Cause Cancer In Humans Research Articles

Transnitrosation of non-mutagenic N-nitrosoproline forms mutagenic N-nitroso-N-methylurea

N-Nitroso-N-methylurea (NMU) is a potent carcinogen and suspected as a cause of human cancer. In this study, mutagenic NMU was detected by HPLC after the transnitrosation of non-mutagenic N-nitrosoproline (NP) to N-methylurea in the presence of thiourea (TU) under acidic conditions. The structure of NMU was confirmed by comparing 1H NMR and IR spectra with that of authentic NMU after fractionation by column chromatography. Furthermore, a fraction containing NMU formed by transnitrosation was mutagenic in Salmonella typhimurium TA1535.NMU was formed in the reaction of NP and N-methylurea in the presence of 1,1,3,3-tetramethylthiourea (TTU) or 1,3-dimethylthiourea in place of TU as an accelerator. The reaction rate constants (k) for NMU formation were correlated with their nucleophilicity of sulfur atom in thioureas. The N-methylurea concentration did not affect the NMU formation, whereas the rate of NMU formation correlated linearly with concentrations of NP, TTU and oxonium ion. The observed kinetics suggests a mechanism by which the nitroso group was transferred directly from the protonated NP to the thiourea then to N-methylurea to form NMU. The rate-determining step was the formation of the complex with the protonated NP and thiourea.

Epstein-Barr virus and Burkitt lymphoma.

In 1964, a new herpesvirus, Epstein-Barr virus (EBV), was discovered in cultured tumor cells derived from a Burkitt lymphoma (BL) biopsy taken from an African patient. This was a momentous event that reinvigorated research into viruses as a possible cause of human cancers. Subsequent studies demonstrated that EBV was a potent growth-transforming agent for primary B cells, and that all cases of BL carried characteristic chromosomal translocations resulting in constitutive activation of the c-MYC oncogene. These results hinted at simple oncogenic mechanisms that would make Burkitt lymphoma paradigmatic for cancers with viral etiology. In reality, the pathogenesis of this tumor is rather complicated with regard to both the contribution of the virus and the involvement of cellular oncogenes. Here, we review the current understanding of the roles of EBV and c-MYC in the pathogenesis of BL and the implications for new therapeutic strategies to treat this lymphoma.

Oral Bacteria and Cancer

Over a number of years, epidemiological studies established several well-defined risk factors for cancer, including age, heredity, diet, tobacco use, chronic viral infections, and inflammation. Paradoxically, the success of these studies left little room for incorporation of any new factors or causative agents, and, consequently, the idea that a bacterial infection could contribute to cancer was generally disregarded. However, landmark studies in the early 1990s established Helicobacter pylori as a causative agent of gastric cancers, resulting in a paradigm shift regarding the relationship between microbial agents and cancers [1]. Indeed, in 1994, H. pylori became the first bacterial species to be officially recognized by the World Health Organization as a definite cause of cancer in humans. Since then, there has been a growing body of evidence supporting an association between specific microorganisms, including those in the oral cavity, and various types of cancers. The oral cavity is inhabited by complex multispecies communities that usually exist in a balanced immunoinflammatory state with the host [2]. Certain species, such as Porphyromonas gingivalis, can disrupt this equilibrium, resulting in a dysbiotic host– microbiota interaction. Subsequently, other community constituents, such as Fusobacterium nucleatum, can become opportunistically pathogenic, and the combined effect of a dysbiotic microbial community along with a dysregulated immune response ultimately causes periodontal disease [2]. These well-studied periodontal organisms have now emerged as the focal point for the developing association between oral bacteria and cancer. Perhaps the most likely carcinogenic link with oral bacteria is with oral squamous cell carcinoma (OSCC), one of the most common cancers worldwide. OSCC surfaces have been reported to harbor significantly higher levels of Porphyromonas and Fusobacterium compared with contiguous healthy mucosa [3]. Moreover, immunohistochemistry with P. gingivalis antibodies revealed higher levels of detection and intensity of staining in gingival carcinomas compared with healthy gingival tissue, although only a small number of cases were examined [4]. A striking association has also been demonstrated between P. gingivalis infection and pancreatic cancer. In a prospective cohort study of over 400 cases and controls, a .2-fold increase in risk of pancreatic cancer was observed among those with high levels of antibodies to P. gingivalis, after adjusting for known risk factors [5]. Similarly, in the extensive National Health and Nutrition Examination Survey III, orodigestive cancer mortality was found to be related to the levels of P. gingivalis antibodies, independent of periodontal disease [6]. Several recent studies have shown a strong association between F. nucleatum and colorectal cancer (CRC) [7–10]. F. nucleatum was found to be one of the more abundant species within and around CRC neoplasms, and levels of F. nucleatum correlated with the presence of lymph node metastases.

Shared Decision-Making: Is It Time to Obtain Informed Consent Before Radiologic Examinations Utilizing Ionizing Radiation? Legal and Ethical Implications

Concerns about the possibility of developing cancer due to diagnostic imaging examinations utilizing ionizing radiation exposure are increasing. Research studies of survivors of atomic bomb explosions, nuclear reactor accidents, and other unanticipated exposures to similar radiation have led to varying conclusions regarding the stochastic effects of radiation exposure. That high doses of ionizing radiation cause cancer in humans is generally accepted, but the question of whether diagnostic levels of radiation cause cancer continues to be hotly debated. It cannot be denied that overexposure to ionizing radiation beyond a certain threshold, which has not been exactly determined, does generate cancer. This causes a dilemma: what should patients be informed about the possibility that a CT or similar examination might cause cancer later in life? At present, there is no consensus in the radiology community as to whether informed consent must be obtained from a patient before the patient undergoes a CT or similar examination. The author analyzes whether there is a legal duty mandating radiologists to obtain such informed consent but also, irrespective of the law, whether there an ethical duty that compels radiologists to inform patients of potential adverse effects of ionizing radiation. Over the past decade, there has been a noticeable shift from a benevolent, paternalistic approach to medical care to an autonomy-based, shared-decision-making approach, whereby patient and physician work as partners in determining what is medically best for the patient. Radiologists should discuss the benefits and hazards of imaging with their patients.

Sister chromatid exchange, (SCE), High-Frequency Cells (HFCs) and SCE distribution patterns in peripheral blood lymphocytes of Spanish adult smokers compared to non-smokers

According to the International Agency for Research on Cancer, smoking tobacco is a major cause of cancer in humans. It causes about half of all male cancer deaths and an ever increasing number of cancer deaths in females. The aim of this study was to establish whether cigarette smoking increases sister chromatid exchanges (SCEs) in peripheral blood lymphocytes in two Spanish population groups; light and heavy smokers. The mean number of High-Frequency Cells (HFCs) was determined and, the SCE distribution pattern among the chromosomes was analysed represented by a ratio described below. A local sample of 101 adult smokers (n=48) and non-smokers (n=53), aged from 18 to 49years, was studied using SCE levels in peripheral lymphocytes. Heavy smoking (⩾10 cigarettes per day) increased significantly the SCE frequency and the HFC parameters. Neither age nor sex significantly influenced the frequencies in the groups studied.

Absence of HHV8 in colon cancer in cameroon

Background Colon cancer is the third most commonly diagnosed cancer in the world; for over 40 years, the incidence has reportedly been lower in West Africans than in Caucasians. HHV8 is a prevalent virus in equatorial Africa were Kaposi’s sarcoma was endemic even before the AIDS epidemic. As a result of the long period of evolutionary history in Africa, there is more genetic diversity between populations living within the African continent than between Africans and the rest of mankind. Not only do populations within Africa vary considerably with respect to their genes, but across the continent there is a very wide range of environments, in terms of climate and vegetation. For all of these reasons, one might expect a wide diversity of cancer patterns, the study of which would be illuminating to our understanding of the causes of human cancer. Cameroon is a blank area on the world cancer map because medical facilities necessary for recording cancer cases and the population data necessary for the calculation of rate are scarce or non-existent. Only 10% of malignant neoplasms are confirmed by histology. Pathology facilities are not available. There are fewer than 10 pathologists and 5 oncologists for the whole population of Cameroon. Liver cancer is the most common cancer with virtually a 100% mortality rate. Cervical cancer and breast cancer each represent 11% of the total cancer cases in the population. Colon cancer is becoming common. Purpose We carried out this descriptive study to find out if HHV8 may be found in colon cancer in our environment where the disease was previously rare. Kaposi’s sarcoma is still epidemic in rural area in this country after the introduction of antiretroviral therapy. Material and method 30 paraffin blocks of colon cancer underwent immunohistochemistry with HHV8 antibodies. Results 135 cases of colon cancer were reported in our single institution over a five year period (2005–2010). Before year 2004, colon cancer was rarely reported in our hospital with less than ten cases per year. It is also known than colonoscopy and occult blood test have been introduced 15 years ago. No case of colon cancer in this series was positive for HHV8 antibody. Conclusion Colon cancer is becoming common in low prevalent settings and no association with HHV8 was found in this series.

Mutation signatures of carcinogen exposure: genome-wide detection and new opportunities for cancer prevention.

Exposure to environmental mutagens is an important cause of human cancer, and measures to reduce mutagenic and carcinogenic exposures have been highly successful at controlling cancer. Until recently, it has been possible to connect the chemical characteristics of mutagens to actual mutations observed in human tumors only indirectly. Now, next-generation sequencing technology enables us to observe in detail the DNA-sequence-level effects of well-known mutagens, such as ultraviolet radiation and tobacco smoke, as well as endogenous mutagenic processes, such as those involving activated DNA cytidine deaminases (APOBECs). We can also observe the effects of less well-known but potent mutagens, including those recently found to be present in some herbal remedies. Crucially, we can now tease apart the superimposed effects of several mutational exposures and processes and determine which ones occurred during the development of individual tumors. Here, we review advances in detecting these mutation signatures and discuss the implications for surveillance and prevention of cancer. The number of sequenced tumors from diverse cancer types and multiple geographic regions is growing explosively, and the genomes of these tumors will bear the signatures of even more diverse mutagenic exposures. Thus, we envision development of wide-ranging compendia of mutation signatures from tumors and a concerted effort to experimentally elucidate the signatures of a large number of mutagens. This information will be used to link signatures observed in tumors to the exposures responsible for them, which will offer unprecedented opportunities for prevention.

Cigarette Smoking and other Risk Factors for Kidney Cancer Death in a Japanese Population: Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC study)

Cigarette smoking is the largest single recognized cause of human cancers. In Western countries, many epidemiologists have reported risk factors for kidney cancer including smoking. However, little is known about the Japanese population. We evaluated the association of smoking with the risk of kidney cancer death in the Japan Collaborative Cohort (JACC) Study. Participants included 46,395 males and 64,190 females. The Cox proportional hazards model was used to determine age-and-sex adjusted relative risks. A total of 62 males and 26 females died from kidney cancer during the follow-up of 707,136 and 1,025,703 person-years, respectively. Heavy smokers (Brinkman index >1200), fondness of fatty foods, hypertension, diabetes mellitus (DM), and obesity were suggested to increase the risk of renal cell carcinoma while walking was suggested to decrease the risk. Even after controlling for age, sex, alcohol drinking and DM, heavy smoking significantly increased the risk. The present study suggests that six factors including smoking may increase and/or reduce the risk of kidney cancer in the Japanese population. Because of the small number of outcomes, however, we did not evaluate these factors after adjusting for all possible confounding factors. Further studies may be needed to confirm the findings in this study.

HPV Prevention series

Human Papilloma Virus (HPV) is a major leading cause of Human Cancer. Through the HPV Prevention series we would like to highlight the quality and the breadth of the research being carried out on the Control and Prevention of HPV and HPV related disease. This series aims to bring together a diverse range of HPV related specialties featuring research that has as ultimate goal insights into HPV related disease reduction. Articles within a wide range of topics such as natural history studies, impact of screening interventions or impact of HPV vaccines will be most welcome.

Lack of human tissue-specific correlations for rodent pancreatic and colorectal carcinogens

To better understand the relationships between chemical exposures and human cancer causation, incidence data for human cancer types were identified and pancreatic and colorectal cancers were studied in-depth to assess whether data supporting the causation of pancreatic or colorectal tumors by chemicals in rodents is predictive of causation by the same chemicals of the same tumors in humans. A search of the Carcinogenic Potency Database, the National Toxicology Program (NTP) technical report database, and the published literature identified 38 and 39 chemicals reported to cause pancreatic and colorectal tumors, respectively, in mice or rats. For each of these chemicals, searches were conducted of the International Agency for Research on Cancer monographs, the NTP Report on Carcinogens, and the published literature for evidence of induction of the same tumors in humans. Based on this evaluation, no conclusive evidence was identified to suggest that chemicals reported to cause pancreatic or colorectal tumors in rodents also cause these tumors in humans. These findings suggest that pancreatic tumor data from mouse and rat bioassays are of limited utility with regard to predicting similar tumor induction in humans. For colorectal cancer, a lack of correlation was noted for the vast majority of chemicals.

Arsenic-induced nitrative DNA damage in human HaCaT keratinocytes

Arsenic is a most likely environmental carcinogenic species that poses a significant health risk in humans. Epidemiological evidence strongly implicates exposure to arsenic in the causation of human cancer of the skin, lung, and urinary bladder (IARC, 2004). Chronic exposure to arsenic leads to the development of lesions on the skin, including hyperkeratosis, hyperpigmentation and cancer. Dermatitis following the exposure to arsenic is a hallmark of the early stages of arsenic poisoning. In this study, we performed immunocytochemical method to examine the formation of 8-nitroguanine, a mutagenic DNA lesion formed during inflammation, in long term arsenic-treated spontaneously immortalized, non-tumorigenic human epidermal keratinocytes (HaCaT) cell line. When HaCaT cells were exposed chronically for 18 weeks to an environmentally relevant level of arsenic (0.05 ppm) in vitro, malignant transformation occurred as evidenced by the formation of highly aggressive squamous cell carcinoma after inoculation into nude mice. Arsenic induced 8-nitroguanine formation, inducible nitric oxide synthase (iNOS) and nuclear factor-kB (NF-kB) expression in the HaCaT keratinocytes and xenograft tumors. The staining intensity of 8-nitroguanine, iNOS, NF-kB and p53 in arsenic-treated cells was significantly greater than that in non-treated control at every twenty four days. These results suggest that arsenic can induce formation of 8-nitroguanine via iNOS expression, which may contribute to carcinogenesis. Therefore, the formation of nitrative DNA damage could be one of the mechanisms responsible for arsenic-induced carcinoma. 8-Nitroguanine could be a useful indicator of the risk of skin cancer development in response to chronic arsenic toxicosis.

Recommendations and proposed guidelines for assessing the cumulative evidence on joint effects of genes and environments on cancer occurrence in humans

We propose guidelines to evaluate the cumulative evidence of gene-environment (G × E) interactions in the causation of human cancer. Our approach has its roots in the HuGENet and IARC Monographs evaluation processes for genetic and environmental risk factors, respectively, and can be applied to common chronic diseases other than cancer. We first review issues of definitions of G × E interactions, discovery and modelling methods for G × E interactions, and issues in systematic reviews of evidence for G × E interactions, since these form the foundation for appraising the credibility of evidence in this contentious field. We then propose guidelines that include four steps: (i) score the strength of the evidence for main effects of the (a) environmental exposure and (b) genetic variant; (ii) establish a prior score category and decide on the pattern of interaction to be expected; (iii) score the strength of the evidence for interaction between the environmental exposure and the genetic variant; and (iv) examine the overall plausibility of interaction by combining the prior score and the strength of the evidence and interpret results. We finally apply the scheme to the interaction between NAT2 polymorphism and tobacco smoking in determining bladder cancer risk.

DNA repair mechanisms protect our genome from carcinogenesis

Human cells are constantly exposed to DNA damage. Without repair, damage can result in genetic instability and eventually cancer. The strong association between the lack of DNA damage repair, mutations and cancer is dramatically demonstrated by a number of cancer-prone human syndromes, such as xeroderma pigmentosum (XP), ataxia-telangiectasia (AT) and Fanconi anemia (FA). This review focuses on the historical discoveries related with these three diseases and describes their impact on the understanding of DNA repair mechanisms and the causes of human cancer. As deficiencies in DNA repair are also often related with progeria symptoms, unrepaired damage and aging are somehow related. Several other pathologies associated with DNA repair defects, genetic instability and increased cancer risk are also discussed. In fact, studies with cells from these many syndromes have helped in understanding important levels of protection against cancer and aging, although little help has actually been conferred to the patients in terms of therapy. Finally, the recent advances in combined basic and translational research on DNA repair and chemotherapy are presented.

In Favor of Controlling Proven, but Not Probable, Causes of Cancer

We wish to compliment and complement the editorial by Landrigan et al. (2011) who inter alia synthesized the “Asturias Declaration” during the “International Conference on Environmental and Occupational Determinants of Cancer: Interventions for Primary Prevention” [World Health Organization (WHO) 2011]. Although the authors list recommendations that are certainly commendable, we strongly disagree with the inclusion of “probable” in the suggestion that “the WHO should develop a global framework for control of environmental and occupational carcinogens that concentrates on the exposures identified by IARC [International Agency for Research on Cancer] as proven or probable causes of human cancer.” Indeed, we would strongly suggest the need to focus on the causes of human cancer that have been identified by IARC as proven, but not on “probable” causes [59 agents have been classified by IARC as group 2A, i.e., probably carcinogenic to humans (IARC 2011)] to then direct premature prevention efforts on the latter. Soberingly, IARC’s diligent evaluation process of what can and what cannot cause cancer in humans would be blurred when equating group 1 (proven carcinogen) classifications with group 2A classifications, as recommended in the Asturias Declaration. A group 2A classification is not necessarily part of a one-way street to a group 1 verdict. To provide a recent, empirical example, shift-work that involves circadian disruption was classified as a probable human carcinogen (Straif et al. 2007). Importantly, though, as long as causality is not established, we should clearly be deterred from activities that are not driven by data. Moreover, means for primary prevention are elusive (Erren et al. 2009): Shift-work is unavoidable in our 24/7 societies, and it is impossible with today’s state of knowledge to identify workers who are robust to shift-work conditions and to dissuade others who may be susceptible to the effects of circadian disruption or chronodisruption (Erren et al. 2008; Erren and Reiter 2008). An IARC classification of “probable” human carcinogen, which implies uncertainty and the possibility that future research may exonerate the “culprit in question,” is certainly not an appropriate yardstick to guide valuable and limited resources. Instead, we should invest in controlling established carcinogens such as asbestos and smoking. Overall, when Richard Nixon declared the war on cancer on 23 December 1971, he remarked, “I hope in the years ahead that we may look back on this day and this action as being the most significant action taken during this administration” (Nixon 1971b). That initiative certainly is not—not only because of the Watergate scandal but, importantly, because of the highly ambitious goal “to find a cure for cancer” (Nixon 1971a). Lacking insights into how to cure cancer in the majority of cases, our objective for now—and presumably for many years to come—should be improved primary prevention of environmentally and occupationally caused cancers. Clearly, although progress in prevention is necessary and feasible, it is imperative to identify realistic and defensible goals and strategies. To this end, a sensible recommendation for strategy would be that “a new global policy framework for environmental cancer” (Landrigan et al. 2011) should focus on established carcinogens such as asbestos, “smoking, overweight, and inactivity” (Willett et al. 2011)—but not on probable culprits.

Human retrovirus XMRV: The end of an exciting story?

Viruses represent an important cause of cancer in humans: infections are estimated to account for close to one cancer case out of five.With the ongoing discovery of new infectious agents, this number should be raising in the near future. In 2006, the discovery of a new _-retrovirus in prostate cancer biopsies launched an intense research activity: could this new xenotropic MLV-related virus (XMRV) be the cause of prostate cancer? Five years later, the initial enthusiasm of retrovirologists has dramatically diminished. One by one, arguments favouring the hypothesis of human infection with XMRV are being refuted. The aim of this review article is to present the discovery of XMRV and to analyze recent data arguing against its existence in humans. A synthetic interpretation of XMRV literature will then be suggested.

Transcriptome Sequencing Demonstrates that Human Papillomavirus Is Not Active in Cutaneous Squamous Cell Carcinoma

Beta-papillomavirus (β-HPV) DNA is present in some cutaneous squamous cell carcinomas (cuSCC), but no mechanism of carcinogenesis has been determined. We used ultra-high throughput sequencing of the cancer transcriptome to assess whether papillomavirus transcripts are present in these cancers. Sixty-seven cuSCC samples were assayed for β-HPV DNA by PCR, and viral loads were measured with type-specific qPCR. Thirty-one SCCs were selected for whole transcriptome sequencing. Transcriptome libraries were prepared in parallel from the HPV18 positive HeLa cervical cancer cell line and HPV16 positive primary cervical and periungual SCC. Thirty percent (20/67) of the tumors were positive for β-HPV DNA, but there was no difference in β-HPV viral load between tumor and normal tissue (p=0.310). Immunosuppression and age were significantly associated with higher viral load (p=0.016 for immunosuppression; p=0.0004 for age). Transcriptome sequencing failed to identify papillomavirus expression in any of the skin tumors. In contrast, HPV 16 and 18 mRNA transcripts were readily identified in primary cervical and periungual cancers and HeLa cells. These data demonstrate that papillomavirus mRNA expression is not a factor in the maintenance of cuSCC.

Global Prevention of Environmental and Occupational Cancer

Cancer has become the second leading cause of death worldwide (Ferlay et al. 2008). Almost 13 million persons are diagnosed each year with cancer, and 7.6 million die (Ferlay et al. 2010). Today more than half of all cancers and 63% of cancer deaths occur in low- and middle-income countries (LMICs), a burden that is expected to grow in future years as the “Western lifestyle” spreads and the number of persons in LMICs who live to old age continues to increase (Ferlay et al. 2010). Toxic exposures in the environment, including workplace exposures, are responsible for a substantial percentage of all cancers (Danaei et al. 2005 Christiani 2011). Precise apportionment is not possible because of gaps in the exposure data, interactions between environmental and lifestyle carcinogens, and differences from country to country in exposure patterns (Pruss-Ustun and Corvalan 2006). However, credible estimates from the World Health Organization (WHO 2009) and the Internation Agency for Research on Cancer (IARC; Straif 2008) suggest that the fraction of global cancer currently attributable to toxic environmental exposures is between 7% and 19%. Asbestos, silica, arsenic, and radon are among the most common environmental carcinogens. All are considered proven causes of human cancer by IARC (El Ghissassi et al. 2009; Straif et al. 2009). Exposures to all remain widespread and are especially intense and uncontrolled in LMICs. Asbestos, for example, continues to be produced and used in quantities of nearly 2 million tons per year (U.S. Geological Survey 2011). While its use in Western Europe, the United States, and Canada has virtually ceased, export to the developing world is aggressively marketed and steadily increasing (Allen and Kazan-Allen 2008). For example, between 2000 and 2007, India’s consumption of asbestos is reported to have doubled (Burki 2010). Many cancers caused by environmental and occupational exposures can be prevented (Christiani 2011). Primary prevention—environmental interventions that halt the exposures that cause cancer—is the single most effective strategy. Primary prevention reduces cancer incidence, and it saves lives and billions of dollars. Successful examples include reductions in lung cancer and mesothelioma following bans on asbestos, reductions in bladder cancer after elimination of aniline dyes, reductions in leukemia following imposition of controls on benzene, and termination of hepatic angiosarcoma in chemical workers following introduction of closed-circuit technology for vinyl chloride polymerization (Christiani 2011). Despite their proven feasibility and cost-effectiveness, efforts to prevent environmental cancers have lagged. In contrast to vigorous and well-coordinated global efforts to prevent cancers caused by tobacco (WHO 2003), much more needs to be done in environmental cancer control and to further develop strategies for prevention of environmental causes of cancer (WHO 2008). To address these gaps and to develop a new global policy framework for environmental cancer, the WHO convened an international conference on “Environmental and Occupational Determinants of Cancer: Interventions for Primary Prevention” in Asturias, Spain, on 17–18 March 2011. The conference produced the “Asturias Declaration” (WHO International Conference on Environmental and Occupational Determinants of Cancer: Interventions for Primary Prevention 2011), which recommends that primary prevention of environmental and occupational cancers be an integral component of global cancer control. Specific recommendations of the declaration include the following: The WHO should develop a global framework for control of environmental and occupational carcinogens that concentrates on the exposures identified by IARC as proven or probable causes of human cancer (IARC 2011). The WHO should develop measurable indicators of carcinogen exposure and cancer burden to guide cancer surveillance worldwide. All countries need to adopt and enforce legislation and regulations to protect their populations, especially the most vulnerable (pregnant women, fetuses, infants, children, and workers) against environmental and occupational cancers. All countries need to develop communication campaigns tailored to local needs to educate their populations about environmental causes of cancer and prevention strategies. Corporations should comply with all rules and regulations for prevention of environmental and occupational cancers and adhere to the same standards in all countries—developed and developing—in which they and their subsidiaries operate. Conference participants agreed that successful prevention of environmental cancer will require partnerships among countries and collaborations of public health authorities with ministries of environment, labor, finance, and trade. In addition, independent, publicly funded research on environmental and occupational causes of cancer is an essential prerequisite to prevention (Tomatis 1995). The recommendations made by the participants in the “Asturias Declaration” complement and reinforce cancer control strategies focused on individual behaviors and medical practice. They will contribute to prevention of diseases beyond cancer and therefore synergize with the United Nations (UN) global agenda for control of noncommunicable diseases that is to be discussed at the UN General Assembly in September 2011 (UN General Assembly 2010). These recommendations will also prevent recurrence of such tragedies as the global asbestos epidemic, which now claims > 100,000 lives each year.

Abstract SY06-01: Critical role of the stress chaperone and cell signaling regulator GRP78 in cancer

Abstract SY06-01: Critical role of the stress chaperone and cell signaling regulator GRP78 in cancer

Mononuclear leukocyte DNA damage and oxidative stress: The association with smoking of hand-rolled and filter-cigarettes

Cigarette smoking is a major cause of human cancer at various sites, although its carcinogenic mechanisms still remain unestablished. Based on the use of a filter, cigarette smoke can be divided into a gas phase and a tar phase. Both contain different concentrations of oxidants, free radicals and tobacco-specific carcinogens. To explore the effects of both filtered and non-filtered cigarette smoke on DNA damage and oxidative status, we measured the level of mononuclear leukocyte DNA damage by use of the single-cell gel electrophoresis (Comet) assay. We also determined malondialdehyde (MDA), protein carbonyl content (PC) and total antioxidative capacity (TAC) levels in blood plasma of smokers of manufactured filter-cigarettes and of hand-rolled cigarettes. Cotinine levels were also measured in plasma to estimate the degree of smoking. Mononuclear leukocyte DNA damage, plasma MDA, plasma PC and plasma cotinine levels were found significantly higher, while plasma TAC levels were found significantly lower in smokers of filter-cigarettes and smokers of hand-rolled cigarettes, compared with control subjects. TAC levels in hand-rolled and manufactured filter-cigarette smokers were not significantly different from each other. However, the levels of DNA damage, plasma MDA, plasma cotinine, and plasma protein oxidation were significantly higher in hand-rolled cigarette smokers than in filter-cigarette smokers. There was a significant positive correlation between MDA and DNA damage in both hand-rolled cigarette smokers and manufactured filter-cigarette smokers. This study indicates that smoking of hand-rolled cigarettes has stronger genotoxic and oxidative effects on the metabolism than smoking of manufactured filter-cigarettes. We propose that these harmful effects could be attributed to the higher level of oxidants.

Mechanisms of Asbestos-Induced Carcinogenesis

Several types of fibrous stone called asbestos have been an unexpected cause of human cancer in the history. This form of mineral is considered precious in that they are heat-, friction-, and acid-resistant, are obtained easily from mines, and can be modified to any form with many industrial merits. However, it became evident that the inspiration of asbestos causes a rare cancer called malignant mesothelioma. Because of the long incubation period, the peak year for malignant mesothelioma is expected to be 2025 in Japan. Thus, it is necessary to elucidate the mechanisms of asbestos-induced mesothelial carcinogenesis. In this review, we summarize the cutting edge results of our 5-year project funded by a MEXT grant, in which local iron deposition and the characteristics of mesothelial cells are the key issues.