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

Infection with the human immunodeficiency virus (HIV) invariably leads to the development of acquired immunodeficiency syndrome (AIDS) in most infected humans, yet does so rarely, if at all, in HIV-infected chimpanzees. The differences between the two species are not due to differences in cellular receptors or an inability of the chimpanzee to be infected, but rather to the lack of pan-immune activation in the infected primate. This results in reduced apoptotic death in CD4+ T-helper lymphocytes and a lower viral load. In humans the degree of chronic immune activation correlates with virus load and clinical outcome with high immune activation leading to high viral loads and the more rapid progression to AIDS and death. The type of immune perturbation seen in HIV-associated AIDS is similar to that of chronic graft-versus-host disease (GVHD) where reduced cell-mediated immune (CMI) responses occur early in the course of the disease and where humoral responses (HI) predominate. A reduced CMI response occurs in a number of chronic infectious diseases, including tuberculosis and leishmaniasis. More recently, it has become increasingly apparent that the CMI response is suppressed in virtually all malignant diseases, including melanoma and colorectal and prostate cancer. This raises the possibility that, as the malignant process develops, the cancer cells evolve to subvert the CMI response. Moreover, the reduced CMI response seen in colorectal cancer (CRC) patients is completely reversed following curative surgery strongly supporting the hypothesis that CRC can suppress the systemic immune response. Wound healing, ovulation, embryo implantation, and fetal growth are all associated with suppressed CMI and neovascularization (the formation of new blood vessels) or angiogenesis (the formation of new blood vessels from an existing vasculature). If unresolved, wound healing results in chronic inflammation, which can give rise to the phenomenon of "scar cancers." Indeed all the chronic inflammatory conditions known to be associated with the subsequent development of malignant disease, including chronic obstructive airway disease (COPD), ulcerative colitis (UC), and asbestosis, give rise to similar proangiogenic, suppressed CMI, and HI-predominant environments. In keeping with this CMI-associated cytokines such as interleukin (IL)-2 and interferon (IFN)-gamma tend to be antiangiogenic, whereas HI cytokines such as IL-6 tend to be proangiogenic. Furthermore, chronic immune activation leads to the synthesis and release of factors such as macrophage inflammatory protein (MIP)-1 that inhibit apoptosis through suppression of p53 activity. The "Golden Triangle" of suppressed CMI, angiogenesis, and reduced apoptosis would provide the ideal environment for the serial mutations to occur that are required for the development of malignant disease. If the observed association is relevant to carcinogenesis, then treatments aimed at reducing the components of these inflammatory conditions may be useful both in the setting of chemoprevention and the therapeutic management of established disease.
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PMID:Chronic immune activation and inflammation in the pathogenesis of AIDS and cancer. 1188 29

The poor overall survival of lung cancer patients treated with conventional therapies (chemotherapy, radiation therapy, and surgery) mandate novel approaches to treatment. Two novel approaches to treat lung cancer include gene therapy and immunologic therapy. Both treatments have preclinical data suggesting potential clinical use. In gene therapy, the identification of specific genes critical to the development of carcinogenesis has offered the opportunity to target these genes or their products for treatment. One possible gene therapy strategy that has been pursued in phase I and II lung cancer trials is to replace nonfunctional tumor suppressor genes such as mutated or deleted p53 genes with wild-type p53 genes by adenoviral gene transfer (Ad-p53). Transduction of the tumors has been accomplished with direct intratumoral injection or broncheoalveolar lavage. These studies have identified a potential role for radiosensitization of previously radiation-resistant local tumors by combining Ad-p53 with radiation or possibly chemoradiation. Another novel strategy that may allow systemic treatment of lung cancers is immunologic therapies. Immunotherapies have focused on augmenting the immune response to cancer by passive strategies (e.g., antivascular endothelial growth factor) or active nonspecific (e.g., interferon), or by specific (e.g., anti-idiotype therapy) strategies. These novel strategies are currently in clinical trials and will potentially allow additional therapeutic options for patients resistant to conventional therapies.
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PMID:Genetic and immunologic therapies for lung cancer. 1189 19

In experimental studies, bovine lactoferrin (bLF) has been found to significantly inhibit colon, esophagus, lung, and bladder carcinogenesis in rats when administered orally in the post-initiation stage. Furthermore, concomitant administration with carcinogens resulted in inhibition of colon carcinogenesis, possibly by suppression of phase I enzymes, such as cytochrome P450 1A2 (CYP1A2), which is preferentially induced by carcinogenic heterocyclic amines. Enhancement of the activities of their phase II counterparts, such as glutathione S-transferase might have also played a critical role in post-initiation suppression in a study of tongue carcinogenesis. Anti-metastatic effects were moreover detected when bLF was given intragastrically to mice bearing highly metastatic colon carcinoma 26 cells (Co 26Lu), with apparent enhancing influence on local and systemic immunity. Marked increase in the number of cytotoxic T and NK cells in the mucosal layer of the small intestine and peripheral blood cells was thus found, this in turn enhancing the production of Interleukin 18 (IL-18) and caspase-1 in the epithelial cells of the small intestine, with possible consequent induction of interferon (IFN)-gamma positive cells. Furthermore, bLF has been found to exert anti-hepatitis C virus (HCV) activity in a preliminary clinical trial in patients with chronic active hepatitis due to this virus, a main causative factor in hepatocellular carcinoma development in Japanese. More extensive clinical trials are now underway in the National Cancer Center Hospital and other institutes to further explore the preventive potential against colon carcinogenesis.
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PMID:Cancer prevention by bovine lactoferrin and underlying mechanisms--a review of experimental and clinical studies. 1190 37

Hepatitis C virus (HCV) infection is responsible for more than a half of the cases of chronic viral hepatitis in Japan. About 20% of patients who are chronically infected with the virus develop cirrhosis about 20-30 years after the infection, with hepatocellular carcinoma developing in about 5% of patients a year. The only drug that effectively reduces the virus is interferon, but complete eradication of the virus can be obtained in only 30%-40% of treated patients. Reevaluation of the predictive factors to eradicate the virus by 24-week interferon therapy showed that the genotype other than 1b, a low virus load, and multiple amino acid substitutions in the interferon sensitivity determining region (ISDR) of genotype 1b are statistically significant predictive factors. Amino acid substitution in the PePHD domain of the E2 protein was rare and was unrelated with the outcome of interferon therapy. The fluctuation of the virus titer measured by branched DNA during a 2-year observation period was less that 10-fold in most patients, and amino acid substitutions in the ISDR were rare in such patients, suggesting that one point measurement of these parameters may be useful to select candidates for interferon therapy. A comparison of patients treated with interferon and untreated patients from the viewpoint of cancer prevention showed only a slight decrease in the risk of treated patients developing hepatocellular carcinoma. However, patients who showed normal alanine amino-transaminase (ALT) irrespective of virus clearance showed a significantly reduced risk of liver carcinogenesis. Similarly, a retrospective study to evaluate the long-term preventive effect of glycyrrhizin on hepatocellular carcinoma development showed that the therapy was effective in lowering the ALT value and in preventing liver carcinogenesis.
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PMID:Management of chronic hepatitis C and prevention of hepatocellular carcinoma. 1210 70

It is very difficult to predict new developments in hepatology so we have decided to analyse the most important issues related to three clinical conditions in hepatology. The first is chronic hepatitis. Here, we discuss the relevance of occult forms of hepatitis B virus infection in the development of cryptogenic liver disease and hepatocellular carcinoma. In addition, the role of genotyping in hepatitis B is analysed, indicating that patients with genotype A have a better prognosis than those with genotype D. The treatment of hepatitis B virus infection is also reviewed, and it has been suggested that research should be directed towards the development of new anti-viral agents to suppress virus replication. The natural history of hepatitis C virus infection is considered, emphasizing the need to know the progression of fibrosis in these patients. The chapter also suggests that treatment of hepatitis C virus infection with pegilated interferon and ribavirin is currently relatively effective. New therapeutic strategies will be required in the future, the most important challenge being the development of a hepatitis C virus vaccine. The second section is on chronic cholestasis. The role of anti-mitochondrial antibodies in primary biliary cirrhosis is considered. The possible infectious agents implicated as potential triggers of primary biliary cirrhosis are also discussed, suggesting that several infections may play a role in the pathogenesis of this condition. Other aetiopathogenic factors, for example organic compounds, drugs and chemicals, are indicated. It is possible that, in the near future, the precise sequence and molecular basis by which infectious agents or xenobiotics may initiate the cascade of the autoimmune response will be defined. One of the most important challenges in primary sclerosing cholangitis concerns the mechanisms that may induce the development of this disease. Up until now, genetic factors have been suggested, recent data reporting a clear-cut association between primary sclerosing cholangitis and the tumour necrosis factor-alpha(2) allele. The third part of this chapter includes recent progress achieved in hepatocellular carcinoma, discussing developments in the knowledge of hepatocellular carcinogenesis. Hepatocellular carcinomas appear so far to be genetically heterogeneous neoplasms, and this heterogeneity may correlate with the variety of aetiological factors involved. The risk factors and primary, secondary and tertiary prevention of the condition are also analysed. Finally, the development of new therapeutic strategies for hepatocellular carcinoma is evaluated by evidence-based studies.
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PMID:Expected developments in hepatology. 1247 1

Activated inflammatory leukocytes generate a variety of reactive oxygen and nitrogen species (RONS) that may have roles in mutagenesis and carcinogenesis. The purpose of the present study was to explore the relationship between inflammatory leukocyte activation and mutagenesis using co-culture systems. We investigated the mutagenic potentials of 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated differentiated HL-60 (human promyelocytic leukemia cells), and RAW 264.7 cells (murine macrophages) stimulated with lipopolysaccharide (LPS) and interferon (IFN)-gamma by co-culturing each cell line with AS52 cells, a transgenic Chinese hamster ovary cell line. HL-60 cells rapidly generated superoxide (O(2)(-)) 15 min to 1 h (peak at 30 min) following TPA stimulation. RAW 264.7 cells stimulated with LPS and IFN-gamma produced O(2)(-), nitric oxide (NO) and peroxynitrite (ONOO(-)) continuously for 5-25 h. There was a 2.0-fold increase in the mutation frequency of the gpt gene in AS52 cells co-cultured with TPA stimulated HL-60 cells, when compared with non-treated cells. Importantly, this increase in mutation frequency was significantly suppressed by antioxidants, such as superoxide dismutase (SOD) and diphenylene iodonium (DPI), an NADPH oxidase inhibitor (inhibition rates: IRs = 18.2 and 35.1%, respectively). Similarly, co-culture of AS52 cells with LPS/IFN-gamma-stimulated RAW 264.7 cells also increased the mutation frequency of the gpt gene by 2.6-fold, and this increase in mutation frequency was suppressed by SOD, DPI and N(5)-(1-iminoethyl)-L-ornithine dihydrochloride (L-NIO), an specific iNOS inhibitor (IRs = 58.3, 70.8 and 70.8%, respectively). In co-culture experiments, activated HL-60 and RAW 264.7 cells increased 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in AS52 cells when compared with non-treated controls (1.7- and 1.6-fold, respectively). Treatment of AS52 cells with hydrogen peroxide (H(2)O(2), 100 micro M), ONOO(-) (100 micro M) and SIN-1 (100 micro M), a ONOO(-) generator, also increased the mutation frequency of the gpt gene (4.6-, 5.4- and 2.8-fold, respectively). Taken together, these results support the hypothesis that RONS, derived from activated inflammatory leukocytes, are mutagenic in the biological systems, and that RONS generation inhibitors are potentially anti-mutagenic, and thus may be useful in cancer preventive strategies.
Carcinogenesis 2003 Feb
PMID:Mutagenicity of reactive oxygen and nitrogen species as detected by co-culture of activated inflammatory leukocytes and AS52 cells. 1258 72

Chronic inflammation contributes to carcinogenesis, but the underlying mechanisms are poorly understood. We report that aged granulocyte-macrophage colony stimulating factor (GM-CSF)-deficient mice develop a systemic lupus erythematosis (SLE)-like disorder associated with the impaired phagocytosis of apoptotic cells. Concurrent deficiency of interferon (IFN)-gamma attenuates the SLE, but promotes the formation of diverse hematologic and solid neoplasms within a background of persistent infection and inflammation. Whereas activated B cells show a resistance to fas-induced apoptosis, antimicrobial therapy prevents lymphomagenesis and solid tumor development. These findings demonstrate that the interplay of infectious agents with cytokine-mediated regulation of immune homeostasis is a critical determinant of cancer susceptibility.
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PMID:Deficiencies of GM-CSF and interferon gamma link inflammation and cancer. 1273 63

Although controversy persists about the influence of cirrhosis on the incidence of portal vein invasion and other prognostic indicators of recurrence and survival (e.g., histologic grade, mitotic activity, multiplicity), it is clear that the degree of cirrhosis is important for the long-term survival of patients with HCC. Multicentricity is especially important because it reflects the field carcinogenesis associated with viral hepatitis and particularly chronic HCV infection [59]. A better understanding of the different mechanisms linked to tumor recurrence will help select the best candidates for curative surgery and help tailor adjuvant therapy, such as interferon therapy, to each patient [60]. Finally, the importance of vascular invasion, number of tumors, and tumor size of HCCs in addition to the effect of fibrosis has led Vauthey et al [20] to propose a simplified staging of HCC with better prognostication of survival.
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PMID:Pathologic spectrum and prognostic significance of underlying liver disease in hepatocellular carcinoma. 1273 26

Abrogating cellular senescence is a necessary step in the formation of a cancer cell. Promoter hypermethylation is an epigenetic mechanism of gene regulation known to silence gene expression in carcinogenesis. Treatment of spontaneously immortal Li-Fraumeni fibroblasts with 5-aza-2'-deoxycytidine (5AZA-dC), an inhibitor of DNA methyltransferase (DNMT), induces a senescence-like state. We used microarrays containing 12 558 genes to determine the gene expression profile associated with cellular immortalization and also regulated by 5AZA-dC. Remarkably, among 85 genes with methylation-dependent downregulation (silencing) after immortalization, 39 (46%) are known to be regulated during interferon signaling, a known growth-suppressive pathway. This work indicates that gene silencing may be associated with an early event in carcinogenesis, cellular immortalization.
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PMID:Epigenetic silencing of multiple interferon pathway genes after cellular immortalization. 1282 46

Viral hepatitis, by either hepatitis C virus (HCV) or hepatitis B virus (HBV), is the dominant cause of hepatocellular carcinoma (HCC). This is to say that HCC may be prevented by controlling viral infection. Horizontal transmission of HCV has become obsolete owing to the discovery of the virus. Vertical transmission of HBV during delivery has been effectively prevented by vaccination and immunization of neonates. The efficacy of interferon therapy against HCV was recently much improved. We now possess several powerful antiviral drugs against HBV. There has been progress also in the treatment of HCC, and together with advances in diagnostics facilitating HCC detection at an early stage, tumor nodules can often be completely removed either by medical ablation or surgical resection. Nevertheless, recurrence of HCC after apparently curative treatment is extraordinarily frequent, since the remaining liver is still at a particularly high risk of HCC. An effective treatment of HCC should include measures to control de novo carcinogenesis.
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PMID:Prevention and treatment of hepatocellular carcinoma. 1476 50


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