epidermal-growth-factor and Cocarcinogenesis

Transforming growth factor alpha (TGF alpha) is one of a group of structurally-related growth factors (the epidermal growth factor family of ligands) that interact with one or other members of the epidermal growth factor family of protein tyrosine kinase receptors (EGF-R's). A number of excellent reviews detailing our knowledge of this area have been recently published (Carpenter and Wahl, 1991; Derynck, 1992; Prigent and Lemoine, 1992). Rather than add to their number, this review focuses on new insights into the importance of TGF alpha and signaling through the EGF receptor considered in the context of the laboratory mouse. The new information has emerged from analysis of mutant mice generated either by classical gene targeting in embryonic stem (ES) cells or by accidents of nature. In addition to their intrinsic interest, these mice are proving invaluable in determining the importance of EGF receptor signaling in wound healing and as a contributing factor in the conversion of a normal cell into its tumorigenic counterpart.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Cell Transformation, Neoplastic; Cocarcinogenesis; Epidermal Growth Factor; ErbB Receptors; Gene Targeting; Hair; Mice; Mice, Knockout; Mice, Mutant Strains; Multigene Family; Mutagenesis, Insertional; Papilloma; Recombination, Genetic; Signal Transduction; Skin Neoplasms; Transforming Growth Factor alpha; Vibrissae; Wound Healing

Topics: Animals; Carcinogens; Cell Adhesion; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cocarcinogenesis; DNA, Neoplasm; Epidermal Growth Factor; Humans; Methylation; Phenotype

Diet is an area of major interest to those investigating the causes of cancer of the oesophagus in the Transkei. This study looked at the associations between intragastric epidermal growth factor level, diet and intragastric pH.. A dietary survey was co-ordinated with studies of gastric luminal epidermal growth factor and gastric fluid pH in 120 rural Transkeians.. Gastric fluid epidermal growth factor was associated with low dietary intake of animal products (p = 0.002) and vegetables (p = 0.026). There was no association with pH.. A dietary subgroup has been identified in the Transkei population with high levels of epidermal growth factor in the upper gastrointestinal lumen. This adds to previously demonstrated diet-related changes in the upper gastrointestinal tract in Transkei. These changes may affect the disease pattern of the population.

Topics: Cocarcinogenesis; Dairy Products; Diet; Diet Surveys; Epidermal Growth Factor; Esophageal Neoplasms; Fruit; Gastric Acidity Determination; Gastric Juice; Gastric Mucosa; Humans; Hydrogen-Ion Concentration; Meat; Metabolic Clearance Rate; Pepsin A; Poverty; Radioimmunoassay; Rural Health; South Africa; Surveys and Questionnaires; Vegetables

Expression of transforming growth factor-alpha (TGF-alpha) and epidermal growth factor (EGF) was studied in normal pancreatic tissue and in (pre)neoplastic pancreatic lesions of azaserine-treated rats. They were given either a low fat, high fiber (low caloric) diet, to inhibit carcinogenesis, or a low fat diet combined with injections of the cholecystokinin analog caerulein to enhance carcinogenesis. The control groups, maintained on a low fat diet, were injected with azaserine or were not treated at all. Autopsy was performed at 6 and 15 months after the last azaserine injection. After both 6 and 15 months immunohistochemistry revealed a weak expression of EGF and TGF-alpha peptides in the acinar cells, and a stronger expression in the ductular and centroacinar cells. TGF-alpha peptide expression was reduced in both putative preneoplastic and neoplastic acinar cell lesions, but no differences in EGF peptide expression were observed between the various stages of exocrine pancreatic carcinogenesis. After 16 months an increase in TGF-alpha mRNA due to treatment with azaserine was detected by semi-quantitative PCR in total pancreatic homogenates, whereas EGF mRNA expression had decreased. TGF-alpha mRNA levels in macroscopically isolated tumors were significantly lower, but EGF mRNA levels were significantly higher, than in total pancreatic homogenates from azaserine-treated rats. Furthermore, EGF and TGF-alpha mRNA levels in isolated tumors did not differ significantly from mRNA levels in non-carcinogen-treated rats. Neither with immunohistochemistry nor with PCR were differences in EGF or TGF-alpha expression observed due to either inhibition or stimulation of carcinogenesis. It is concluded that putative preneoplastic acinar cell lesions induced in rat pancreas by azaserine may develop into acinar adenocarcinomas independently of TGF-alpha and EGF. The results suggest involvement of these growth factors at the early stage of the carcinogenic process, during the initiation of normal acinar cells into putative preneoplastic cells. However, modulation of azaserine-induced pancreatic carcinogenesis by cholecystokinin or a low fat, high fiber (caloric restricted) diet appeared not to be regulated by EGF or TGF-alpha.

Topics: Animals; Azaserine; Base Sequence; Body Weight; Carcinogens; Ceruletide; Cocarcinogenesis; Diet, Fat-Restricted; Dietary Fiber; Drug Synergism; Energy Intake; Epidermal Growth Factor; Immunohistochemistry; Male; Molecular Sequence Data; Organ Size; Pancreas; Pancreatic Neoplasms; Polymerase Chain Reaction; Rats; Rats, Wistar; RNA, Messenger; Transforming Growth Factor alpha

The mechanisms by which the peroxisome proliferator (PP) class of non-genotoxic carcinogens perturb growth regulation and cause rodent liver cancer are unknown. Using a soft agar cloning assay, we have demonstrated that PPs synergize with the physiological liver mitogen epidermal growth factor (EGF) to cause the clonal expansion of rat hepatocytes associated with the early stages of tumourigenesis. In the presence of EGF (25 ng/ml), the PP nafenopin (100 microM) was able to stimulate a 5-fold increase in the number of colonies (35 colonies/50,000 hepatocytes compared to seven in the control). EGF alone or nafenopin alone gave 11 and 14 colonies respectively. TGF alpha, which acts through the EGF receptor, also synergized with nafenopin, whereas HGF was inactive, despite its potency as an hepatocyte growth factor. The ability to promote colony formation was shared by the potent PP Wyeth-14,643 but not by the less potent compounds methylclofenapate or trichloroacetic acid. TGF beta, a physiological negative regulator of liver growth, was able to inhibit the nafenopin/EGF-stimulated colony formation at 0.25 ng/ml, a concentration below that required for TGF beta-induced hepatocyte apoptosis. The colonies formed are derived from and consist of hepatocytes, since they express the hepatocyte-specific marker albumin, although the majority are negative for the PP-induced cytochrome, P4504A1. Pre-treatment in vivo with the genotoxic carcinogen dimethylhydrazine hydrochloride (150 mg/kg) caused a doubling in the number of colonies from 35 to 75/50,000 hepatocytes. Taken together, these data suggest that some PPs act as hepatocarcinogens by synergizing with EGF and/or TGF alpha to promote the clonal expansion of spontaneously initiated hepatocytes. This clonal expansion may be inhibited by TGF beta. Such a synergy may provide a mechanistic basis for the hepatocarcinogenicity of this class of non-genotoxic carcinogens.

Topics: Albumins; Animals; Biomarkers; Carcinogens; Cell Division; Cell Transformation, Neoplastic; Cells, Cultured; Clone Cells; Cocarcinogenesis; Colony-Forming Units Assay; Cytochrome P-450 CYP4A; Cytochrome P-450 Enzyme System; DNA Replication; Drug Synergism; Epidermal Growth Factor; Hyperplasia; Liver; Liver Neoplasms, Experimental; Male; Microbodies; Mixed Function Oxygenases; Nafenopin; Rats; Rats, Wistar; Transforming Growth Factor alpha

We analysed the effects of cytokines, anti-cancer agents and cocarcinogen on DNA synthesis in human hair germinative cells cultured in serum-free media. Epidermal growth factor and gamma interferon were found to inhibit DNA synthesis slightly, while strong inhibition was demonstrated by doxorubicin, cytosine arabinoside and tetradecanoyl-phorbolacetate. Basic fibroblast growth factor had very little influence on DNA synthesis. This organ culture model in serum-free media is a useful method by which to examine the effects of various cytokines and drugs on DNA synthesis in hair germinative cells and/or to study the pathogenesis of various alopecia diseases.

Topics: Antineoplastic Agents; Cells, Cultured; Cocarcinogenesis; Culture Media, Serum-Free; Cytarabine; Cytokines; DNA; Doxorubicin; Epidermal Growth Factor; Fibroblast Growth Factor 2; Hair; Humans; Interferon-gamma; Tetradecanoylphorbol Acetate

EJ-A is a Balb-3T3 transfectant cell line that bears a small number of EJ-ras oncogene copies/cell, has low EJ-ras expression, and resembles the parental cell line in displaying a non-transformed phenotype. The glucocorticoid hormone dexamethasone reversibly induces transformation traits in EJ-A cells, namely: 1) morphological transformation; 2) increased growth rate and saturation density; 3) reduced G1 length; and 4) independence of the FGF requirement to initiate DNA synthesis. Western blot analysis revealed that dexamethasone does not increase the p21ras protein intracellular level. beta-IFN, added to the culture medium, does not suppress the dexamethasone-induced growth stimulation and morphological transformation. Therefore, glucocorticoid hormones can complement low EJ-ras expression to transform Balb-3T3 cells, by a mechanism that is likely to be independent of p21ras increase and beta-IFN decrease.

Topics: Animals; Cell Line, Transformed; Cell Transformation, Neoplastic; Cocarcinogenesis; Dexamethasone; DNA; Dose-Response Relationship, Drug; Epidermal Growth Factor; Fibroblast Growth Factors; Genes, ras; Insulin; Interferon Type I; Mice; Mice, Inbred BALB C; Oncogene Protein p21(ras); Transfection; Transformation, Genetic

The incidence of Syrian golden hamsters with pancreatic cancer induced by subcutaneous injections of N-nitroso-bis(2-oxopropyl)amine for 19 weeks (each 10 mg/kg) increased from 44% to 75% (p=0.016) when epidermal growth factor was also administered from week 5 through week 8 (5 mug energy three days for injections). Epidermal growth factor increased pancreatic weight and body weight. The incidence of animals with bronchial cancer doubled. Epidermal growth factor could be a cocarcinogen as a result of its mitogenic activity.

Topics: Animals; Bronchial Neoplasms; Carcinogens; Cocarcinogenesis; Cricetinae; Epidermal Growth Factor; Female; Mesocricetus; Nitrosamines; Pancreatic Neoplasms

Because epidermal growth factor (EGF) is rapidly bound and internalized into rat pancreas, stimulates uptake of tritiated thymidine, and increases pancreatic weight, a cocarcinogenic effect on pancreatic cancer seemed likely. Pancreatic adenocarcinomas were induced in 70 female Syrian hamsters by 19 weekly s.c. injections of N-nitrosobis(2-oxopropyl)amine (BOP) (10 mg/kg). From Wk 5 through Wk 8 of BOP injections, additional s.c. injections of EGF (5 micrograms every 3 days for 10 injections) were given to 45 animals, while 25 received saline solution. An additional group of 10 received EGF alone, and another 10 animals received saline solution alone (controls). Eleven wk later, the mean body weight of EGF-treated animals increased by 29% as compared with that of controls, and their mean pancreatic weight relative to body weight increased by 44% as compared with controls. The mean body weight of EGF + BOP-treated animals increased by 10%, and their pancreatic weight relative to body weight increased by 22% as compared with that of animals treated with BOP alone. The incidence of pancreatic cancer in the EGF + BOP-treated animals was 75% versus 44% in those treated with BOP alone (P = 0.016). No tumors developed in either animals treated with EGF alone or control animals. EGF augments pancreatic carcinogenesis induced by BOP. The incidence of bronchial carcinomas doubles.

Topics: Adenocarcinoma; Animals; Body Weight; Bronchial Neoplasms; Carcinogens; Cocarcinogenesis; Cricetinae; Epidermal Growth Factor; ErbB Receptors; Female; Mesocricetus; Nitrosamines; Oncogenes; Pancreatic Neoplasms; Receptors, Cell Surface; Receptors, Platelet-Derived Growth Factor

Unlike 12-O-tetradecanoylphorbol-13-acetate, epidermal growth factor (EGF) could not promote the appearance of type III foci from initiated C3H10T1/2 cells. At appropriate concentrations, EGF induced the formation of type II colonies in the absence of any initiator. At higher concentrations, EGF suppressed the induction of both type II and type III colonies elicited by methylcholanthrene.

Topics: Animals; Carcinogens; Cell Transformation, Neoplastic; Cells, Cultured; Cocarcinogenesis; Epidermal Growth Factor; Fibroblasts; Methylcholanthrene; Mice; Mice, Inbred C3H; Tetradecanoylphorbol Acetate; Tumor Stem Cell Assay

Topics: Carcinogens; Cocarcinogenesis; Cyclamates; Dose-Response Relationship, Drug; Epidermal Growth Factor; ErbB Receptors; HeLa Cells; Humans; Phorbols; Receptors, Cell Surface; Saccharin; Structure-Activity Relationship; Temperature; Tetradecanoylphorbol Acetate

Topics: Animals; Anti-Inflammatory Agents; Cell Count; Cell Division; Cell Line; Cell Transformation, Neoplastic; Cocarcinogenesis; DNA Repair; Epidermal Growth Factor; Mice; Mitomycins; Mutation; Phorbols; Radiation, Ionizing; Tetradecanoylphorbol Acetate; X-Rays

Topics: Animals; Carcinogens; Cell Transformation, Neoplastic; Cocarcinogenesis; Dietary Fats; Epidermal Growth Factor; Humans; Neoplasms; Ornithine Decarboxylase; Phenobarbital; Plasminogen Activators; Receptors, Drug; Saccharin; Smoking; Tetradecanoylphorbol Acetate