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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nicotine [3-(1-methyl-2-pyrrolidinyl)-pyridine], a major alkaloid in tobacco, has been implicated as playing a role in carcinogenesis. Our previous study showed that passive cigarette smoking promoted inflammation-associated colonic adenoma formation in mice, and 5-lipoxygenase (5-LOX) plays an important role in this process. In the present study, we aimed to investigate whether nicotine could stimulate colon cancer cell proliferation and tumor growth in nude mice xenograft model and the possible mechanisms involved. Results showed that nicotine stimulated SW1116 colon cancer cell proliferation in a dose-dependent manner. Epidermal growth factor receptor (EGFR) and c-Src phosphorylation levels together with protein expression of 5-LOX were also significantly enhanced in this proliferation process. Inhibitors of EGFR and c-Src alleviated the actions of nicotine on cell proliferation and 5-LOX protein expression. Combination of both agents produced additive effect. In contrast, 5-LOX inhibitor had no direct effect on the phosphorylation levels of EGFR and c-Src and yet inhibited cell proliferation. In the colon cancer xenograft model, nicotine also significantly enhanced tumor growth. This acceleration of tumor growth corresponded well with increased vascularization and its proangiogenic factors. Inhibitors of EGFR, c-Src, and 5-LOX all significantly impeded the tumor growth induced by nicotine. Together, nicotine can promote colonic tumorigenesis both in vitro and in vivo. Activation of the phosphorylated form of EGFR and c-Src followed by an increased 5-LOX expression are the prime pathogenic mechanisms in the tumorigenic process in the colon.
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PMID:Nicotine promoted colon cancer growth via epidermal growth factor receptor, c-Src, and 5-lipoxygenase-mediated signal pathway. 1456 62

Cyclooxygenase (Cox)-2 plays an important role in cell proliferation, carcinogenesis and tumor growth, in part through the synthesis of prostaglandin E2 (PGE2) as well as through other yet unknown routes. Epidermal growth factor receptor (EGFR) signaling regulates Cox-2 expression, which has not been thoroughly examined in bronchial carcinomas. The current study examined the expression of Cox-2, EGFR, P53 and proliferative marker Ki-67 immunoreactivities by immunohistochemistry in 71 surgically removed stage I bronchial adenocarcinomas. Furthermore, we evaluated the prognostic value of these molecules to elucidate the biological significance of Cox-2 expression. Higher Cox-2 expression (more than 10% immunoreactivities in tumor cells) was strongly associated with higher EGFR and P53 expression as well as a Ki-67 LI above 20% (P < 0.01). Cox-2 and EGFR immunoreactive tumor cells showed a similar distribution pattern. Five-year survival rate was 73% in 57 cases showing higher Cox-2 expression and 100% in 14 cases showing lower expression, indicating a significant difference in survival (P = 0.040). Higher Cox-2 expression might be associated with tumor progression and worse prognosis through EGFR signaling interaction in Stage I bronchial adenocarcinomas.
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PMID:Co-expression of Cox-2 and EGFR in stage I human bronchial adenocarcinomas. 1524 87

Epidermal growth factor receptor (EGFR) is frequently overexpressed in esophageal carcinoma and its precursor lesions. To gain insights into how EGFR overexpression affects cellular functions in primary human esophageal cells, we performed gene expression profiling and identified insulin-like growth factor-binding protein (IGFBP)-3 as the most up-regulated gene. IGFBP-3 regulates cell proliferation through both insulin-like growth factor-dependent and independent mechanisms. We found that IGFBP-3 mRNA and protein expression was increased in EGFR-overexpressing primary and immortalized human esophageal cells. IGFBP-3 was also up-regulated in EGFR-overexpressing cells in organotypic culture and in EGFR transgenic mice. Furthermore, IGFBP-3 mRNA was overexpressed in 80% of primary esophageal squamous cell carcinomas and 60% of primary esophageal adenocarcinomas. Concomitant up-regulation of EGFR and IGFBP-3 was observed in 60% of primary esophageal squamous cell carcinomas. Immunohistochemistry revealed cytoplasmic localization of IGFBP-3 in the preponderance of preneoplastic and neoplastic esophageal lesions. IGFBP-3 was also overexpressed in esophageal cancer cell lines at both mRNA (60%) and protein (40%) levels. IGFBP-3 secreted by cancer cells was capable of binding to insulin-like growth factor I. Functionally, epidermal growth factor appeared to regulate IGFBP-3 expression in esophageal cancer cell lines. Finally, suppression of IGFBP-3 by small interfering RNA augmented cell proliferation, suggesting that IGFBP-3 may inhibit tumor cell proliferation as a negative feedback mechanism. In aggregate, we have identified for the first time that IGFBP-3 is an aberrantly regulated gene through the EGFR signaling pathway and it may modulate EGFR effects during carcinogenesis.
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PMID:Epidermal growth factor receptor regulates aberrant expression of insulin-like growth factor-binding protein 3. 1552 Jan 75

Epidermal growth factor receptor (EGFR) overexpression and activation is critical in the initiation and progression of cancers, especially those of epithelial origin. EGFR activation is associated with the induction of divergent signal transduction pathways and a gamut of cellular processes; however, the cell-type and tissue-type specificity conferred by certain pathways remains to be elucidated. In the context of the esophageal epithelium, a prototype stratified squamous epithelium, EGFR overexpression is relevant in the earliest events of carcinogenesis as modeled in a three-dimensional organotypic culture system. We demonstrate that the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, and not the MEK/MAPK (mitogen-activated protein kinase) pathway, is preferentially activated in EGFR-mediated esophageal epithelial hyperplasia, a premalignant lesion. The hyperplasia was abolished with direct inhibition of PI3K and of AKT but not with inhibition of the MAPK pathway. With the introduction of an inducible AKT vector in both primary and immortalized esophageal epithelial cells, we find that AKT overexpression and activation is permissive for complete epithelial formation in organotypic culture, but imposes a growth constraint in cells grown in monolayer. In organotypic culture, AKT mediates changes related to cell shape and size with an expansion of the differentiated compartment.
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PMID:AKT induces senescence in primary esophageal epithelial cells but is permissive for differentiation as revealed in organotypic culture. 1704 53

The latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) is an oncoprotein expressed in several EBV-associated malignancies. We have utilised mice expressing the Cao strain of LMP1 in epithelia to explore the consequences of expression in vivo, specifically the changes that occur prior to neoplasia, in the hyperplastic but degenerating tissue. Epidermal growth factor receptor (EGFR) ligands (transforming growth factor alpha (TGFalpha), heparin-binding EGF-like growth factor and epiregulin) are constitutively induced by LMP1, leading to EGFR phosphorylation but also down-regulation, degradation or turn-over, with the appearance of cleaved EGFR fragments. This is accompanied by down-regulation of Akt and activation of caspase-3 and p38 mitogen-activated protein kinase (MAPK). Surprisingly, removal of TGFalpha (using the null strain) does not ameliorate the LMP1-induced phenotype, but instead accelerates the deterioration. Consistent with this, EGFR is reduced less rapidly and MAPK/ERK kinase (MEK) and extracellular-signal-regulated kinase (ERK) are initially activated in the null background, suggesting that TGFalpha or excess of the ligands together act to divert phosphorylated EGFR into a cleavage pathway. In addition, LMP1 leads to the activation of c-Jun N-terminal kinase 2 (JNK2) followed by JNK1 in the effected tissue. Specific AP1 family members FosB, Fra-1 and JunB are constitutively induced and serum response factor, AP1 and nuclear factor kappaB (incorporating p65) are activated in the transgenic tissue compared with wild-type. This system allows the analysis of early events resulting from the expression of a viral oncogene with broad impact in the signalling milieu and the attempts at homeostasis in the responding tissue. It reveals what regulatory circuits are in place in a normal tissue, thus facilitating further prediction of causative events in carcinogenic progression.
Carcinogenesis 2007 Aug
PMID:Latent membrane protein 1-induced EGFR signalling is negatively regulated by TGF alpha prior to neoplasia. 1736 Oct 12

Epidermal growth factor receptor-dependent mechanisms have been implicated in growth signal transduction pathways that contribute to cancer development, including dermal carcinogenesis. Detection of the extracellular domain of the epidermal growth factor receptor (EGFR ECD) in serum has been suggested as a potential biomarker for monitoring this effect in vivo. Arsenic is a known human carcinogen, producing skin and other malignancies in populations exposed through their drinking water. One such exposed population, which we have been studying for a number of years, is in Bangladesh. The purpose of this study was to examine the EGFR ECD as a potential biomarker of arsenic exposure and/or effect in this population. Levels of the EGFR ECD were determined by enzyme-linked immunosorbent assay in the serum samples from 574 individuals with a range of arsenic exposures from drinking water in the Araihazar area of Bangladesh. In multiple regression analysis, serum EGFR ECD was found to be positively associated with three different measures of arsenic exposure (well water arsenic, urinary arsenic and a cumulative arsenic index) at statistically significant levels (p<or=0.034), and this association was strongest among the individuals with arsenic-induced skin lesions (p <or= 0.002). When the study subjects were stratified in tertiles of serum EGFR ECD levels, the risk of skin lesions increased progressively for each increase in all three arsenic measures (also stratified in tertiles) and this increasing risk became more pronounced among subjects within the highest tertile of EGFR ECD levels. These results suggest that serum EGFR ECD levels may be a potential biomarker of effect of arsenic exposure and may indicate those exposed individuals at greatest risk for the development of arsenic-induced skin lesions.
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PMID:Serum levels of the extracellular domain of the epidermal growth factor receptor in individuals exposed to arsenic in drinking water in Bangladesh. 1745 40

Oral cancer is a common neoplasm worldwide with tobacco and alcohol being the major etiological factors contributing to its pathogenesis. Epidermal growth factor receptor (EGFR) and ErbB2 are known to be involved in the development of oral cancer with the former up-regulated in up to 90% human cases. The goal of this study was to evaluate the chemopreventive effects of a dual inhibitor of EGFR and ErbB2 tyrosine kinases, GW2974, in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch model. A short-term experiment (3-week topical DMBA followed by 1-week topical GW2974) was conducted to examine the effects of GW2974 on aberrant arachidonic acid (AA) metabolism and cell proliferation in the hamster oral epithelium. Topical application of 0.1 ml GW2974 (160 microM, three times a week) significantly reduced the levels of prostaglandin E2 (PGE2), leukotriene B4 (LTB4), 5-, 12-, 15-hydroxyeicosatetraenoic acid (HETE), and cell proliferation (BrdU-labeling index). In a long-term post-initiation experiment (6-week topical DMBA followed by 18-week topical GW2974), GW2974 (4 mM and 8 mM) significantly inhibited the incidence, number and size of visible tumors. Under microscope, the numbers of oral lesions (hyperplasia, dysplasia, carcinoma) and the incidence of squamous cell carcinoma (SCC) were also significantly suppressed by GW2974. In summary, our study indicated that dual inhibition of EGFR and ErbB2 tyrosine kinases by GW2974 was effective in preventing oral carcinogenesis in DMBA-induced hamster cheek pouch model. GW2974 exerted its chemopreventive effects in part by suppressing aberrant AA metabolism.
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PMID:Chemoprevention of 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis in hamster cheek pouch by topical application of a dual inhibitor of epidermal growth factor receptor (EGFR) and ErbB2 tyrosine kinases. 1793 75

Epidermal growth factor receptor (EGFR) function is transregulated by a variety of stimuli, including agonists of certain G-protein-coupled receptors (GPCRs). One of the most ubiquitous GPCRs is the P2Y(1) receptor (P2RY1, hereafter referred to as P2Y(1)R) for extracellular nucleotides, mainly ADP. Here, we show in tumoral HeLa cells and normal FRT epithelial cells that P2Y(1)R broadcasts mitogenic signals by transactivating the EGFR. The pathway involves PKC, Src and cell surface metalloproteases. Stimulation of P2Y(1)R for as little as 15-60 minutes triggers mitogenesis, mirroring the half-life of extracellular ADP. Apyrase degradation of extracellular nucleotides and drug inhibition of P2Y(1)R, both reduced basal cell proliferation of HeLa and FRT cells, but not MDCK cells, which do not express P2Y(1)R. Thus, cell-released nucleotides constitute strong mitogenic stimuli, which act via P2Y(1)R. Strikingly, MDCK cells ectopically expressing P2Y(1)R display a highly proliferative phenotype that depends on EGFR activity associated with an increased level of EGFR, thus disclosing a novel aspect of GPCR-mediated regulation of EGFR function. These results highlight a role of P2Y(1)R in EGFR-dependent epithelial cell proliferation. P2Y(1)R could potentially mediate both trophic stimuli of basally released nucleotides and first-line mitogenic stimulation upon tissue damage. It could also contribute to carcinogenesis and serve as target for antitumor therapies.
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PMID:Nucleotide P2Y1 receptor regulates EGF receptor mitogenic signaling and expression in epithelial cells. 1805 28

Epidermal growth factor receptor (EGFR) gene alterations have been found in human lung cancers. However, there is no information on the factors inducing EGFR mutations. In rodents, K-ras mutations are frequently found in many lung carcinogenesis models, but hitherto, Egfr mutations have not been reported. Their presence was therefore investigated in representative lung carcinogenesis models with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N-nitrosobis(2-hydroxypropyl)amine (BHP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and ethyl carbamate (urethane), as well as X-ray irradiation. With the chemical carcinogenesis models, no mutations were detected in Egfr, which is in clear contrast to the high rates observed in either codon 12 or 61 of K-ras (21/23 of the lung tumors induced with NNK, 4/5 with MeIQx, 1/4 with urethane and 7/18 with BHP). However, in the X-ray-induced lung tumors, Egfr mutations with amino acid substitution were observed in exons 18 and 21 (4/12, 33%), but no activating mutation of K-ras was detected. In addition, one and four silent mutations were identified in K-ras (exon 1) and Egfr (exons 18, 20 and 21), respectively. Most mutations in both Egfr and K-ras were G/C-->A/T transitions (7/8, 88% and 31/34, 91%, respectively). Although, the mutational patterns in equivalent human lesions were not completely coincident, this first report of Egfr mutations in an experimental lung tumor model suggests that X-rays or other factors producing oxygen radicals could cause EGFR mutations in some proportion of lung cancers in humans.
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PMID:Occurrence of mutations in the epidermal growth factor receptor gene in X-ray-induced rat lung tumors. 1827 21

While a link between Helicobacter pylori exposure and gastric cancer has been established, the underlying mechanisms remain unclear. H. pylori induces a chronic inflammatory response in infected individuals. A link between chronic inflammation and carcinogenesis has long been suggested but never elucidated. Epidermal growth factor receptor (EGFR) signaling plays an important role in both proinflammatory and procarcinogenic mechanisms and is upregulated on gastric epithelial cells (GECs) during H. pylori exposure. The aim of this study was to examine the effects of two important proinflammatory cytokines released during H. pylori infection, macrophage migration inhibitory factor (MIF) and interleukin-8 (IL-8), on the expression and transactivation of EGFR and on the proliferation of GECs during H. pylori exposure. The expression of EGFR by GECs was increased by exposure to either H. pylori, recombinant MIF, or recombinant IL-8. However, cag pathogenicity island knockout strains of H. pylori had very little effect on expression. MIF and IL-8 also induced phosphorylation of EGFR, signaling events, and proliferation during H. pylori exposure, all of which were decreased when they were neutralized by these cytokines or were blocked from their receptors. The overall role of EGFR in these responses to H. pylori exposure was assessed by knocking down EGFR expression by small interfering RNA.
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PMID:Macrophage migration inhibitory factor and interleukin-8 produced by gastric epithelial cells during Helicobacter pylori exposure induce expression and activation of the epidermal growth factor receptor. 1847 53


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