The food-borne trematodes, Opisthorchis viverrini and Clonorchis sinensis, are classified as group 1 biological carcinogens: definitive causes of cancer. By contrast, infections with Fasciola hepatica, also a food-borne trematode of the phylum Platyhelminthes, are not carcinogenic. This review explores the premise that the differential activation of macrophages during infection with these food-borne trematodes is a major determinant of the pathological outcome of infection. Like most helminths, the latter stages of infection with all 3 flukes induce M2 macrophages, a phenotype that mediates the functional repair of tissue damaged by the feeding and migratory activities of the parasites. However, there is a critical difference in how the development of pro-inflammatory M1 macrophages is regulated during infection with these parasites. While the activation of the M1 macrophage phenotype is largely suppressed during the early stages of infection with F. hepatica, M1 macrophages predominate in the bile ducts following infection with O. viverrini and C. sinensis. The anti-microbial factors released by M1 macrophages create an environment conducive to mutagenesis, and hence the initiation of tumour formation. Subsequently, the tissue remodelling processes induced by the M2 macrophages promote the proliferation of mutated cells, and the expansion of cancerous tissue. This review will also explore the interactions between macrophages and parasite-derived signals, and their contributions to the stark differences in the innate immune responses to infection with these parasites.

Quantitative measurement of relative flexibility have been made on amphibole fibres based on calculation of bending strain of maximally bent fibre segments. Enhanced flexibility was found to be an inverse function of fibre diameter. Asbestos is therefore a morphological entity. These conclusions are supported by consistent observations of fibre diameter/flexibility relationships in amphiboles, serpentine, and rutile. Flexibility may arise from growth of thin crystals (primary flexibility), or from crystal diameter reduction (secondary flexibility). Mechanisms for secondary flexibility in amphiboles include splitting and solution along cleavage planes. Gross morphological characteristics are a poor indicator of microscopic habit, since coarsely fibrous minerals such as picrolite antigorite may not be fibrous after particle width reduction, and secondary asbestiform fibres are often derived from minerals with a non-fibrous morphology on gross examination.

Scientific evidence strongly suggests that parasites are directly or indirectly associated with carcinogenesis in humans. However, studies have also indicated that parasites or their products might confer resistance to tumour growth. Plasmodium protozoa, the causative agents of malaria, exemplify the ambivalent link between parasites and cancer. Positive relationships between malaria and virus-associated cancers are relatively well-documented; for example, malaria can reactivate the Epstein-Barr Virus, which is the known cause of endemic Burkitt lymphoma. Nevertheless, possible anti-tumour properties of malaria have also been reported and, interestingly, this disease has long been thought to be beneficial to patients suffering from cancers. Current knowledge of the potential pro- and anti-cancer roles of malaria suggests that, contrary to other eukaryotic parasites affecting humans, Plasmodium-related cancers are principally lymphoproliferative disorders and attributable to virus reactivation, whereas, similar to other eukaryotic parasites, the anti-tumour effects of malaria are primarily associated with carcinomas and certain sarcomas. Moreover, malarial infection significantly suppresses murine cancer growth by inducing both innate and specific adaptive anti-tumour responses. This review aims to present an update regarding the ambivalent association between malaria and cancer, and further studies may open future pathways to develop novel strategies for anti-cancer therapies.

Prostate cancer is the most common malignancy and the second leading cause of cancer death, in men, in western countries. Prostate cancer is diagnosed in very few people aged younger than 50 years (<0.1% of all patients). The mean age of patients with this disorder is 72–74 years. Most men aged older than 85 years have histological prostate cancer. Androgen deprivation reduces tumour activity in approximately 80% of patients with advanced disease, but most tumours relapse within 2 years to an incurable castrate-resistant state. Treatment options for patients with castrate-resistant prostate cancer are very limited and, even with toxic therapy, such as docetaxel, the life expectancy is only improved by a median of 2 months. Hence earlier diagnosis and improved treatments for prostate cancer are urgently required. Novel drugs, such as Abiratorone acetate and MDV-3100 have shown promise in pre-clinical and early clinical trials, and a number are now in phase III clinical trials, alone or in combination with docetaxel.

At least six types of gene–environment interactions (GEI) have been proposed (Kouhry and Wagener, 1993) In the first type, neither the environmental exposure (EE) nor the genetic risk factor (GRF) have any effect by themselves, but interaction between them causes disease. This is the case of phenylalanine exposure and the phenylketonuria genotype. Type 2 is a situation in which the GRF has no effect on disease in the absence of exposure, but exacerbates the effects of the latter. This is the most important type of GEI in relation to metabolic susceptibility genes and human carcinogenesis. The third type is the converse of the second (EE is ineffective per se, but enhances the effect of GRF). Type 4 occurs when both EE and GRF increase the risk for disease, but the combination is interactive or synergistic: an example is the interaction between Xeroderma Pigmentosum and UV radiation. Types 5 and 6, according to the classification proposed by Kouhry, refer to cases in which the GRF is protective.

The model of GEI that is emerging as the most important in chemical carcinogenesis refers to metabolic susceptibility genes. The general population can be divided into subgroups depending on their susceptibility to the action of carcinogens, based on their ability to metabolize such compounds to electrophilic, reactive metabolites (which form adducts with DNA), or, respectively, electrophobic metabolites that are excreted. The present contribution is a short review of the relevant literature, with particular emphasis on some polymorphisms involved in dietary exposures. In addition, the practical implications of genetic testing in this field are discussed.

Le rayonnement ultraviolet est responsable d’un large impact sur les structures biologiques. C’est un carcinogène bien documenté. Alors qu’un certain nombre d’effets positifs peut être associé à ce rayonnement, les surexpositions induisent des effets aigus et chroniques sur la peau, les yeux et le système immunitaire. Les effets négatifs associés aux expositions peuvent être largement évités. Réduire les expositions au rayonnement UV par des modifications du comportement et de l’environnement constitue le but principal des mesures préventives. Longtemps considéré comme « innocent », le rayonnement UVA possède des propriétés mutagènes et carcinogènes qui sont aujourd'hui bien documentées et leurs mécanismes de production semblent aujourd'hui élucidés et en particulier la photochimie des UVA solaires dans la peau. Aujourd'hui, les mécanismes de la photocarcinogenèse induite par les UVA ou par les UVB paraissent identiques, leur importance étant égale dans le rayonnement solaire. Les efforts de prévention doivent s’adresser en priorité aux enfants mais également dans le cadre du travail, en particulier en extérieur. Des guides pratiques sont fournis par l’OMS pour aider les autorités sanitaires dans la mise en application d’une politique de prévention afin de réduire les risques associés au rayonnement ultraviolet.

The p53 protein is a multi-function nuclear factor that is activated in response to multiple forms of stress and controls the proliferation, survival, DNA repair and differentiation of cells exposed to potentially genotoxic DNA damage. Loss of p53 function by mutation is a frequent event in human cancer, and is thought to result in the capacity of cells to acquire and accumulate oncogenic mutations during the progression of neoplasia. The p53 protein is a metal-binding transcription factor that is inactivated by metal chelation and by oxidation in vitro. In intact cells, p53 protein activity is crucially dependent on the availability of Zn ions and is impaired by exposure to Cd, a metal which readily substitutes for Zn in a number of transcription factors. Inactivation by Cd suppresses the p53-dependent responses to DNA damage. Overall, these findings indicate that regulation by metals plays an important role in the control of p53, and that perturbation of this control may explain the carcinogenic potential of several metal compounds. Résumé La protéine p53 est un facteur nucléaire multi-fonctionnel qui est activé en réponse à de multiples formes de stress et qui contrôle la prolifération, la survie, la réparation de l’ADN et la différenciation de cellules exposées à des agents génotoxiques. La perte de la fonction de p53 par mutation est un évènement fréquent dans les cancers chez l’homme, et l’on considère que cette inactivation a pour conséquence de rendre la cellule susceptible d’accumuler rapidement des mutations oncogéniques au cours de la progression du cancer. La protéine p53 est un facteur de transcription qui lie les métaux et qui peut être inactivée in vitro par chélation des métaux ainsi que par oxydation. Dans des cellules en culture, l’activité biologique de la p53 dépend de la bio-disponibilité en Zn, et est altérée par l’exposition des cellules au Cd, un métal qui se substitue facilement au Zn dans nombre de facteurs de transcription Zn-dépendants. L’inactivation de p53 par le Cd inhibe les réponses p53-dépendantes suite à la formation de lésions de l’ADN. Globalement, ces données suggèrent que la régulation par les métaux joue un rôle important dans le contrôle de la p53, et que des perturbations de ce contrôle pourraient contribuer à expliquer le potentiel carcinogénique de certains composés métalliques.

Our preliminary observation, that sera from schistosomiasis patients react with carcinomas, raised the possibility of antigenic cross-reactivity. We here extend this observation to show that mice experimentally infected with Schistosoma mansoni react with human urothelial and transitional bladder carcinomas and also with a gastric carcinoma cell line, AGS. To identify cross-reacting epitopes, we looked for the expression of carcinoma markers in schistosome worms and eggs using monoclonal antibodies against tumour antigens MUC1, Tn and TF (also known as the oncofetal Thomsen-Friedenreich antigen or T antigen). Immunohistochemical staining showed that the TF-epitope is present in adult intravascular S. mansoni worms and eggs deposited in tissues of infected animals. The localization of TF-immuno-reactive material in schistosomes was seen at the parasite surface between male and female worms and around trapped eggs in the liver. This localization is consistent with the antigen being secreted. Mice experimentally infected with S. mansoni, developed circulating antibodies against the TF-epitope (identified as Gal(beta1-3) GalNAc-O-R) as seen in ELISA using TF-expressing asialoglycophorin (AGP) as antigen. The observed anti-TF response in S. mansoni-infected mice reflects the complexity of host-parasite interactions in this infection.

The aim of the present study was to identify functional antisense oligodeoxynucleotides (ODNs) against the rat glutathione S-transferase Mu (GSTM) isoforms, GSTM1 and GSTM2. These antisense ODNs would enable the study of the physiological consequences of GSTM deficiency. Because it has been suggested that the effectiveness of antisense ODNs is dependent on the secondary mRNA structures of their target sites, we made mRNA secondary structure predictions with two software packages, Mfold and STAR. The two programs produced only marginally similar structures, which can probably be attributed to differences in the algorithms used. The effectiveness of a set of 18 antisense ODNs was evaluated with a cell-free transcription/translation assay, and their activity was correlated with the predicted secondary RNA structures. Four phosphodiester ODNs specific for GSTM1, two ODNs specific for GSTM2, and four ODNs targeted at both GSTM isoforms were found to be potent, sequence-specific, and RNase H-dependent inhibitors of protein expression. The IC50 value of the most potent ODN was approximately 100 nM. Antisense ODNs targeted against regions that were predicted by STAR to be predominantly single stranded were more potent than antisense ODNs against double-stranded regions. Such a correlation was not found for the Mfold prediction. Our data suggest that simulation of the local folding of RNA facilitates the discovery of potent antisense sequences. In conclusion, we selected several promising antisense sequences, which, when synthesized as biologically stable oligonucleotides, can be applied for study of the physiological impact of reduced GSTM expression.

Results of international correlation and migrant studies suggest that dietary fat promotes carcinogenesis in hormone-sensitive sites, but this is disputed. In the present study, we used a Noble rat model of sex hormone-induced cancers to examine the effect of a high-fat diet on the incidence and latency of prostate and mammary cancer in male (n 139) and female (n 72) animals respectively. We also measured α-tocopherol levels in female breast tissue to determine whether a high intake of polyunsaturated fatty acids depletes antioxidant defence in target tissues, providing a possible potentiating mechanism for carcinogenesis. Results showed a very high incidence of hormone-induced adenocarcinomas of prostate and mammary gland, irrespective of diet. There was no difference in the pattern of carcinogenesis in different prostatic locations, weight of the prostate, or weight gain between male rats on the high-fat diet compared with the control (standard, low-fat) diet. In female rats, the incidence of mammary cancer and the body-weight gain were the same in both dietary groups, and breast α-tocopherol was also unaffected by dietary fat intake. Our present results are supportive of recent cohort studies that reported no significant association between intake of fat and the development of human prostate and breast cancer, and do not support a role for dietary fat in promoting sex hormone-induced prostate and mammary carcinogenesis.

This paper discusses the distribution of tumor size at detection derived within the framework of a new stochastic model of carcinogenesis. This distribution assumes a simple limiting form, with age at detection tending to infinity which is found to be a generalization of the distribution that arises in the length-biased sampling. Two versions of the model are considered with reference to spontaneous and induced carcinogenesis; both of them show similar asymptotic behavior. When the limiting distribution is applied to real data analysis its adequacy can be tested through testing the conditional independence of the size, V, and the age, A, at detection given A > t*, where the value of t* is to be estimated from the given sample. This is illustrated with an application to data on premenopausal breast cancer. The proposed distribution offers the prospect of the estimation of some biologically meaningful parameters descriptive of the temporal organization of tumor latency. An estimate of the model stability to the prior distribution of tumor size and some other stability results for the Bayes formula are given.

Cell culture systems have been developed to assess the potential pathogenicity of mineral dusts. The in vitro cytotoxicities of a variety of dusts towards mouse peritoneal macrophages, Chinese hamster lung cells (V79 cell line) and human alveolar type II cells (A549 cell line) were investigated.

Non-pathogenic dusts were found to be inert in vitro. Fibrogenic non-fibrous dusts such as silica were only cytotoxic towards macrophages. Fibrous dusts which are both fibrogenic and carcinogenic in vivo are cytotoxic towards all three cell types, their cytotoxicity being dependent on fibre size. The size range important for the observed biological effect is longer than about 8 μm and thinner than about 1·5 μm.