Trichloroethylene and Human Cancer

Evidence to suggest that trichloroethylene may be a human carcinogen comes mainly from two small epidemiological studies with supporting evidence from human toxicity and genotoxicity studies and from rodent cancer bioassays. Careful analysis of these data reveal marked inconsistencies between the data, differences in the conclusions drawn by various authorities reviewing the same data and, for certain key human studies, a complete absence of exposure data. Much of the rodent cancer data may be dismissed as not indicative of a human hazard because the tumors result from either peroxisome proliferation, or as a consequence of exceptionally high metabolic rates that are found uniquely in mouse tissues, or because the tumors only occur in the presence of overt toxicity. A common mechanism invoked to account for the development of renal tumors in both rats and humans is unproven, there is contrary evidence to suggest that this mechanism does not result in renal cancer, and alternative mechanisms have been proposed. Overall, the uncertainty and lack of consistency throughout the trichloroethylene studies, whether they are in humans, in animals, or in tests in vitro, lead to the conclusion that it would be wholly inappropriate to classify trichloroethylene as a human carcinogen.     

The mystery of chromosomal translocations in cancer

Chromosomal translocations in human cancer may result in products that can be suppressed by targeting drugs. An example is bcr-abl tyrosine kinase in chronic myelogenous leukemia that can be treated with imatinib mesylate. However, the mechanisms of translocations or exchanges of chromosomal segments are virtually unknown. In this summary, chromosomal translocations in human cancer are compared with 'crossing over' of chromosomal segments occurring during the first meiotic division. Several proposed mechanisms of the exchange of DNA between and among chromosomes are discussed. The conditions that appear essential for these events to occur are listed. Among them are proximity of the involved DNA segments, mechanisms of excising the target DNA, its transport to the new location, and integration into the pre-existing chromosome. The conclusion based on extensive review of the literature is that practically nothing is known about the mechanism of 'crossing over' or translocation. Based on prior work on normal human cells, it is suggested that only one of the two autosomes participates in these events that may include loss of heterozygozity, another common abnormality in human cancer.     

Fusion of short telomeres in human cells is characterized by extensive deletion and microhomology,and can result in complex rearrangements

Telomere fusion is an important mutational event that has the potential to lead to large-scale genomic rearrangements of the types frequently observed in cancer. We have developed single-molecule approaches to detect, isolate and characterize the DNA sequence of telomere fusion events in human cells. Using these assays, we have detected complex fusion events that include fusion with interstitial loci adjacent to fragile sites, intra-molecular rearrangements, and fusion events involving the telomeres of both arms of the same chromosome consistent with ring chromosome formation. All fusion events were characterized by the deletion of at least one of the telomeres extending into the sub-telomeric DNA up to 5.6 kb; close to the limit of our assays. The deletion profile indicates that deletion may extend further into the chromosome. Short patches of DNA sequence homology with a G:C bias were observed at the fusion point in 60% of events. The distinct profile that accompanies telomere fusion may be a characteristic of the end-joining processes involved in the fusion event.     

Cancer epigenetics: linking basic biology to clinical medicine

Cancer evolution at all stages is driven by both epigenetic abnormalities as well as genetic alterations. Dysregulation of epigenetic control events may lead to abnormal patterns of DNA methylation and chromatin configurations, both of which are critical contributors to the pathogenesis of cancer. These epigenetic abnormalities are set and maintained by multiple protein complexes and the interplay between their individual components including DNA methylation machinery, histone modifiers, particularly, polycomb (PcG) proteins, and chromatin remodeling proteins. Recent advances in genome-wide technology have revealed that the involvement of these dysregulated epigenetic components appears to be extensive. Moreover, there is a growing connection between epigenetic abnormalities in cancer and concepts concerning stem-like cell subpopulations as a driving force for cancer. Emerging data suggest that aspects of the epigenetic landscape inherent to normal embryonic and adult stem/progenitor cells may help foster, under the stress of chronic inflammation or accumulating reactive oxygen species, evolution of malignant subpopulations. Finally, understanding molecular mechanisms involved in initiation and maintenance of epigenetic abnormalities in all types of cancer has great potential for translational purposes. This is already evident for epigenetic biomarker development, and for pharmacological targeting aimed at reversing cancer-specific epigenetic alterations.     

Mechanism of oxidative DNA damage repair and relevance to human pathology

Since DNA is prone to oxidative attack cells have evolved multiple protective strategies to prevent the deleterious effects of DNA oxidation. Base excision repair is the major mechanism for repair of DNA base damage by reactive oxygen species but recent evidence indicate that nucleotide excision repair proteins, that are mutated in human syndromes, are involved too. The mechanisms of repair dealing with the direct oxidation of DNA will be reviewed taking as prototype the oxidized base 7,8-dihydro-8-hydroxyguanine. The function of the individual repair components as inferred from model mice indicate that the ablation of two gene functions is mostly required to lead to accumulation of oxidative DNA damage, mutagenesis and cancer development. The recent identification of human diseases associated with mutations in oxidative damage repair show that defects in this pathway may lead to increased cancer but their major causative role seems to be in neurological diseases.     

Mechanisms of DNA damage repair in adult stem cells and implications for cancer formation

Maintenance of genomic integrity in tissue-specific stem cells is critical for tissue homeostasis and the prevention of deleterious diseases such as cancer. Stem cells are subject to DNA damage induced by endogenous replication mishaps or exposure to exogenous agents. The type of DNA lesion and the cell cycle stage will invoke different DNA repair mechanisms depending on the intrinsic DNA repair machinery of a cell. Inappropriate DNA repair in stem cells can lead to cell death, or to the formation and accumulation of genetic alterations that can be transmitted to daughter cells and so is linked to cancer formation. DNA mutational signatures that are associated with DNA repair deficiencies or exposure to carcinogenic agents have been described in cancer. Here we review the most recent findings on DNA repair pathways activated in epithelial tissue stem and progenitor cells and their implications for cancer mutational signatures. We discuss how deep knowledge of early molecular events leading to carcinogenesis provides insights into DNA repair mechanisms operating in tumours and how these could be exploited therapeutically.     

Nutrition and epigenetics: an interplay of dietary methyl donors, one-carbon metabolism and DNA methylation

DNA methylation is the most extensively studied mechanism of epigenetic gene regulation. Increasing evidence indicates that DNA methylation is labile in response to nutritional and environmental influences. Alterations in DNA methylation profiles can lead to changes in gene expression, resulting in diverse phenotypes with the potential for increased disease risk. The primary methyl donor for DNA methylation is S-adenosylmethionine (SAM), a species generated in the cyclical cellular process called one-carbon metabolism. One-carbon metabolism is catalyzed by several enzymes in the presence of dietary micronutrients, including folate, choline, betaine and other B vitamins. For this reason, nutrition status, particularly micronutrient intake, has been a focal point when investigating epigenetic mechanisms. Although animal evidence linking nutrition and DNA methylation is fairly extensive, epidemiological evidence is less comprehensive. This review serves to integrate studies of the animal in vivo with human epidemiological data pertaining to nutritional regulation of DNA methylation and to further identify areas in which current knowledge is limited.     

Mapping Approaches to Gene Identification in Humans

Although a number of human genes that cause disease have been traced through the defective product, most genetic defects are recognized only by phenotype. When the biochemical defect is unknown, a gene can be located only through molecular approaches based on coinheritance (genetic linkage) of the disease phenotype with a particular allele of a polymorphic DNA marker that has already been mapped to a specific chromosomal region. Linkage studies in affected families have already localized genes for several important diseases, including cystic fibrosis. Finding a genetic linkage in families in which a disease segregates requires that the human genetic map have a large number of polymorphic markers; when the map is dense enough, any disease gene can be located by linkage to a known marker. Many DNA segments with a high degree of polymorphism are being found and mapped as markers in normal reference pedigrees. Genetic linkage mapping has implications even broader than its application to prenatal diagnosis or therapeutic strategy; analyzing mutations in important genes will illuminate basic mechanisms in molecular biology and the early events that lead to cancer and other disorders.     

Deployment of short-term assays for the detection of carcinogens; genetic and molecular considerations

The deployment of short-term assays for the detection of carcinogens inevitably has to be based on the genetic alterations actually involved in carcinogenesis. This paper gives an overview of oncogene activation and other mutagenic events connected with cancer induction. It is emphasized that there are indications of DNA alterations in carcinogenicity, which are not in accordance with "conventional" mutations and mutation frequencies, as measured by short-term assays of point mutations, chromosome aberrations and numerical chromosome changes. This discrepancy between DNA alterations in carcinogenicity and the endpoints of short-term assays in current use include transpositions, insertion mutations, polygene mutations, gene amplifications and DNA methylations. Furthermore, tumourigenicity may imply an induction of a genetic instability, followed by a cascade of genetic alterations. The evaluation of short-term assays for carcinogenesis mostly involves two correlations that is, between mutation and animal cancer data on the one hand and between animal cancer data and human carcinogenicity on the other. It should be stressed that animal bioassays for cancer in general imply tests specifically for the property of chemicals to function as complete carcinogens, which may be a rather poor reflection of the actual situation in human populations. The primary aim of short-term mutagenicity assays is to provide evidence as to whether a compound can be expected to cause mutations in humans, and such evidence has to be considered seriously even against a background of negative cancer data. For the evaluation of data from short-term assays the massive amount of empirical data from different assays should be used and new computer systems in that direction can be expected to provide improved predictions of carcinogenicity.     

Ionizing radiation-induced DNA injury and damage detection in patients with breast cancer

Breast cancer is the most common malignancy in women. Radiotherapy is frequently used in patients with breast cancer, but some patients may be more susceptible to ionizing radiation, and increased exposure to radiation sources may be associated to radiation adverse events. This susceptibility may be related to deficiencies in DNA repair mechanisms that are activated after cell-radiation, which causes DNA damage, particularly DNA double strand breaks. Some of these genetic susceptibilities in DNA-repair mechanisms are implicated in the etiology of hereditary breast/ovarian cancer (pathologic mutations in the BRCA 1 and 2 genes), but other less penetrant variants in genes involved in sporadic breast cancer have been described. These same genetic susceptibilities may be involved in negative radiotherapeutic outcomes. For these reasons, it is necessary to implement methods for detecting patients who are susceptible to radiotherapy-related adverse events. This review discusses mechanisms of DNA damage and repair, genes related to these functions, and the diagnosis methods designed and under research for detection of breast cancer patients with increased radiosensitivity.     

International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC publication No. 13. The need for biological risk assessment in reaching decisions about carcinogens

The prudent assumption that carcinogen bioassays in rodents predict for human carcinogenicity is examined. It is suggested that in certain cases, as for example the induction of tumors against a high incidence in controls, or in situations in which high dose toxicity may be a critical factor in the induction of cancer, the probability that animal bioassays predict for humans may be low. The term 'biological risk assessment' is introduced to describe that part of risk assessment concerned with the relevance of specific animal results to the induction of human cancer. Biological risk assessment, which is almost entirely dependent on an understanding of carcinogenesis mechanisms, is an important addition to present mathematical modeling used to predict the effects of animal carcinogens that have been demonstrated after high dose exposure, to the effects of the much smaller doses to which humans are perceived to be exposed. Evidence for the conclusions reached by biological risk assessment may sometimes be supported by a careful review of human epidemiological data.     

Understanding the molecular basis of common fragile sites instability: Role of the proteins involved in the recovery of stalled replication forks

Common fragile sites (CFS) are difficult-to-replicate genomic regions that show a high propensity to breakage following certain forms of DNA replication stress. Long considered a fascinating component of human chromosome structure, their relevance for biology is proven by the fact that they are frequently rearranged in cancer cells. Furthermore, CFS were found to be the preferential targets for genome instability in the early stages of human tumorigenesis. In recent years, much progress has been made in understanding the structural features of CFS and the mechanisms that monitor and regulate their integrity. From these studies it has emerged that the reason for their fragility may depend on the abnormal high-frequency of fork stalling events occurring at CFS during DNA replication. Consistently, the ATR-dependent checkpoint together with several proteins involved in response to replication fork stalling have been implicated in maintaining CFS stability. Furthermore, more recent findings propose that the scarcity of replication initiation events within CFS may contribute to their expression upon replication perturbation. This review will focus on the molecular determinants responsible for genomic instability at CFS and the systems used by cells to address this eventuality.     

Effects of Polyphenols on Brain Ageing and Alzheimer’s Disease: Focus on Mitochondria

The global trend of the phenomenon of population ageing has dramatic consequences on public health and the incidence of neurodegenerative diseases. Physiological changes that occur during normal ageing of the brain may exacerbate and initiate pathological processes that may lead to neurodegenerative disorders, especially Alzheimer's disease (AD). Hence, the risk of AD rises exponentially with age. While there is no cure currently available, sufficient intake of certain micronutrients and secondary plant metabolites may prevent disease onset. Polyphenols are highly abundant in the human diet, and several experimental and epidemiological evidences indicate that these secondary plant products have beneficial effects on AD risks. This study reviews current knowledge on the potential of polyphenols and selected polyphenol-rich diets on memory and cognition in human subjects, focusing on recent data showing in vivo efficacy of polyphenols in preventing neurodegenerative events during brain ageing and in dementia. Concentrations of polyphenols in animal brains following oral administration have been consistently reported to be very low, thus eliciting controversial discussion on their neuroprotective effects and potential mechanisms. Whether polyphenols exert any direct antioxidant effects in the brain or rather act by evoking alterations in regulatory systems of the brain or even the body periphery is still unclear. To understand the mechanisms behind the protective abilities of polyphenol-rich foods, an overall understanding of the biotransformation of polyphenols and identification of the various metabolites arising in the human body is also urgently needed.     

Prevention of cancer: vegetables and plants

1. Results of epidemiological studies indicate that a human diet rich in vegetables may lower the incidence of cancer. 2. This preventive effect of the vegetable diet against cancer could be ascribed to lowered intake of energy (joules) and its content of vitamins and carotene. 3. The consumption of vegetables means also less meat and fats as well as increased fiber content and specific chemopreventive compounds (indoles, plant phenols) present in such a diet. 4. The supposed mechanisms of prevention may include enhanced enzymatic detoxification of harmful compounds, and inhibition of their binding to cellular DNA, their adsorption on fiber, detoxification of radical forms of carcinogens by natural antioxidants in plants and probably many other ways too.     

Mechanisms of DNA oxidation

Oxidative damage of DNA caused by a variety of chemical and physical agents appears to be linked to cancer. However, it is becoming increasingly clear that endogenous generation of oxidants, such as hydroxyl radical and peroxynitrite, lead to oxidation of DNA, and this may cause cancer in individuals where no obvious exposure to chemical or physical agents known to be carcinogenic has occurred. The mechanisms for generation of these two oxidants in living organisms will be discussed and their reactivities with DNA to produce oxidized products (e.g., 8-oxo-dG) will be presented with special emphasis on the individual characteristics of the generation and reactivity of each oxidant.     

人乳头瘤病毒的致瘤性及机制

高危型人乳头瘤病毒(HPV)可能引发多种癌症,公认的如宫颈癌和宫颈上皮内瘤变.近年来的研究表明,HPV还与头颈部鳞癌、食管癌及乳房癌等的发生密切相关.HPV引起头颈部鳞癌的机制在某种程度上与宫颈癌相似,但又有所不同.因此,阐明HPV的致癌机制对于HPV相关肿瘤的治疗具有重要意义.     

Age-specific acceleration of cancer

One of the great challenges of cancer research is to explain the epidemiological patterns of cancer incidence based on the molecular processes that lead to uncontrolled cellular proliferation. The epidemiological data demonstrate that the age-specific incidence of many cancers increases in an approximately linear way with age when plotted on a log-log scale, with different slopes for different cancers. However, those epidemiological data also show that cancers of various tissues depart from log-log linearity in particular ways. Here, I illustrate those departures from log-log linearity by introducing plots of the age-specific acceleration of cancer. I then develop a very general model of cancer progression, which I use to explain the observed differences between tissues in age-specific acceleration. In one application of the model, I show that the spectacular rise and fall in age-specific acceleration observed in prostate cancer may be explained by multiple rounds of clonal expansion. In a second application, I demonstrate that the steady decline in age-specific acceleration of breast cancer may occur because precancerous mutations accumulate in many cellular lineages.