Mechanisms Of Cancer Induction Research Articles

Molecular Mechanisms Contributing Bacterial Infections to the Incidence of Various Types of Cancer

Cancer causes a major health concern worldwide due to high incidence and mortality rates. To accomplish this purpose, the Scopus, PubMed, and Web of Science databases were searched using the keywords bacteria and cancer. Most of published research addressed several different factors that induced cancer, such as toxins, medications, smoking, and obesity. Nonetheless, few studies are dealing with cancer induction via bacterial infection. In addition, mechanisms of cancer induction via bacterial infections are not well understood. Therefore, in this review, we will shed light on different bacteria that induced cancer via different molecular mechanisms. Among the bacterial infection that induced cancer, Helicobacter pylori was the first recognized bacteria which caused gastric cancer and might be also linked to extragastric cancer in humans. H. pylori has been associated with adenocarcinoma in the distal stomach by its ability to cause severe inflammations. It has been found that inflammations induced cancer via different mechanisms including induction of cell proliferation and production of high levels of free radicals. Recently, free radicals were found to induce and cause various types of cancer. Salmonella typhi has been found to be associated with gallbladder carcinoma (GBC). Also, intercellular infection of lungs with Chlamydia pneumoniae was found to contribute as one of the ethological factors of lung cancer. Moreover, infection of the urinary tract with Staphylococcus aureus, Klebsiella spp., and Proteus mirabilis has been found to cause bladder cancer. These microorganisms produce a high level of N-nitrosamines which are metabolically activated leading to the generation of alkylating agents that damage DNA and other macromolecules. It is concluded that a certain bacterium is linked with induction of a specific type of cancer via different molecular and biochemical mechanisms as discussed in the text in details. This infection could potentially affect human health in different ways. In addition, it is important to know the possible factors involved in cancer induction for better treatment of cancer patients.

Is There a Role for Antioxidants in the Prevention of Infection-Associated Carcinogenesis and in the Treatment of Infection-Driven Tumors?

Causative connections between infections and cancer are ascertained for several types of viruses, bacteria, and parasites. The mechanisms of cancer induction in chronically infected inflamed tissues strongly implicate oxygen- and nitrogen-centered reactive species, and an impairment of redox-sensitive molecular pathways involved in the tumorigenic transformation, tumor growth, altered immune defense, and in the mechanisms of tumor cell death and survival. Here, we briefly reviewed mechanistic data on carcinogenesis and tumor progression of three major infection-associated tumors, human papillomavirus-induced cervical cancer, hepatitis B virus-positive hepatocarcinoma, and Helicobacter pylori-positive gastric cancer. Notwithstanding the contradictory results of clinical studies on cancer chemoprevention with long-term, high dosage antioxidant vitamin/micronutrient supplementation, natural and synthetic agents with proven capacity to affect redox-dependent molecular pathways still hold the promise for preventing/delaying carcinogenesis initiation, as well as the overt malignancy evolution from dysplastic/ aplastic stages. Novel directions for a targeted antioxidant-based approach to the reduction of persistent infection-driven cancer risk stems from the current knowledge of critical factors in the host-microbe interaction leading to oncogenesis. An emerging role of redox active substances in the chemotherapy of tumors relies on their stimulating effects towards TRAIL-related apoptosis and the induction of intracellular oxidative stress.

Mechanisms of Cancer Induction by Tobacco-Specific NNK and NNN.

Tobacco use is a major public health problem worldwide. Tobacco-related cancers cause millions of deaths annually. Although several tobacco agents play a role in the development of tumors, the potent effects of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) are unique. Metabolically activated NNK and NNN induce deleterious mutations in oncogenes and tumor suppression genes by forming DNA adducts, which could be considered as tumor initiation. Meanwhile, the binding of NNK and NNN to the nicotinic acetylcholine receptor promotes tumor growth by enhancing and deregulating cell proliferation, survival, migration, and invasion, thereby creating a microenvironment for tumor growth. These two unique aspects of NNK and NNN synergistically induce cancers in tobacco-exposed individuals. This review will discuss various types of tobacco products and tobacco-related cancers, as well as the molecular mechanisms by which nitrosamines, such as NNK and NNN, induce cancer.

Hormesis, an update of the present position.

The ongoing debate over the possible beneficial effects of ionising radiation on health, hormesis, is reviewed from different perspectives. Radiation hormesis has not been strictly defined in the scientific literature. It can be understood as a decrease in the risk of cancer due to low-dose irradiation, but other positive health effects may also be encompassed by the concept. The overwhelming majority of the currently available epidemiological data on populations exposed to ionising radiation support the assumption that there is a linear non-threshold dose-response relationship. However, epidemiological data fail to demonstrate detrimental effects of ionising radiation at absorbed doses smaller than 100-200 mSv. Risk estimates for these levels are therefore based on extrapolations from higher doses. Arguments for hormesis are derived only from a number of epidemiological studies, but also from studies in radiation biology. Radiobiological evidence for hormesis is based on radio-adaptive response; this has been convincingly demonstrated in vitro, but some questions remain as to how it affects humans. Furthermore, there is an ecologically based argument for hormesis in that, given the evolutionary prerequisite of best fitness, it follows that humans are best adapted to background levels of ionising radiation and other carcinogenic agents in our environment. A few animal studies have also addressed the hormesis theory, some of which have supported it while others have not. To complete the picture, the results of new radiobiological research indicate the need for a paradigm shift concerning the mechanisms of cancer induction. Such research is a step towards a better understanding of how ionising radiation affects the living cell and the organism, and thus towards a more reliable judgement on how to interpret the present radiobiological evidence for hormesis.

Characterizing dose-response relationships in multiple cancer bioassays.

In the evaluation of chemical compounds for carcinogenic risk, regulatory agencies such as the U.S. Environmental Protection Agency and National Toxicology Program (NTP) have traditionally fit a dose-response model to data from rodent bioassays, and then used the fitted model to estimate a Virtually Safe Dose or the dose corresponding to a very small increase (usually 10(-6)) in risk over background. Much recent interest has been directed at incorporating additional scientific information regarding the properties of the specific chemical under investigation into the risk assessment process, including biological mechanisms of cancer induction, metabolic pathways, and chemical structure and activity. Despite the fact that regulatory agencies are currently poised to allow use of nonlinear dose-response models based on the concept of an underlying threshold for nongenotoxic chemicals, there have been few attempts to investigate the overall relationship between the shape of dose-response curves and mutagenicity. Using data from an historical database of NTP cancer bioassays, the authors conducted a repeated-measures Analysis of the estimated shape from fitting extended Weibull dose-response curves. It was concluded that genotoxic chemicals have dose-response curves that are closer to linear than those for nongenotoxic chemicals, though on average, both types of compounds have dose-response curves that are convex and the effect of genotoxicity is small.

Persistence of increased levels of ribosomal gene activity in CHO-K1 cells treated in vitro with demethylating agents

The rate of ribosomal gene activity was evaluated by silver straining of the Nucleolus Organisers (NOs) in cultured CHO-K1 cells after a 12 h pulse with two demethylating agents (L-ethionine and 5-azacytidine). Silver staining of the NOs was measured every 24 h, from 24 up to 110 h after seeding. The purpose was to test the hypothesis that drug-induced demethylation is associated to heritable modifications of rDNA activity. Ribosomal gene activity was shown to be significantly increased by both agents. The increase persisted throughout the experiments, thereby suggesting the heritability of this epigenetic modification. The analysis of heritable DNA damage or modification is an important task in studying the risk of cancer onset and the mechanisms of cancer induction. In these studies two main results were obtained; (i) heritable DNA variations can be induced by both mutational and epigenetic changes; (ii) the modified end-point was not negatively selected.

Structural evidence for a dichotomy in rodent carcinogenesis: Involvement of genetic and cellular toxicity

The structural determinants identified as associated with carcinogenicity in rodents were compared to the structural determinants associated with mutagenicity in Salmonella and toxicity to cultured cells. The analysis revealed that the determinants of carcinogenicity could be separated into two almost mutually exclusive groups: Those associated with mutagenicity (and electrophilicity) and those associated with cell toxicity. These findings provide evidence for two mechanisms of cancer induction: A genotoxic one and a non-genotoxic one associated with cell toxicity.

Implications for the Future: Regulation of Chemicals and Prevention of Cancer

Lifetime feeding studies, when positive for cancer induction, do not provide information to differentiate between primary and secondary mechanisms of cancer induction. So many factors can influence the ultimate risk of incurring cancer in animals or humans that the observation of an increased incidence of cancer in association with exposure to any particular test substance should not lead automatically to the inference that the substance is a carcinogen per se. An increased incidence of cancer can result not only from exposure to “complete” carcinogens, but also from critical exposures to the following factors: those that decrease biological resistance to other independently occurring cancer risk factors, those that cause toxic hyperplasia, or those that act as classical promoters. Both initiation and promotion are prerequisites to cancer induction. Initiation can result independently from the effects of viruses, radiation, chemical initiators, and aging. For example: endogenously-formed nitrosamines are capable of effecting initiation in hepatic cells. Many non-genotoxic hepatic so-called “carcinogens” appear to be “promoters” of cancer induction rather than complete carcinogens. Hepatic cancer induction can be enhanced by classical promotion phenomena, by toxic hyperplasia, or by selective pressures on cell replication created by hormones. Substantial and consistent exposure doses are required to invoke secondary mechanisms of enhancing cancer induction; these secondary events occur in dosage ranges associated with observable histopathologic effects and thus can be detected and measured. By using combinations of in vitro and in vivo techniques, no-adverse-effect dosage levels can be determined whereby the risks for enhancing cancer induction can be avoided.