these cell lines, however, acquired anchorage-independent growth or unlimited growth potential in culture after chronic application of TPA. These observations suggest clearly that skin fibroblasts from individuals with either a genetic predisposition to or a high risk of cancer may not exist in a preneoplastic or "initiated" state susceptible to oncogenic transformation by TPA alone and that the mechanism of genetically determined cancer induction may be different from that of chemical carcinogenesis.

Topics: Cell Adhesion; Cell Division; Cell Line; Cell Transformation, Neoplastic; Cytoskeleton; Disease Susceptibility; Down Syndrome; Epidermal Growth Factor; Fanconi Anemia; Female; Fibroblasts; Humans; Intestinal Polyps; Male; Neoplasms; Phorbols; Tetradecanoylphorbol Acetate; Trypsin; Xeroderma Pigmentosum