Mechanisms for species differences in receptor-mediated carcinogenesis

Species differences resulting from a number of mechanisms are common in receptor-mediated chemical carcinogenesis. In this review, examples of possible mechanisms underlying these differences are discussed, including ligand metabolism, receptor polymorphisms, receptor isoforms, receptor levels, and crosstalk between signal transduction pathways. In addition, a number of other mechanisms also are likely to be important. The developmental state of the animal will determine the expression of receptors in different tissues. The regulatory pathways for cell proliferation and cell death and cell cycle check point controls can vary among species and tissues. Adaptation or potentiation of responses during chronic exposures to chemicals can greatly influence species differences. The mechanisms of adaptive processes are poorly understood but probably highly important for chronic toxicities such as cancer. Finally, different species may have different stem cell populations that are the targets for neoplastic transformation, and this will influence receptor-mediated carcinogenic responses. The implications of species differences in receptor-mediated responses for risk assessment are discussed.     

Chemical carcinogenesis and toxicity models: Matching complexity to objectives

Mathematical models predicting tissue doses of chemical toxicants can be either highly complex or simple, depending upon the end results needed. As an example of a highly complex mathematical model, the Miller Model of the distribution of reactive gases in human and animal lungs is described. The Miller Model accounts for the convection, the radial and axial diffusion, and the chemical reactions of gases as an inhaled breath passes down the airways. The geometry and physiology of human and animal lungs are used to calculate the convection and diffusion likely in each generation or bifurcating series of airways commencing with the trachea and extending 24 generations in humans. The chemical reactivity of ozone, an air pollutant, is accounted for by simulating second-order chemical reactions with the fluid lining materials of the lung and tissue biological molecules. The flux of ozone into three compartments (pulmonary tissue, overlying liquid layer and capillary blood) in each generation of the lung is calculated to provide molecular doses of ozone reaching each region of the lung. These results of calculated molecular dose are then used to construct dose-response curves for a variety of biological endpoints. A much simpler model is also described which recognizes the saturable or Michaelis-Menten type of kinetics controlling the removal of nickelous ion (nickel) from the lung. This model is used to calculate the chronic lung burden of the human lung for occupational, environmental and cigarette smoking exposure scenarios. In both the complex Miller Model and the simpler nickel lung burden model, the results can be used to calculate molecular doses at the potential site of action of these environmental chemicals and to unify a wide variety of studies. The predictions made are more likely to be valid since multiple investigators using a variety of animal species have participated in generation of the primary data. As a methodology, mathematical modeling based on physiological, physicochemical and anatomical principles provides a means of eliminating non-scientific considerations from the important process of regulating and recognizing toxic or cancer causing chemicals in the human environment.     

Glutamate receptor-mediated currents and toxicity in embryonal carcinoma cells

While primary neuronal cell cultures have been used to investigate excitotoxicity, development of cell lines exhibiting glutamate receptor-mediated death is desirable. P19 mouse embryonal carcinoma cells, exposed to retinoic acid and plated onto a layer of cultured mouse cortical glial cells, differentiated into neuron-like elements immunoreactive for neurofilaments and neuron-specific enolase. Whole-cell recordings revealed inward currents in response to extracellular application of either NMDA or kainate. The NMDA-induced currents exhibited a voltage-dependent blockade by magnesium, required glycine for maximal activation, and were blocked by the NMDA antagonist dizocilpine. Kainate-induced currents were blocked by the AMPA/kainate receptor antagonist CNQX. Exposure to 500 μM NMDA for 24 h destroyed most P19 cells (EC₅₀ approximately 70 μM); death was prevented by dizocilpine or D-APV. Exposure to 500 μM kainate also resulted in widespread death reduced by CNQX. Thus differentiated P19 cells exhibited both excitatory amino acid responses and vulnerability to excitotoxicity, characteristic of CNS neurons. These cells may provide a genetically open system useful for studying glutamate receptor-mediated phenomena at a molecular level. © 1993 John Wiley & Sons, Inc.     

Mobile dispersed genetic elements and their possible relation to carcinogenesis

In this paper, a hypothesis is described according to which mobile dispersed genetic elements are related to endogenous viral genomes and may be involved in oncogenic transformation by uptaking cellular genes important for cellular growth. It is also possible that, in certain cases, they can switch off the genes involved in the control of differentiation.     

Genetic epidemiology of multistage carcinogenesis

It is commonly believed that cancer is a multistage, polygenic disease. Even though conceptually appealing, the evidence supporting the multistage theory remains limited. Most known tumor suppresser genes are associated with monogenic dominant cancers following a two-hit pathway. We review results from a recent twin study on 90000 individuals that give support to the multistage theory. Statistically significant heritability estimates were shown for cancers of the colorectum (35%), breast (27%), and prostate (42%). These estimates are much higher than those obtained from family studies in which parents and offspring, or sibs are compared. The difference can be accounted for by the involvement of many genes. A polygenic cancer would show small effects in family studies but large effects in twin studies. We present calculations on the decrease in familial risks when the number of genes involved increases or when the penetrance decreases. We test the apparent number of stages involved in the main cancers from the Swedish Family-Cancer Database. The logarithms of the slopes suggest large differences in the apparent numbers of mutations involved in different cancers. The number of mutations required appears to be less in familial breast cancer compared to sporadic breast cancer. Study designs for gene identification should be revised to accommodate polygenic cancers.     

Genetic and epigenetic alteration in gastric carcinogenesis

Gastric cancer (GC) is an important cause of morbidity and mortality worldwide. In addition to environmental factors, genetic factors also play an important role in GC etiology, as demonstrated by the fact that only a small proportion of individuals exposed to the known environmental risk factors develop GC. Molecular studies have provided evidence that GC arises not only from the combined effects of environmental factors and susceptible genetic variants but also from the accumulation of genetic and epigenetic alterations that play crucial roles in the process of cellular immortalization and tumorigenesis. This review is intended to focus on the recently described basic aspects that play key roles in the process of gastric carcinogenesis. Genetic variation in the genes DNMT3A, PSCA, VEGF, and XRCC1 has been reported to modify the risk of developing gastric carcinoma. Several genes have been newly associated with gastric carcinogenesis, both through oncogenic activation (MYC, SEMA5A, BCL2L12, RBP2 and BUBR1) and tumor suppressor gene inactivation mechanisms (KLF6, RELN, PTCH1A, CLDN11, and SFRP5). At the level of gastric carcinoma treatment, the HER-2 tyrosine kinase receptor has been demonstrated to be a molecular target of therapy.     

Genetic and epigenetic alterations in pancreatic carcinogenesis

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Despite significant progresses in the last decades, the origin of this cancer remains unclear and no efficient therapy exists. PDAC does not arise de novo: three remarkable different types of pancreatic lesions can evolve towards pancreatic cancer. These precursor lesions include: Pancreatic intraepithelial neoplasia (PanIN) that are microscopic lesions of the pancreas, Intraductal Papillary Mucinous Neoplasms (IPMN) and Mucinous Cystic Neoplasms (MCN) that are both macroscopic lesions. However, the cellular origin of these lesions is still a matter of debate. Classically, neoplasm initiation or progression is driven by several genetic and epigenetic alterations. The aim of this review is to assemble the current information on genetic mutations and epigenetic disorders that affect genes during pancreatic carcinogenesis. We will further discuss the interest of the genetic and epigenetic alterations for the diagnosis and prognosis of PDAC. Large genetic alterations (chromosomal deletion/amplification) and single point mutations are well described for carcinogenesis inducers. Mutations classically occur within key regions of the genome. Consequences are various and include activation of mitogenic pathways or silencing of apoptotic processes. Alterations of K-RAS, P16 and DPC4 genes are frequently observed in PDAC samples and have been described to arise gradually during carcinogenesis. DNA methylation is an epigenetic process involved in imprinting and X chromosome inactivation. Alteration of DNA methylation patterns leads to deregulation of gene expression, in the absence of mutation. Both genetic and epigenetic events influence genes and non-coding RNA expression, with dramatic effects on proliferation, survival and invasion. Besides improvement in our fundamental understanding of PDAC development, highlighting the molecular alterations that occur in pancreatic carcinogenesis could provide new clinical tools for early diagnosis of PDAC and the molecular basis for the development of new effective therapies.     

Molecular mechanisms of metal toxicity and carcinogenesis

Many metals and metal-containing compounds have been identified to be potent mutagens and carcinogens. Recently, a new sub-discipline of molecular toxicology and carcinogenesis has been developed. The combination of newly developed molecular techniques and free radical approach makes it possible to insightfully examine metal-induced carcinogenesis in precise molecular terms so that intricate biological interrelationships can be elucidated. In consideration of the increased amount of new findings deciphered by utilizing these new methods, the 1st Conference on Molecular Mechanisms of Metal Toxicity and Carcinogenesis was held. In this conference, more than 50 scientists from nine countries presented their novel discoveries concerning metal-induced carcinogenesis, delineated molecular mechanism of metal carcinogenesis, and proposed novel therapeutic intervention and prevention strategies. This article reviewes some of the state-of-the-art information presented at the meeting regarding the molecular mechanisms of metal cytotoxicity and carcinogenesis.     

Oxidative mechanism of arsenic toxicity and carcinogenesis

Arsenic is a known toxin and carcinogen that is present in industrial settings and in the environment. The mechanisms of disease initiation and progression are not fully understood. In the last a few years, there has been increasing evidence of the correlation between the generation of reactive oxygen species (ROS), DNA damage, tumor promotion, and arsenic exposure. This article summarizes the current literature on the arsenic mediated generation of ROS and reactive nitrogen species (RNS) in various biological systems. This article also discusses the role of ROS and RNS in arsenic-induced DNA damage and activation of oxidative sensitive gene expression.     

Dopamine D1 receptor-mediated toxicity in human SK-N-MC neuroblastoma cells

Striatal degeneration occurs through unknown mechanisms in certain neurodegenerative disorders characterized by increased and sustained synaptic levels of dopamine. In the present studies, we examined the effects of treatment of SK-N-MC neuroblastoma cells with dopamine to understand the participation of dopamine D(1) receptor in postsynaptic cytotoxicity. Treatment of SK-N-MC cells either with dopamine or the D(1) receptor agonist SKF R-38393 resulted in a significant increase in the production of reactive oxygen species (by approximately 2.75-fold) and cell death ( approximately 50%), while antagonism of the D(1) receptor with SCH 23390 significantly reversed (to approximately 75% of control level) these effects. Accumulation of cAMP in dopamine treated cells (t(1/2)=1.5h) preceded changes in ionic gradient (t(1/2)=6.5h), as measured by intracellular potassium concentration and leakage of cytochrome c into the cytosol (t(1/2)=13 h), suggesting a possible staging of toxic events as a result of activation of D(1) receptor by dopamine. Examination of cellular metabolic properties with (13)C NMR spectroscopy showed an inhibitory effect on tricarboxylic acid cycle metabolism via D(1)-mediated receptors after treatment with dopamine, suggesting a direct role for D(1) receptor in dopamine-induced postsynaptic cell death. The present studies provide novel insight into a possible patho-physiological staging of cytotoxic events that are mediated by activation of D(1) receptor.     

Genetic studies in relation to kuru: an overview

Kuru is a subacute neurodegenerative disease presenting with limb ataxia, dysarthria, and a shivering tremor. The disease progress to complete motor and mental incapacity and death within 6 to 24 months. Neuropathologically, a typical pattern of neuronal loss, astrocytic and microglial proliferation, characteristic "kuru-type" amyloid plaques, and PrP deposits in the cerebral cortex and cerebellum are observed. Kuru is the prototype of a group of human transmissible spongiform encephalopathies (TSEs), or "prion" diseases, that include hereditary, sporadic and infectious forms. The latest member of this group, the variant Creutzfeldt-Jakob disease (vCJD), linked to transmission of bovine spongiform encephalopathy (BSE) to humans, shows features similar to kuru. Kuru has emerged at the beginning of the 1900s in a small indigenous population of New-Guinean Eastern Highlands, reached epidemic proportions in the mid-1950s and disappeared progressively in the latter half of the century to complete absence at the end of the 1990s. Early studies made infection, the first etiologic assumption, seem unlikely and led to a hypothesis that kuru might be a genetically determined or genetically mediated illness. After transmissibility of kuru had been discovered and all major epidemiologic phenomena adequately explained by the spread of an infectious agent with long incubation period through the practice of cannibalism, the pattern of occurrence still continued to suggest a role for genetic predisposition. Recent studies indicate that individuals homozygous for Methionine at a polymorphic position 129 of the prion protein were preferentially affected during the kuru epidemic. The carriers of the alternative 129Met/Val and 129Val/Val genotypes had a longer incubation period and thus developed disease at a later age and at a later stage of the epidemic. Observations made during the kuru epidemic are helpful in the understanding of the current vCJD outbreak, and vice versa clinical and experimental data accumulated in studies of other TSE disorders contribute to better understanding of the documented kuru phenomena.     

Genetic background of carcinogenesis in the thyroid gland

The process of carcinogenesis is permanently one of the most interesting and significant issues for researchers in different fields of medicine. Therefore, we attempted to bring closer the problem of neoplastic transformation in the thyroid gland. This article covers the latest data about genetic factors, involved in thyroid carcinogenesis. We have presented results of the most recent studies referred to molecular biology of thyroid neoplasms. We have demonstrated not only the genetic background of cancers, derived from the thyroid follicular cell, but also genetic aspects related to medullary thyroid carcinoma and some benign thyroid lesions. The review describes DNA methylation disturbances and the mutations in thyrotropin receptor and G protein genes. Furthermore, we introduce the results of studies performed at our laboratory, concerning mutations in the following protooncogenes: RAS, RET, Trk, MET, and BRAF. Also, we present our data, regarding the loss of heterozygosity (LOH) in the short arm of chromosome 3. Additionally, we discuss overexpression of cyclin D1 gene in benign and malignant thyroid lesions. Previous studies performed at our laboratory indicate the role of IGF-I in the pathogenesis and invasiveness of thyroid cancers. The review indicates that progress in genetics of the thyroid cancer is extremely rapid.     

Genetic variability in Plantago species in relation to their ecology

Summary Populations of the three Plantago species P. major, P. lanceolata and P. coronopus were scored for allozyme variability. They showed normal variability levels compared with other, similar plant species. Differentiation among populations appeared to be rather low in comparison with other species, probably due to a considerable amount of long distance seed transport. In order to be able to make an analysis of small-scale gene flow, all (sub)populations were critically checked for the existence of population structure equilibrium. The allozyme variation was tested for neutrality by testing homogeneity of F values among loci: between populations (Lewontin-Krakauer test) and within populations. No systematic deviations from the prediction of the neutral theory could be established. From the population structure analyses, little gene flow in the species P. major (with high selfing levels) and P. coronopus could be concluded, whereas P. lanceolata showed relatively high levels of gene flow. The degree of homozygosity in the latter species was too high to explain with the available data. In P. coronopus, on the other hand, an unusually high number of heterozygotes were observed.Grassland Species Research Group Publication No. 73     

Genetic variability in Plantago species in relation to their ecology

Summary Twelve Plantago major plants, good representatives of their populations, appeared to be genetically different for several characters which are important for adaptation to the respective habitat conditions. These characters are: juvenile growth, leaf morphology, production of secondary rosettes, flowering time, seed production, seed size and adult leaf production. The adaptive value of some of these characters was investigated by transplantation experiments in the field and by intraspecific competition experiments. The roadside type of ssp. major was adapted to trampling by being erect and elastic. The lawn type of ssp. major was adapted to a short, frequently cut, vegetation by being prostrate and by producing leaves with short petioles throughout the growth season. In the natural situations in which ssp. pleiosperma occurs, growth rate and first-year seed production of this subspecies were considerably higher than that of ssp. major. In a number of experiments, F₁s and F₂s were included, derived from crosses between the original plants. The F₁s were generally rather well adapted to both parental habitats, whereas the F₂s appeared to be less fit. The various alternatives in spending resources relevant for fitness optimization in different habitats are discussed.Grassland Species Research Group Publication No. 93     

Genetic variability in Plantago species in relation to their ecology

Summary Genetic variation in leaf and inflorescence morphology and in generative development within the species Plantago major has been analysed by means of crosses between members of two different subspecies. The variable characters chosen are supposed to be important for determining the ecological differences between the subspecies and other ecotypes. The analyses of F₂'s indicated that a substantial number of loci controlling the above mentioned characters are situated near the Pgm-1 locus, forming a gene complex. This gene complex can exist in at least three different forms in ssp. pleiosperma, ssp. major lawn type and ssp. major roadside type, respectively. In addition, some important factors for ecotypic differentiation are situated in the neighbourhood of the Got-1 locus and in a linkage group containing three other allozyme loci. These linkages between allozyme loci and fitness-affecting loci can explain the restriction of some enzyme alleles to a particular subspecies.Grassland Species Research Group Publication No. 50     

Genetic variability in Plantago species in relation to their ecology

Summary A survey of enzyme variability in several populations of Plantago major in the Netherlands has been made. Nine of 36 loci were found to be polymorphic. The most extensively studies population showed 7 polymorphic loci (19%). The average heterozygosity was 0.005, a low value since P. major is predominantly inbreeding; a first estimate of the outcrossing rate is only 10%. All nine variable loci show simple Mendelian inheritance, seven of them could be placed into four different linkage groups. Marked differences in allele frequencies were found between two subspecies: ssp. major and ssp. pleiosperma. Two enzyme loci possess subspecies-specific alleles, Pgm-1 and Got-1. The most likely explanation of this phenomenon is the existence of fitness differences, caused either by the enzyme loci themselves or by linked loci.Grassland Species Research Group Publication no. 14