Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The epidermal growth factor (EGF) receptor has been suggested to have an important role in tumor initiation and progression of human bladder cancers. Grb2 protein, which is the downstream effector of the EGF receptor, acts as an adaptor protein between the EGF receptor and the Ras guanine-nucleotide exchange factor, son of sevenless (Sos) protein. Sos protein regulates the action of Ras protein by promoting the exchange of GDP for GTP. However, the significance of Grb2 and Sos proteins, which is related to EGF-triggered Ras activation, has not been elucidated in human bladder cancer. The aim of the present study is to clarify the significance of these proteins in human bladder cancer cell lines. In the present study, we used four human bladder cancer cell lines (T24, KU-7, UMUC-2, UMUC-6) and two kinds of cultured normal urothelial cells (HMKU-1, HMKU-2) isolated from patients with no malignancy. We examined the expression of EGF receptor, Grb2, and Sos proteins in these cells by Western blot analysis. Furthermore, the bladder cancer cell lines were subjected to sequence analysis to identify a point mutation in the c-H-ras gene at codon 12. There was no marked difference in the expression of the EGF receptor between human bladder cancer cell lines and cultured normal urothelial cells. On the other hand, expression of Grb2 and Sos proteins was substantially increased in all human bladder cancer cell lines examined in comparison with cultured normal urothelial cells, whether codon 12 of H-ras was mutated or not. These results suggest that the amplification of both Grb2 and SOS proteins plays an important role in the carcinogenesis of human bladder cancer.
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PMID:Significance of the Grb2 and son of sevenless (Sos) proteins in human bladder cancer cell lines. 1099 35

This investigation evaluated the preventive effect of curcumin on radiation-induced tumor initiation in rat mammary glands. Fifty-four female rats were mated and then divided into two groups at day 11 of pregnancy. As the control group, 27 rats were fed a basal diet during the experimental period. As the experimental group, 27 rats were fed a diet containing 1% curcumin between day 11 of pregnancy and parturition (day 23 of pregnancy). All rats of both groups received whole body irradiation with 1.5 Gy gamma-rays from a (60)Co source at day 20 of pregnancy and were then implanted with a diethylstilbestrol pellet 1 month after weaning. A high incidence (70.3%) of mammary tumorigenesis was observed in the control group. The tumor incidence (18.5%) was significantly reduced in the rats fed curcumin during the initiation stage. The appearance of the first palpable tumor was delayed by 6 months in the curcumin-fed group and the average latent period until the appearance of mammary tumors was 2.5 months longer in the curcumin-fed group than in the control group. By histological examination, the proportion of adenocarcinoma (16.7%) in total tumors in the curcumin-fed rats was found to be decreased to half that (32.1%) in the control group. Compared with the control rats, the body weight of rats in the experimental group was decreased slightly by administration of the curcumin diet from day 11 of pregnancy, in spite of a similar intake of diet, but had recovered to the level of the control by the end of the experiment. At the time of irradiation, curcumin did not have any effect on organ weight or on the development and differentiation of mammary glands of pregnant rats. In addition, the serum concentrations of fatty acids, thiobarbituric acid-reactive substances and ovarian and pituitary hormones, except LH, remained at the control level. Also, no change in litter size and body weight of pups born from curcumin-fed rats indicated no toxicity of curcumin. These results suggest that curcumin does not have any side-effects and is an effective agent for chemoprevention acting at the radiation-induced initiation stage of mammary tumorigenesis.
Carcinogenesis 2000 Oct
PMID:Potent preventive action of curcumin on radiation-induced initiation of mammary tumorigenesis in rats. 1102 41

Murine and human skin express an abundance of lipoxygenase isoforms whose functions are not understood. Substantial data have implicated a role for the 'platelet-type' 12-lipoxygenase (P-12LO) metabolite, 12(S)-hydroxy-eicosatetraenoic acid (12-HETE), in a variety of tumor functions. Using P-12LO deficient mice, we sought to examine the role of the P-12LO pathway in tumor initiation and progression. Two distinct genetic strains of P-12LO deficient and wild-type mice, B6/129 Sv and SENCAR, were evaluated in two-stage carcinogenesis experiments. Carcinoma incidence was significantly reduced in the P-12LO deficient mice of the B6/129 Sv background but not the SENCAR-backcrossed mice. In contrast, papilloma incidence was reduced on the SENCAR background but not in the B6/129 Sv strain mice. A separate experiment employing a complete carcinogenesis protocol failed to find any difference in papilloma or carcinoma incidence. Overall, these data suggest that the P-12LO pathway may contribute to tumor incidence and progression in two-stage, but not complete, carcinogenesis, depending on the genetic background.
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PMID:Role of 'platelet-type' 12-lipoxygenase in skin carcinogenesis. 1114 21

Formation of depurinating adducts by reaction of catechol estrogen-3,4-quinones with DNA was proposed to be a tumor initiating event by estrogens [E.L. Cavalieri et al. (1997) Proc. Natl Acad. Sci. USA, 94, 10937-10942]. Under estrogenic imbalance, oxidation of catechol estrogens to quinones may compete with their detoxification by protective enzymes. The quinones formed can be detoxified by reaction with glutathione (GSH) or can covalently bind to DNA. To provide more support for this hypothesis, we developed a method to identify and quantify GSH, cysteine (Cys) and N-acetylCys conjugates of 4-hydroxyestrogens (4-OHE) in the kidneys of male Syrian hamsters treated with 4-hydroxyestradiol (4-OHE2) by intraperitoneal injection. The highest level of conjugates was observed 1 h after treatment, and almost none was detected after 24 h. Dose-response studies indicated conjugate formation after treatment with 0.5 micromol of 4-OHE2/100 g body weight, and formation increased up to a treatment level of 12 micromol/100 g body weight. GSH, Cys and N-acetylCys conjugates of 4-OHE were identified in the picomole range by high-performance liquid chromatography (HPLC) with multichannel electrochemical detection and confirmed by HPLC/tandem mass spectrometry. Treatment of tissue homogenates with beta-glucuronidase/sulfatase at 37 degrees C for 6 h before extraction resulted in a 12- to 20-fold increase in Cys conjugates from picomole to nanomole levels. Similar enhancement was observed by just incubating the tissue at 37 degrees C for 6 h. Evidence for the 4-OHE-1-N7Gua depurinating adducts was obtained by mass spectrometry. We conclude that GSH and Cys conjugates of the 4-OHE and the 4-OHE-N7Gua adducts can be utilized as biomarkers to detect estrogenic imbalance and potential susceptibility to tumor initiation.
Carcinogenesis 2001 Mar
PMID:Catechol estrogen conjugates and DNA adducts in the kidney of male Syrian golden hamsters treated with 4-hydroxyestradiol: potential biomarkers for estrogen-initiated cancer. 1123 91

The role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in tumorigenesis is complex. On the one hand, GM-CSF can promote tumor cell growth, survival, and even metastasis. On the other hand, it can stimulate tumor cell rejection. In skin, it is early expressed after topic application of tumor-promoting agents and therefore may be responsible for changes that correlate with skin tumor promotion (e.g., epidermal hyperproliferation and inflammation). To analyze GM-CSF function in skin tumorigenesis, we generated transgenic mice epidermally overexpressing either GM-CSF or a GM-CSF antagonist. Both types of transgenic mice exhibited significantly increased numbers of benign tumors in a two-step skin carcinogenesis experiment using 7',12'-dimethylbenz[a]anthracene (DMBA) as initiator and 12-O-tetradecanoylphorbol-CSF displayed a significantly elevated carcinoma burden following a single-step carcinogenesis protocol consisting of tumor initiation only. Therefore, endogenous promotion is responsible for elevated tumor development in GM-CSF-overexpressing mice. In antagonist transgenic animals, an increased tumorigenicity of modified B16 tumor cells after cutaneous transplantation as compared with nontransgenic or GM-CSF transgenic mice was observed. Thus, the antitumor activity leading to the repression of tumor cell growth in control mice is GM-CSF dependent and is compromised in mice expressing the antagonist. We suggest that both, up-regulation and down-regulation of GM-CSF activity in skin, increase the incidence and growth of tumors via two independent mechanisms: endogenous tumor promotion in the case of increased GM-CSF activity and compromised tumor cell rejection in the case of decreased GM-CSF activity.
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PMID:Up- and down-regulation of granulocyte/macrophage-colony stimulating factor activity in murine skin increase susceptibility to skin carcinogenesis by independent mechanisms. 1128 Aug 4

Estrogen-induced carcinogenesis involves enhanced cell proliferation (promotion) and genotoxic effects (initiation). To investigate the contribution of estrogens and their metabolites to tumor initiation, we examined DNA damage induced by estradiol and its metabolites, the catechol estrogens 2-hydroxyestradiol (2-OHE(2)) and 4-hydroxyestradiol (4-OHE(2)). In the presence of Cu(II), catechol estrogens formed piperidine-labile sites at thymine and cytosine residues in (32)P 5'-end-labeled DNA fragments and induced the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine. NADH markedly enhanced Cu(II)-dependent DNA damage mediated by nanomolar concentrations of catechol estrogens. Catalase and bathocuproine inhibited the DNA damage, suggesting the involvement of H(2)O(2) and Cu(I). These results suggest that H(2)O(2), generated during Cu(II)-catalyzed autoxidation of catechol estrogens, reacts with Cu(I) to form the Cu(I)-peroxide complex, leading to oxidative DNA damage, and that NADH enhanced DNA damage through the formation of redox cycle. To investigate the role of estrogens and their metabolites in tumor promotion, we examined their effects on proliferation of estrogen-dependent MCF-7 cells. Estradiol enhanced the proliferation of MCF-7 cells at much lower concentrations than catechol estrogens. These findings indicate that catechol estrogens play a role in tumor initiation through oxidative DNA damage, whereas estrogens themselves induce tumor promotion and/or progression by enhancing cell proliferation in estrogen-induced carcinogenesis.
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PMID:Catechol estrogens induce oxidative DNA damage and estradiol enhances cell proliferation. 1129 Oct 67

The molecular pathways and the timing of genetic events during human colorectal carcinogenesis are still not fully understood. We have addressed the intratumor heterogeneity of the mutational status of the k-ras oncogene and of the p53 oncosuppressor gene during the adenoma-carcinoma sequence by investigating 26 human colorectal adenomas containing early cancer. An intratumor comparative analysis was obtained among the adenomatous and carcinomatous component pairs. Additionally, we have analyzed 17 adenomas having cancer in the near vicinity. The adenomatous components of the adenomas containing early cancer and the adenomas having cancer in the near vicinity had comparable frequencies for k-ras mutations (28 and 47%) but different for p53 mutations (52 and 7%, p-value = 0.01). Interestingly, the adenomatous and carcinomatous components of the adenomas containing early cancer were rarely heterogeneous for the k-ras mutational status (only in 13% of the cases) but were characterized by heterogeneity of the p53 status in 59% of the cases (p-value < 0.01). In addition, the mutations of p53 for the adenomatous components of the adenomas containing early cancer were statistically significantly associated with severe dysplasia (p-value = 0.01). Intratumor homogeneity of k-ras status during the human colorectal adenoma-carcinoma sequence suggests that the role of k-ras is more related to tumor initiation than to tumor progression. On the contrary, intratumor heterogeneity of p53 mutations indicates that the type of the p53 mutations may also be relevant for selection and expansion of new subclones leading to tumor progression.
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PMID:Intratumor heterogeneity of k-ras and p53 mutations among human colorectal adenomas containing early cancer. 1131 Jun 41

Increased iron stores are associated with free radical generation and carcinogenesis. Lipid peroxidation is involved in DNA damage, thus indirectly participating in the early steps of tumor initiation. Melatonin and structurally related indoles are effective in protecting against oxidative stress. The aim of the study was to compare the relative efficacies of melatonin, N-acetylserotonin (NAS), indole-3-propionic acid (IPA), and 5-hydroxy-indole-3-acetic acid (5HIAA) in altering basal and iron-induced lipid peroxidation in homogenates of hamster testes. To determine the effect of the indoles on the autoxidation of lipids, homogenates were incubated in the presence of each agent in concentrations of 0.0, 0.01, 0.05, 0.1, 0.25, 0.5, 0.75, 1.0, 2.0, 2.5, or 5.0 mM. To study their effects on induced lipid peroxidation, homogenates were incubated with FeSO(4) (30 microM + H(2)O(2) (0.1 mM) + each of the indoles in the same concentrations as above. The degree of lipid peroxidation was expressed as concentrations of malondialdehyde + 4-hydroxyalkenals (MDA + 4-HDA) per mg protein. The indoles decreased both basal and iron-related lipid peroxidation in a concentration-dependent manner. Melatonin reduced basal MDA + 4-HDA levels when used at the concentrations of 0.25 mM or higher, and prevented iron-induced lipid peroxidation at concentrations of 1.0, 2.0, 2.5, or 5.0 mM. The lowest effective concentrations of NAS required to lower basal and iron-related lipid peroxidation were 0.05 mM and 0.25 mM, respectively. IPA, only when used in the highest concentrations of 2.5 mM or 5 mM inhibited basal lipid peroxidation levels and it was ineffective on the levels of MDA + 4-HDA due to iron damage. 5HIAA reduced basal lipid peroxidation when used at concentrations of 0.25 mM or higher, and it prevented iron-induced lipid peroxidation only at the highest applied concentration (5 mM). In conclusion, melatonin and related indoles at pharmacological concentrations protect against both the autoxidation of lipids as well as induced peroxidation of lipids in testes. In doing so, these agents would be expected to reduce testicular cancer that is initiated by products of lipid peroxidation.
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PMID:Relative efficacies of indole antioxidants in reducing autoxidation and iron-induced lipid peroxidation in hamster testes. 1132 24

Esophageal squamous cell carcinoma is a common fatal cancer, and Shanxi province, a region in north-central China, has some of the highest esophageal cancer rates in the world. Chromosomal regions with frequent allelic loss may point to major susceptibility genes that will assist us in understanding the molecular events involved in esophageal carcinogenesis and may serve as the basis for the development of markers for genetic susceptibility and screening for early detection of this cancer. This study was designed to identify events in the molecular progression of precursor and invasive lesions of squamous esophageal cancer. Twelve marker loci identified during our previous studies as having some of the highest rates of loss of heterozygosity (LOH) in invasive esophageal cancer were evaluated in laser-microdissected DNA obtained from low- and high-grade dysplastic lesions and invasive tumor foci from 10 fully embedded esophageal resection specimens. Each resection specimen contained a spectrum of disease, from epithelium that appeared histologically normal to invasive cancer, including a single dominant tumor surrounded by a region of precursor lesions (low- and high-grade dysplasia) and occasional "remote," nonadjacent precancerous foci. Using the 12 polymorphic markers, LOH was found in all of the three stages of disease. The frequency of LOH for all of the markers together increased with increasing disease severity. Among the informative low-grade dysplasia samples, LOH was detected with markers D3S1766 (3p), D4S2632 (4p), D9S910 (9q), and D13S1493 (13q), suggesting that LOH at these loci may be associated with early stages of tumor initiation and/or progression. LOH was detected among the informative high-grade (but not low-grade) dysplasia samples for the other eight markers tested, suggesting that LOH at these loci may occur later in the neoplastic process. In addition to the association between disease progression and these genetic changes, considerable genetic heterogeneity was found in each fully embedded resection specimen both between and within geographically separate neoplastic lesions.
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PMID:Genetic progression and heterogeneity associated with the development of esophageal squamous cell carcinoma. 1135 32

The malignant phenotype results from multiple genetic alterations, including the activation of oncogenes and inactivation of tumor suppressor genes. Activation of the Ki-ras oncogene has been implicated as an early event in the pathogenesis of lung adenocarcinomas in humans and experimental animal models. Previous studies from this laboratory have shown that, following treatment of pregnant [D2 x B6D2F(1)]F(2) or Balb/c mice with the polycyclic aromatic hydrocarbon, 3-methylcholanthrene (MC), lung tumors from the transplacentally exposed offspring exhibited a high incidence of mutations in the Ki-ras gene. The role of genetic alterations at other oncogenic or tumor suppressor loci that can mediate lung tumor initiation and/or progression have not been well characterized in either human or murine models. Using the transplacental carcinogenesis model, which results in the induction of both lung and liver tumors following in utero exposure to MC, the results of this and our previous studies show that alterations in the Ink4a locus occur in only 15 and 27% of the lung and liver tumors, respectively. Preliminary data also suggests that the type of mutation induced in the Ki-ras gene following the initial exposure to MC may influence lung tumor progression. These results imply that damage to the Ink4a gene is not a frequent pathway to malignant progression in mouse lung and liver tumors following in utero exposure to environmental carcinogens.
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PMID:Alterations at the Ink4a locus in transplacentally induced murine lung tumors. 1159 30


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