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

Apoptosis plays a critical role in the development and progression of ultraviolet-induced skin cancers. In particular, Fas and Fas ligand (FasL) interactions are known to control the development of "sunburn cells" or apoptotic keratinocytes in the UV-exposed epidermis. In the absence of functional Fas/FasL signaling, UV-induced apoptosis is diminished and mutations rapidly accumulate. UV-induced suppression of host immunity, a process regulating skin cancer outgrowth, is also controlled through Fas/FasL interactions. Other death receptors, such as the receptor for tumor necrosis factor, may also contribute to UV-induced carcinogenesis and progression. Understanding the involvement of cell death in cancers caused by exposure to sunlight may provide novel approaches for prevention and therapy of these ever-increasing malignancies.
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PMID:Mad dogs, Englishmen and apoptosis: the role of cell death in UV-induced skin cancer. 1281 74

The chemopreventive properties of the isothiocyanates have been attributed to their ability to inhibit phase I enzymes that activate procarcinogens, induce phase II protective enzymes and trigger apoptosis in transformed cells. In this study we provide evidence for a new mechanism of chemoprevention, wherein sublethal doses of phenethyl isothiocyanate (PEITC) sensitize cells to Fas-mediated apoptosis. The phenomenon was observed in the Fas-resistant T24 bladder carcinoma cell line and in Jurkat T cells overexpressing the anti-apoptotic protein Bcl-2. Caspase-3-like activity was increased up to 20-fold of that observed with either PEITC or anti-Fas antibody alone. While PEITC activated ERK, JNK and p38, inhibitors of these MAP kinases did not block apoptosis. PEITC transiently depleted cellular glutathione, providing a putative mechanism for sensitizing the cells to apoptosis. However, lowering glutathione with buthionine sulfoximine did not mimic the effect of PEITC. Instead, we propose that PEITC promotes apoptosis by directly modifying intracellular thiol proteins. The ability of PEITC to sensitize cells to receptor-mediated apoptosis provides an additional mechanism to explain its chemopreventive properties.
Carcinogenesis 2004 May
PMID:The chemopreventive agent phenethyl isothiocyanate sensitizes cells to Fas-mediated apoptosis. 1472 92

Flavonoids are a broadly distributed class of plant pigments, universally present in vascular plants and responsible for much of the coloring in nature. They are strong antioxidants that occur naturally in foods and can inhibit carcinogenesis in rodents. In this study, we examined acacetin (5,7-dihydroxy-4'-methoxyflavone), a flavonoid compound, for its effect on proliferation in a human liver cancer cell line, Hep G2. The results showed that acacetin inhibited the proliferation of Hep G2 by inducing apoptosis and blocking cell cycle progression in the G1 phase. Enzyme-linked immunosorbent assay showed that acacetin significantly increased the expression of p53 and p21/WAF1 protein, contributing to cell cycle arrest. An enhancement in Fas/APO-1 and its two form ligands, membrane-bound Fas ligand and soluble Fas ligand, as well as Bax protein, was responsible for the apoptotic effect induced by acacetin. Taken together, our study suggests that the induction of p53 and activity of the Fas/Fas ligand apoptotic system may participate in the antiproliferative activity of acacetin in Hep G2 cells.
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PMID:Acacetin inhibits the proliferation of Hep G2 by blocking cell cycle progression and inducing apoptosis. 1510 35

Despite the fact that expression of Fas ligand (FasL) in cytotoxic T lymphocytes (CTLs) and in natural killer (NK) cells plays an important role in Fas-mediated tumor killing, During tumor progression FasL-expressing tumor cells are involved in counterattacking to kill tumor-infiltrating lymphocytes (TILs). Soluble FasL levels also increase with tumor progression in solid tumors, and this increase inhibits Fas-mediated tumor killing by CTLs and NK cells. The increased expression of FasL in tumor cells is associated with decreased expression of Fas; and the promoter region of the FASL gene is regulated by transcription factors, such as neuronal factor kappaB (NF-kappaB) and AP-1, in the tumor microenvironment. Although the ratio of FasL expression to Fas expression in tumor cells is not strongly related to the induction of apoptosis in TILs, increased expression of FasL is associated with decreased Fas levels in tumor cells that can escape immune surveillance and facilitate tumor progression and metastasis. Transforming growth factor beta (TGF-beta) is a potent growth inhibitor and has tumor-suppressing activity in the early phases of carcinogenesis. During subsequent tumor progression, the increased secretion of TGF-beta by both tumor cells and, in a paracrine fashion, stromal cells, is involved in the enhancement of tumor invasion and metastasis accompanied by immunosuppression. Herein, the authors review the clinical significance of FasL and TGF-beta expression patterns as features of immune privilege accompanying tumor progression in the tumor microenvironment. Potential strategies for identifying which molecules can serve as targets for effective antitumor therapy also are discussed.
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PMID:The role of Fas ligand and transforming growth factor beta in tumor progression: molecular mechanisms of immune privilege via Fas-mediated apoptosis and potential targets for cancer therapy. 1516 Mar 30

Bovine lactoferrin, a multifunctional glycoprotein, has been shown to strongly inhibit development of azoxymethane (AOM)-induced rat colon tumors. Little, however, is known about the inhibitory mechanisms. We have demonstrated recently that lactoferrin enhances the expression of a member of the tumor necrosis factor receptor family, Fas, in the colon mucosa during both early and late stages of carcinogenesis. Thus, Fas could be involved in bovine lactoferrin-mediated inhibition of tumor development. To investigate this possibility, we studied the influence of bovine lactoferrin on Fas-mediated apoptosis with regard to expression of Fas, activation of caspase-8 and caspase-3, and DNA fragmentation in the colon mucosa of AOM-treated rats. Western blot analysis demonstrated a >2.5-fold increase in Fas protein expression, as well as elevation of the active forms of both caspase-8 and caspase-3. Immunohistochemical analysis revealed Fas-positive cells and apoptotic cells preferentially within the proximal colon region, clearly at the site of bovine lactoferrin-mediated tumor inhibition. These results suggest that apoptosis caused by elevated expression of Fas is involved in chemoprevention by lactoferrin of colon carcinogenesis.
Carcinogenesis 2004 Oct
PMID:Lactoferrin enhances Fas expression and apoptosis in the colon mucosa of azoxymethane-treated rats. 1519 17

Colorectal carcinoma cells are characterized by over-expression of IL-6 and the IL-6 receptor, an autocrine loop that promotes the development of many tumors. To determine the importance of this pathway, we examined the role that IL-6 plays in the biology of 228 and RKO colorectal tumor cells. IL-6 induced prominent tyrosine phosphorylation of the transcription factor STAT1 in both cell types. Furthermore, IL-6 exerts functional effects in these cells in that it inhibited apoptosis induced by Fas ligation, and up-regulated Bcl-xl, a STAT target gene, which can promote cell survival. Butyrate, a compound formed in the intestines of people who consume a high-fiber diet, may confer protection against the development of colorectal cancer. Given the potential importance of IL-6 in the pathogenesis of colorectal tumors, we tested the hypothesis that butyrate acts by inhibiting IL-6-induced signaling events in colorectal carcinoma cells. Following treatment with butyrate, the activation of STAT1 in response to IL-6, but not interferon-gamma, was completely lost. Butyrate induced a prominent decrease of mRNA and cell surface expression of the IL-6 receptor alpha (IL-6Ralpha) chain. Introduction of a soluble form of the IL-6Ralpha chain restored IL-6-induced STAT1 activation and resistance to apoptosis of butyrate treated cells. These experiments indicate that IL-6 may play an important role in the pathogenesis of colorectal cancers, and that butyrate may exert its protective effect by specifically blocking IL-6-induced signaling events.
Carcinogenesis 2004 Nov
PMID:IL-6-induced survival of colorectal carcinoma cells is inhibited by butyrate through down-regulation of the IL-6 receptor. 1528 82

Transduction of signalling through Fas receptor has been implicated in physiological regulation of apoptosis process as well as pathogenesis of various human diseases. The gene encoding Fas receptor contains single nucleotide polymorphism at -670 position, which influences the expression by different transcriptional efficiency of this gene. The aim of this study was to determine the distribution of -670 A/G Fas gene promoter polymorphism in cervical cancer patients and healthy control group in Poland in order to evaluate the potential association between Fas genotype and cervical carcinogenesis. Our results do not confirm the hypothesis that AA genotype in Fas gene promoter may be engaged in the development of cervical neoplasia.
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PMID:Evaluation of Fas gene promoter polymorphism in cervical cancer patients. 1528 3

Lactoferrin, an iron-binding glycoprotein, exhibits suppressive effects on development of azoxymethane (AOM)-induced tumors in the rat colon, but the mechanisms are largely unknown. In this study, we investigated the effect of lactoferrin on the gene expression of 10 apoptosis-related molecules in colon mucosa of AOM-treated rats during early and late stages of colon carcinogenesis by reverse transcription PCR. Here we document that a death-inducing receptor, Fas, and a pro-apoptotic Bcl-2 family member, Bid, are increased in the colon mucosa in proportion to decreases in AOM-induced aberrant crypt foci by lactoferrin. Similarly, increased expression of the pro-apoptotic Bcl-2 family member, Bax, was also observed in AOM-induced tumors in rats fed by lactoferrin. These results indicate that Fas and pro-apoptotic Bcl-2 members participate in the lactoferrin action and may contribute to suppressive effects on tumor development in the rat colon.
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PMID:Lactoferrin modifies apoptosis-related gene expression in the colon of the azoxymethane-treated rat. 1531 80

Opposing effects of inflammation on cancer have been described. Acute inflammation usually counteracts cancer development, while chronic inflammation promotes cancer development. Just as inactivation of the p53 pathway may be universal in the neoplasia, the activation of the NFkappaB pathway may, conversely, be frequent in carcinogenesis, and a requirement for inflammation and promotion. TNF, a key pro-inflammatory cytokine when binding to TNF receptor 1 (TNFR1), may cause survival or apoptosis, dependent on biochemical modifications that determine the type of complex formed; one complex causes NFkappaB activation and gives a cell survival signal (pro-oncogenic), while the other (modified) complex recruits caspases and causes apoptosis (anti-oncogenic). Fas-ligand (FasL)-Fas interaction can also result in opposing effects on carcinogenesis due to similar mechanisms. While IL-6 counteracts apoptosis and can promote cancer development, interferons can increase DNA repair and stabilize p53, thereby be anti-oncogenic.
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PMID:Inflammation as a tumor promoter in cancer induction. 1548 36

Hepatitis C virus (HCV) is a leading cause of morbidity and mortality worldwide but the pathogenesis of liver cell injury and the molecular mechanism of persistent infection of HCV are not well understood. The aim of this work is to establish the animal model of HCV infection for studying the biosynthesis and pathogenesis of HCV structural protein in transgenic mice. The structural genes (C+ E1 + E2) and 5'-uncoding region gene (5'UCR) of HCV isolated from China was inserted into pcDNA3 vector. The transgenic mice were produced by microinfecting this plasmid into mouse (C57BL/6 x ICR) embryos and the integrated mice were identified. The expression of core protein of HCV and mFas molecule were confirmed by immunohistochemical analysis using monoclonal antibody. The results revealed that the expression of core protein was detected in many mouses' tissues with nuclear staining, while the heart tissue was with cytoplasmic staining. The expression level in tissues was indicated as: heart>lung>kidney>liver. At meantime, Fas molecule was detected in heart, kidney and liver tissues, and the expression of Fas was parallel to that of core protein. Transgenic mouse containing HCV structural gene was established and the expression of Fas molecule may be associated with the expression of core protein of HCV. The Fas system or other signaling pathway to the programmed cell death may play important roles in HCV infection. Our transgenic mouse will provide a useful animal model to critically address issues of immune pathogenesis, direct cytopathic potential and carcinogenesis of the structural protein of HCV.
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PMID:[Core protein of hepatitis C virus expressed in transgenic mice is associated with the expression of Fas molecule]. 1561 29


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