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

The expression of epidermal growth factor receptor and transglutaminase type I, polyamine (putrescine, spermidine, and spermine) levels, ornithine decarboxylase activity, and micronuclei occurrence were assessed in the 7,12-dimethylbenz(a)anthracene (DMBA)-induced hamster buccal pouch model to elucidate the role and timing of changes in different growth and differentiation markers during carcinogenesis. DMBA (0.5%) in heavy mineral oil was applied to the right buccal pouch 3 times per wk for up to 16 wk; controls received heavy mineral oil alone. Hamsters were killed after 0, 4, 8, and 16 wk. Frozen tissue was chemically analyzed for polyamine levels and ornithine decarboxylase activity and was also used for immunohistochemical analysis of transglutaminase I. Paraffin-embedded sections were used for epidermal growth factor receptor immunohistochemical determinations and for micronucleated cell assays. Hyperplasia was detected by histological analysis at 4 wk, dysplasia with or without papillomatous changes at 8 wk, and squamous cell carcinoma at 16 wk. Epidermal growth factor receptor was not expressed in the normal buccal epithelial layer, at a moderate level in both the superficial keratin and basal cell layers in hyperplastic epithelium, and at very high levels in both dysplasia and squamous cell carcinoma. Transglutaminase I was expressed at a limited level in normal buccal mucosa, was expressed at a low level in the basal layer of hyperplastic lesions, was somewhat elevated in dysplasia, and was markedly enhanced in squamous cell carcinoma. Putrescine and spermidine levels and ornithine decarboxylase activity increased dramatically after 8 and 16 wk of DMBA. Micronucleated cells increased after 4 wk of DMBA treatment, that high level sustained during all stages of carcinogenesis. We suggest that these biological markers could be excellent intermediate end points in assessing the effects of various chemopreventive agents to be tested in the hamster buccal pouch model and in human clinical trials.
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PMID:Expression of epidermal growth factor receptor, polyamine levels, ornithine decarboxylase activity, micronuclei, and transglutaminase I in a 7,12-dimethylbenz(a)anthracene-induced hamster buccal pouch carcinogenesis model. 196 30

Transforming growth factor alpha (TGF alpha) is a mitogenic growth factor for hepatocytes that may play a role in the development of liver cancer in rodents and humans. Epidermal growth factor receptor (EGFR) is the receptor for TGF alpha; its expression is also altered in mitogenic and carcinogenic processes. Homogeneous basophilic foci (HBF), the precursor lesion to hepatocellular carcinomas in peroxisome proliferator (PP)-treated rats, have labeling indices much greater than surrounding liver (approximately 5- to 20-fold) and other types of foci (approximately 2-fold greater than eosinophilic foci; EF). To test the hypothesis that PP-induced HBF over-express TGF alpha and/or EGFR, male F344 rats were treated with the PP WY-14,643 for 22 weeks (1000 p.p.m. in the diet) with (DEN-WY) and without (WY) prior diethylnitrosamine initiation (150 mg/kg body wt i.p.). Serial paraffin sections of liver were stained for TGF alpha or EGFR and with hematoxylin and eosin. DEN-WY and WY abrogated the small amount of centrilobular TGF alpha staining observed in livers from control rats. Increased staining for TGF alpha was not observed in HBF induced by WY (0/22) or DEN-WY (0/101). Additionally, increased EGFR expression was not observed in HBF induced by WY (0/22) or DEN-WY (0/19) or in EF induced by DEN-WY (0/30). An unexpectedly large proportion of EF induced by DEN-WY (6/38) and DEN-control (3/11) were TGF alpha-positive. None of the tumors induced by WY (0/13) or DEN-WY (0/11) over-expressed TGF alpha. All 13 WY-induced tumors also lacked increased expression of EGFR. TGF alpha over-expression noted in a significant proportion of EF was associated only with those regimens including DEN initiation. In conclusion, TGF alpha or EGFR over-expression is not associated with early appearing, rapidly proliferating HBF or tumors induced by PP.
Carcinogenesis 1995 Jan
PMID:TGF alpha differentially expressed in liver foci induced by diethylnitrosamine initiation and peroxisome proliferator promotion. 753 Jun 5

Livers of mangrove rivulus (Rivulus ocellatus marmoratus) were examined after an acutely necrogenic dose of diethyl-nitrosamine (DEN). Immunohistochemical detection of oncoproteins and bromodeoxyuridine (BrdU), enzyme histochemical detection of gamma-glutamyltranspeptidase, and histological stains were used in an attempt to separate changes in protooncogene expression related to hepatic regeneration from those changes that were putatively preneoplastic. Perivenous hepatocytes were rounded and shrunken within 3 days of the beginning of DEN exposure, and widespread necrosis and hepatocyte proliferation occurred by 21 days (the last day of DEN exposure). Twenty-four days after the end of DEN exposure, livers were primarily composed of nodules of regenerated hepatocytes. Epidermal growth factor receptor expression in hepatocytes increased in inflamed areas and then returned to control levels as inflammation subsided. Increased expression of Fos, Ras and Myc occurred prior to necrosis in a zonal and chronological progression consistent with regeneration of hepatocytes. Fos, Ras, Myc and p53 expression persisted in scattered cells and foci for 24 days after the end of DEN exposure, and this expression was at levels higher than during normal cell-cycle progression. The spatial pattern and persistence of cells expressing Fos, Ras, Myc and p53 at high levels may have represented preneoplastic changes.
Carcinogenesis 1994 Sep
PMID:Oncogene expression in hepatocytes of the fish Rivulus ocellatus marmoratus during the necrotic and regenerative phases of diethylnitrosamine toxicity. 792 94

Epidermal growth factor receptor is considered to play an important role in the carcinogenesis and progression of breast cancer, but its clinical significance remains controversial mainly due to different methods and methodical problems. We determined EGF-R expression by an immunohistochemical assay on paraffin-embedded primary breast cancer tissue by means of the anti EGF-R mab E30 (Merck, FRG) and streptavidin-peroxidase technique. Material and clinical data were available from 111 patients with a mean follow-up time of 75.4 +/- 1.1 months (range 61-90 months). 21 (18.9%) of the breast cancer specimens showed positive staining for EGF-R 5 year-overall survival in patients with EGF-R negative tumors was 61.7% compared with 41.6% of patients with EGF-R positive breast carcinomas. No correlation was found between the expression of EGF-R and other prognostic factors except an inverse relationship with the expression of the estrogen receptor (p < 0.05). Whereas EGF-R expression demonstrated prognostic significance in univariate analysis, this could not be confirmed by multivariate analysis. Immunohistochemical determination of EGF-R represents a reliable and simple method to obtain more data about the biological behavior of malignant breast disease with increasing impact on therapeutic procedures.
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PMID:Epidermal growth factor receptor-immunohistochemical detection and clinical significance for treatment of primary breast cancer. 925 18

Activation of the ras oncogene is an important step in carcinogenesis. Human MCF-10A mammary epithelial cells were transformed with a point-mutated form of the Ha-ras oncogene. Epidermal growth factor receptor (EGFR) phosphorylation levels were chronically elevated after EGF induction and the EGFR ligand-driven internalization rate was slower in Ha-ras transformed MCF-10A cells. Additionally, basal levels of p42/44 mitogen-activated protein kinase (MAPK) expression and enzyme activity were significantly higher in Ha-ras transformed cells, localized predominantly in the nucleus. The anti-EGFR monoclonal antibody (MAb) 225 and the EGFR tyrosine kinase inhibitor PD153035 blocked anchorage-independent growth of Ha-ras transformed cells in soft agar and were more effective when used in combination. The MEK inhibitor PD98059 and anti-erbB-2 MAb L26 also suppressed colony formation of Ha-ras transformed cells in soft agar. Therefore, Ha-ras transformation leads to an augmentation in signaling through the EGFR as a result of an increase in ligand-dependent phosphorylation, a decrease in its internalization and an up-regulation in basal p44/42 MAPK levels. These effects may contribute to uncontrolled growth of Ha-ras-transformed human mammary epithelial cells.
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PMID:RAS transformation causes sustained activation of epidermal growth factor receptor and elevation of mitogen-activated protein kinase in human mammary epithelial cells. 1096 38

Epidermal growth factor receptor (EGFR) frequently overexpresses in cancers, including oral squamous cell carcinomas (OSCC). We previously identified a truncated EGFR (tEGFR) in human oral keratinocytes. In this study, we evaluated the prognostic value of tEGFR in 45 cases of OSCC. tEGFR expression inversely correlated with EGFR expression (r=-0.83, P<0.01), decreased with T-stage progression and lymph-node metastasis (P<0.05). The EGFR/tEGFR ratio correlated with the lymph-node metastasis (P<0.05) and survival outcome (hazard ratio =3.601; P<0.05). These results suggest that tEGFR may play an important roles in oral carcinogenesis and that the EGFR/tEGFR ratio may be a prognostic factor for OSCC.
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PMID:Expression of a truncated epidermal growth factor receptor in oral squamous cell carcinomas. 1107 8

Epidermal growth factor receptor (EGFR), erbB2, erbB3 and erbB4 are four transmembrane glycoproteins belonging to the subtype I tyrosine kinases. They share structure homologies and are believed to direct cellular growth through the ligand-stimulated tyrosine phosphorylation of intracellular substrate. The overexpression of these tyrosine kinases has been linked to various cancers. To examine the role of the erbB family in the neoplastic transformation of the human colon, we analysed the protein expression of these four members by immunohistochemistry in paraffin-embedded specimens from 125 resected colorectal cancers. Our data showed that for EGFR expression, 62 (50%) were scored as '+', and 2 (2%) as '++'. For erbB2 expression, 39 (31%) were classified as '+', and 5 (4%) as '++'. For erbB3 expression, 43 (34%) were scored as '+', and 3 (2%) as '++'. A significantly higher percentage of overexpressed erbB3 was observed in early stage carcinomas (Dukes' stage A or B) (50%) than in advanced stage cancers (Dukes' stage C or D) (15%) (P<0.0001). For erbB4 expression, 22 (18%) were scored as '+', and 5 (4%) as '++'. Early stage patients had a lower percentage of erbB4 overexpression than the late stage ones (18% versus 28%). Concomitant overexpression of erbB2 and erbB3 occurred in 21% (16/78) of the early stage carcinomas, whereas it occurred in only 2% (1/47) of the late stage ones (P=0.003). Conversely, simultaneous overexpression of erbB2 and erbB4 occurred in 17% (8/47) of the late stage carcinomas but in only 4% (3/78) of the early stage ones (P=0.02). Overexpression of EGFR, erbB2, erbB3 or erbB4 alone was not significantly associated with a shortened survival. However, patients with a simultaneous overexpression of erbB2 and erbB4 had a shorter overall survival time than others in the univariate analysis (P=0.01). This significance disappeared after adjustment for Dukes' staging in the Cox model. In conclusion, overexpressed erbB3 was common in early stage colorectal cancers, but its prevalence was significantly reduced in late stage ones. The percentage of its coexpression with erbB2 was significantly higher in early stage than in late-stage cancers. Heterodimerisation between erbB2 and erbB4 may play a role in the late stages of carcinogenesis.
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PMID:Investigation of the prognostic value of coexpressed erbB family members for the survival of colorectal cancer patients after curative surgery. 1200 94

Epidermal growth factor receptor (EGFR) plays a critical role in epidermal biology. Abnormal EGFR function has been described in epithelial tumors including those induced by two-stage chemical carcinogenesis in mouse skin. A large body of evidence indicates that in this model, activation of Ha-ras is the critical event in papilloma formation, a process that involves epidermal proliferation and stroma remodeling, which includes angiogenesis. This study reports that activated Ha-ras results in a dramatic induction of EGFR in epidermal tumor cells and provides experimental evidence that EGFR signaling is responsible for Ha-ras-dependent vascular endothelial growth factor (VEGF) induction, as well as for the repression of other angiogenic factors such as angiopoietin 1. The pivotal role of functional EGFR in throwing the angiogenic switch necessary for tumor growth was confirmed by s.c. injection of immunodeficient mice with epidermal tumor cells carrying a dominant negative (dn) EGFR and by in vivo chemical skin carcinogenesis assays in transgenic mice expressing the same dn EGFR form in the epidermis. Immunohistochemical analysis of the tumors obtained by both ex vivo and in vivo approaches showed that dn EGFR expression abolished the changes in blood vessels that occurred during tumor progression. A strong reduction of VEGF expression in dn EGFR tumors appears to be the key event responsible for angiogenesis and tumor growth suppression. The apoptotic rate was increased, and Akt activity was decreased, suggesting that impaired nutrient and oxygen supply might contribute to diminished cell survival in dn EGFR tumors. Support for this mechanism is provided by the fact that the ectopic expression of VEGF in dn EGFR-expressing tumor cell lines restored tumor growth capacity. Although ras activation might suffice for epidermal transformation and the stroma-remodeling events of tumor induction, such effects may not be operative without a functional upstream EGFR. It is tempting to speculate that EGFR family members may function as angiogenic regulators in other epithelial tumors such as those of the colon, breast, and prostate, reinforcing their value as targets for therapeutic intervention.
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PMID:A critical role for ras-mediated, epidermal growth factor receptor-dependent angiogenesis in mouse skin carcinogenesis. 1206 82

The transcription factor AP-2/promoter system is essential for gene expression associated with ectodermal development, particularly in the neural crest and skin. Three AP-2 isoforms, alpha, beta, and gamma, exhibit a highly homologous structure, but their functions are considered to be different. Here, we report on the role of each AP-2 isoform in complex keratinocyte biology including proliferation, differentiation, and carcinogenesis. The expression of AP-2 was investigated immunohistochemically in serial skin sections from normal and psoriatic skin, and squamous cell carcinoma (SCC). AP-2alpha was present only in the nuclei of normal basal keratinocytes, but was significantly increased in lesional proliferating keratinocytes of both diseases. AP-2beta was completely absent from all skin samples except dermal sweat glands, whereas AP-2gamma was present homogeneously throughout the epidermis in normal and psoriatic skin as well as in the SCC lesion. Their restricted expression patterns correlated with in vitro DNA binding assays using selective keratinocyte gene promoters and three recombinant AP-2 isoforms generated bacterially as glutathione S-transferase fusion protein. Epidermal growth factor receptor and basal keratin K14 promoters bound to AP-2alpha and AP-2gamma with similar affinities, whereas suprabasal keratin K1, type I transglutaminase, and involucrin promoters predominantly bound to AP-2gamma rather than AP-2alpha. In contrast, AP-2beta did not bind to any of the five promoters despite specific binding to the AP-2 consensus probe. These results suggest that AP-2alpha is closely associated with keratinocyte proliferation and/or carcinogenesis rather than differentiation, while AP-2gamma is ubiquitous in all stages of keratinocyte biology. Taken together, three AP-2 isoforms perform unique roles in the spatial and temporal expression of human keratinocyte-related genes, thereby maintaining epidermal homeostasis. Disruption of the epidermal AP-2 balance may contribute to hyperproliferative conditions, such as psoriasis and SCC.
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PMID:Different properties of three isoforms (alpha, beta, and gamma) of transcription factor AP-2 in the expression of human keratinocyte genes. 1219 91

Epidermal growth factor receptor (EGFR) overexpression is observed in a number of malignancies, especially those of esophageal squamous cell origin. However, little is known about the biological functions of EGFR in primary esophageal squamous epithelial cells. Using newly established primary human esophageal squamous epithelial cells as a platform, we overexpressed EGFR through retroviral transduction and established novel three-dimensional organotypic cultures. Additionally, EGFR was targeted in a cell type- and tissue-specific fashion to the esophageal epithelium in transgenic mice. EGFR overexpression in primary esophageal keratinocytes resulted in the biochemical activation of Akt and STAT pathways and induced enhanced cell migration and cell aggregation. When established in organotypic culture, EGFR-overexpressing cells had evidence of epithelial cell hyperproliferation and hyperplasia. These effects were also observed in EGFR-overexpressing transgenic mice and the esophageal cell lines established thereof. In particular, EGFR-induced effects upon aggregation appear to be mediated through the relocalization of p120 from the cytoplasm to the membrane and increased interaction with E-cadherin. EGFR modulates cell migration through the up-regulation of matrix metalloproteinase 1. Taken together, the functional effects of EGFR overexpression help to explain its role in the initiating steps of esophageal squamous carcinogenesis.
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PMID:Epidermal growth factor receptor mediates increased cell proliferation, migration, and aggregation in esophageal keratinocytes in vitro and in vivo. 1243 27


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