Cell Proliferation In Carcinogenesis Research Articles

Historical perspective on the role of cell proliferation in carcinogenesis for DNA-reactive and non-DNA-reactive carcinogens: Arsenic as an example

Our understanding of the etiology of cancer has developed significantly over the past fifty years, beginning with a single-hit linear no-threshold (LNT) conceptual model based on early studies conducted in Drosophila. Over the past several decades, multiple lines of evidence have accumulated to support a contemporary model of chemical carcinogenesis: a multi-hit model involving a prolonged stress environment that over time may drive the mutation of multiple cells into an injured state that ultimately could lead to uncontrolled proliferation via clonal expansion of mutation-carrying daughter cells. Arsenic carcinogenicity offers a useful case study for further exploration of advanced conceptual models for chemical carcinogenesis. A threshold for arsenic carcinogenicity is supported by its mode of action, characterized by repeating cycles of cytotoxicity and cellular regeneration. Furthermore, preliminary meta-analyses of epidemiology dose-response data for inorganic arsenic (iAs) and bladder cancer, correlated to dose-response data measured in vitro, support a threshold of effect in humans on the order of 50−100 μg/L in drinking water. In light of recent developments in our understanding of cancer etiology, we urge strong consideration of the existing mode-of-action evidence supporting a threshold of effect for arsenic carcinogenicity, as well as consideration of the potential methodological pitfalls in evaluating epidemiology dose-response data that could potentially bias in the direction of low-dose linearity.

Expression of Cyclooxygenase-2 (COX-2) in Colorectal Adenocarcinoma: an Immunohistochemical and Histopathological Study

The aim of this study was to evaluate cyclooxygenase-2 (COX-2) immunoreactivity in colorectal adenocarcinomas and to find correlations with different pathological features. This study included 35 cases of colorectal carcinoma for which surgical colectomy specimens were collected. Immunohistochemical staining of COX-2 (cyclooxygenase-2) is done by using the Streptavidin-biotin technique. This work reveals that COX-2 is positive in most cases of colorectal carcinoma and negative in normal colon tissue with statistically non significant relations between COX-2 immunostaining and different pathological features. Our data suggest overexpression of COX-2 protein in colorectal carcinoma in contrast to normal mucosa, with a possible role in cell proliferation in carcinogenesis.

Soluble and insoluble nickel compounds exert a differential inhibitory effect on cell growth through IKKalpha-dependent cyclin D1 down-regulation.

It is well-known that insoluble nickel compounds possess much more potent carcinogenic activities as compared with soluble nickel compounds. Although it is assumed that the different entry and clearance rate are responsible for the difference, the mechanisms underlying the different carcinogenic activities are still not well understood yet. In the present study, we found that exposure to soluble, but not insoluble nickel compounds, caused a significant inhibition of cell growth and G1/G0 cell cycle arrest, which was concomitant with a marked down-regulation of cylin D1, an essential nuclear protein for controlling G1/S transition, while both soluble and insoluble nickel compounds showed similar effects on NFkappaB activation, HIF-1alpha protein accumulation and TNF-alpha transcription and CAP43 protein expression at same doses range. The down-regulation of cyclin D1 is due to protein degradation rather than inhibition of transcription, because the nickel compounds treatment did not change cyclin D1 mRNA level, while MG132, the proteasome inhibitor, can rescue the degradation of cyclin D1 caused by soluble nickel compound. Moreover, the soluble nickel-induced cyclin D1 degradation is dependent on its Thr286 residue and requires IKKalpha, but not HIF-1alpha, which are both reported to be involved in cyclin D1 down-regulation. Taken together, we demonstrate that soluble, but not insoluble nickel compound, is able to cause cyclin D1 degradation and a cell growth arrest in an IKKalpha-dependent manner. Given the role of cyclin D1 and cell proliferation in carcinogenesis, we anticipate that the different effects of soluble and insoluble nickel compounds on cyclin D1 degradation and cell growth arrest may at least partially account for their different carcinogenic activities.

Cyclooxygenase-2 expression and its relationship with proliferation of colorectal adenomas.

Cyclooxygenase (COX)-2 may be linked to carcinogenesis. In the previous study, we examined COX-2 expression immunohistochemically in 95 adenomas and reported a significant correlation between its expression and the grade of dysplasia. To clarify the correlation between COX-2 expression and cell proliferation, we investigated Ki-67 labeling index using immunohistochemistry and its correlation with COX-2 expression. Immunohistological staining for Ki-67 antigen was performed on 95 colorectal adenomas previously reported. The Ki-67 labeling index was significantly higher in the high-COX-2 group than in the low-COX-2 and negative groups in adenomas with moderate (44.5 +/- 6.4% vs 33.0 +/- 2.6%, 39.0 +/- 6.2%; P = 0.01, P < 0.001, respectively) or severe dysplasia (47.2 +/- 7.6% vs 40.3 +/- 7.2%, 35.0 +/- 5.4%; P = 0.02, P = 0.005, respectively). There was no correlation between Ki-67 labeling index and COX-2 expression in mild dysplasia. These results suggest that COX-2 may play a causal role in cell proliferation in carcinogenesis.

Dehydroepiandrosterone inhibits DNA synthesis of rat hepatocytes induced by partial hepatectomy or mitogen (ciprofibrate)

In a previous study we have shown that dehydroepiandrosterone (DHEA) inhibits hepatocyte DNA synthesis after short-term administration and induces hepatocellular carcinomas after long-term administration in the rat. It is not known whether DHEA is also capable of inhibiting replicative and mitogen-induced DNA synthesis. In the present study, we have evaluated the effect of DHEA on DNA synthesis in the rat liver after partial hepatectomy and mitogen administration. After partial hepatectomy, DHEA significantly inhibited DNA synthesis at 20, 26, 32 and 38 h. Similarly, combined administration of ciprofibrate, a peroxisome proliferator and mitogen, and DHEA also resulted in significant hepatocyte DNA synthesis. However, DHEA did not affect liver enlargement caused by ciprofibrate. This experimental system will serve as useful tool to evaluate the role of cell proliferation in carcinogenesis.

Cell proliferation induced by laxatives and related compounds in the rat intestine.

Induction of cell proliferation by laxatives and related compounds in rat intestines was analysed by BrdU-labelling and compared with histopathological changes in the mucosa and findings for feces. Male F344 rats were fed a diet containing danthron, sennosid A, bisacodyl, 1-hydroxyanthraquinone (1-HAQ), magnesium sulfate (MgSO4), dextran sulfate sodium (DSS), pectin, carboxymethylcellulose sodium (CMC-Na) or sodium chloride (NaCl) for 7 days. The stimulant laxatives, danthron, sennosid A and bisacodyl, significantly induced cell proliferation in almost the entire intestinal epithelia in a clear dose-dependent manner. DSS also induced cell proliferation in some portions at high doses. Increase in BrdU-labelling indices was correlated well with the severity of inflammatory changes in the intestinal mucosa as well as with purging effects of stimulant laxatives and DSS. In contrast, the bulk-forming laxative CMC-Na did not consistently enhance cell proliferation nor cause apparent cytotoxicity in the intestine despite exerting remarkable purging effects. 1-HAQ and MgSO4 slightly induced cell proliferation in the cecum and the colorectum, although there was little or no intestinal cytotoxicity. Pectin and NaCl did not influence cell kinetics of the epithelia, nor cause any inflammatory changes in the mucosa. Our results thus indicate that diarrhea caused by laxatives is not necessarily correlated with induction of cell proliferation, as in the intestinal mucosa, and that inflammatory changes followed by regenerative process could be responsible for enhancing cell kinetics. Although the precise significance of cell proliferation in carcinogenesis remains unclear, it is crucial for setting doses of carcinogenicity testings that charges in cell kinetics caused by chemicals be taken into account.

Role of Chemically Induced Cell Proliferation in Carcinogenesis and Its Use in Health Risk Assessment

Role of Chemically Induced Cell Proliferation in Carcinogenesis and Its Use in Health Risk Assessment

Cell Proliferation and Carcinogenesis: A Brief History and Current View Based on an IARC Workshop Report

The International Agency for Research on Cancer recently convened a Working Group of Experts (June 11-18, 1991) to discuss the use of information on carcinogenesis mechanisms in carcinogenic risk identification. The role of cell proliferation in carcinogenesis was among the items discussed in detail. It was recognized that cell proliferation is an important mechanistic aspect for both genotoxic and nongenotoxic carcinogens. It may act at each stage of the carcinogenesis process altering the size of the pool of cells at risk for a next event. Cell proliferation was considered to be important, especially as a) an integral part of the process of converting DNA adducts to mutation, b) an enhancing factor for the mutation frequency by inducing errors in replication, and c) an important factor in determining dose-response relationships for some carcinogens. It was also recognized that not all agents that induce cell proliferation are necessarily involved in carcinogenesis; for example, a) not all skin hyperplasia-inducing compounds are skin tumor promoters, b) agents that induce regenerative cell proliferation appear to have different effects on tumor induction from agents that have a direct mitogenic effect, and c) the carcinogenic activity of many nonmutagenic agents depends on the continuous administration of the agent. In addition, tissues with a high rate of cell proliferation do not have a higher risk of developing cancer. Thus, no simple relationship exists between cell proliferation and carcinogenesis.

Cell proliferation: concluding remarks

In beginning this overview, I want to acknowledge the fact that, even though I disagree with most of his conclusions, Bruce Ames has played an important role in further stimulating interest in cell proliferation in carcinogenesis. This meeting has provided a balanced discussion of the current state of knowledge in this Eleld. It has also highlighted the complexities of cell proliferation, the need for further mechanistic studies, and the desirability of developing new methods that can be used to precisely quantitate the various parameters related to cell proliferation in the intact organism. At this meeting and in a recent paper (1), Ames has put forth several postulates that I believe represent an oversimplification of the multistage carcinogenic process. These postulates include the following: a) the aging process per se is a major factor in human cancer causation; b) oxidative damage due to endogenous factors plays a major role in human cancer causation; c) mitogenesis (induced cell division) plays a major role in carcinogenesis by increasing mutagenesis; d) the standard National Toxicology Program (NTP) rodent bioassay frequently yields unreliable results with respect to predicting human carcinogens; and e) synthetic pesticides and certain other synthetic chemicals pose lesser carcinogenic risks than nature's pesticides and other naturally occurring chemicals in various food stuffs. Elsewhere, I have reviewed evidence that calls into question these conclusions (2,3). Some of this evidence was discussed at this meeting and will be briefly reviewed here. Some of Ames' postulates may apply in specific cases. I do not believe, however, that there is sufElcient evidence at the present time to use these postulates as a general basis for discarding current methods of carcinogen detection and risk extrapolation or for altering current guidelines for regulating potential carcinogens. With respect to Ames' criticism of the standard NTP rodent carcinogen bioassay, we have heard evidence

Hypomethylation of DNA: A Possible Nongenotoxic Mechanism Underlying the Role of Cell Proliferation in Carcinogenesis

Hypomethylation of DNA: A Possible Nongenotoxic Mechanism Underlying the Role of Cell Proliferation in Carcinogenesis

Cell proliferation and carcinogenesis: a brief history and current view based on an IARC workshop report. International Agency for Research on Cancer.

The International Agency for Research on Cancer recently convened a Working Group of Experts (June 11-18, 1991) to discuss the use of information on carcinogenesis mechanisms in carcinogenic risk identification. The role of cell proliferation in carcinogenesis was among the items discussed in detail. It was recognized that cell proliferation is an important mechanistic aspect for both genotoxic and nongenotoxic carcinogens. It may act at each stage of the carcinogenesis process, altering the size of the pool of cells at risk for a next event. Cell proliferation was considered to be important, especially as a) an integral part of the process of converting DNA adducts to mutation, b) an enhancing factor for the mutation frequency by inducing errors in replication, and c) an important factor in determining dose-response relationships for some carcinogens. It was also recognized that not all agents that induce cell proliferation are necessarily involved in carcinogenesis; for example, a) not all skin hyperplasia-inducing compounds are skin tumor promoters, b) agents that induce "regenerative" cell proliferation appear to have different effects on tumor induction from agents that have a direct mitogenic effect, and c) the carcinogenic activity of many nonmutagenic agents depends on the continuous administration of the agent. In addition, tissues with a high rate of cell proliferation do not have a higher risk of developing cancer. Thus, no simple relationship exists between cell proliferation and carcinogenesis.

Role of chemically induced cell proliferation in carcinogenesis and its use in health risk assessment.

There is much interest in incorporating knowledge of biological mechanisms of carcinogenesis into assessments of health risks to humans posed by chemicals in the environment. Debate over the soundness of using data from animal bioassays conducted at minimally toxic doses or fractions thereof for predicting cancer risks to humans exposed to much lower doses has stimulated interest in the question of whether genotoxic or mitotic effects predominate in chemical carcinogenesis. Cell division plays a key role at each stage in the evolution of cancer, and it is well documented that increased rates of cell proliferation can escalate the risk of malignancy. This article examines the current understanding of both mechanisms by which chemicals provoke cell proliferation and the contribution of various kinetic patterns of cell proliferation to carcinogenesis.

Hypomethylation of DNA: a possible nongenotoxic mechanism underlying the role of cell proliferation in carcinogenesis.

DNA methylation (i.e., the 5-methylcytosin content of DNA) plays a role in the regulation of gene activity. There is a persuasive body of evidence indicating that differential methylation of DNA (i.e., 5-methylcytosine versus cytosine) is a determinant of chromatin structure and that the methyl group provides a chemical signal that is recognized by trans-acting factors that regulate transcription. Hypomethylation (i.e., low levels of DNA 5-methylcytosine) of a gene is necessary but not sufficient for its expression, and, therefore, a hypomethylated gene can be considered to possess an increased potential for expression as compared to a hypermethylated gene. Cell proliferation is a fundamental component of carcinogenesis. It plays a key role in expanding clones of initiated cells and, in addition, cell replication may contribute to carcinogenesis by facilitating mutagenesis. This can occur either by causing the fixation of promutagenic DNA-damage before repair or as a consequence of a "normal" error occurring during DNA replication. During periods of cell proliferation the established pattern of DNA methylation is maintained by the action of a maintenance methylase following DNA replication. Changes in the methylation status of a gene provide a mechanism by which its potential for expression can be altered in an epigenetic heritable manner, and it is expected that modifications in DNA methylation would result from threshold-exhibiting events.

Cell proliferation and nasal carcinogenesis.

The nasal passages of rodents provide valuable opportunities for research on relationships between cell proliferation and cancer. The nose, which has multiple functions, possesses a diverse range of tissue types, each with its own morphologic, physiologic, and metabolic characteristics and site-specific cell turnover rates. Moreover, for inhaled materials deposited in the nose, complex regional uptake or deposition patterns can result in site-specific responses, including cancer. Presented here are important criteria necessary for undertaking cell proliferation studies in the nasal passages. The current literature concerning nasal toxicity and the toxicant-induced proliferative response are also reviewed. Rodent nasal epithelium provides a fruitful area for research on the role of cell proliferation in carcinogenesis.