Target Cells For Carcinogenesis Research Articles

Superiority of rat over murine model for studies on the evolution of cancer genome

Evolution of the species and carcinogenesis are similar in that genomic alterations are the key events. Oxidative stress derived from various etiologies is one of the major causes of carcinogenesis by inducing mutations in the genome. Persistent oxidative stress in the renal proximal tubules through Fenton reaction catalysed by ferric nitrilotriacetate (Fe-NTA) generates renal cell carcinoma (RCC) in mice and rats. Here, in order to observe the species difference in oxidative stress-induced carcinogenesis and to obtain an insight regarding the characteristics of each species, we compared the genomic alterations using array-based comparative genome hybridisation among RCCs in Mutyh knockout/wild-type mice (C57BL/6 background) induced by Fe-NTA, RCCs in F1 hybrids of Brown-Norway/Fischer-344 wild-type rats and clear cell renal cell carcinoma (CCRCC)/papillary renal cell carcinoma (PRCC) of humans. The average deviated fraction of genomic segments, either loss or gain, from the standard biallelic position was 0.220 (N = 4), 0.304 (N = 11), 0.283 (N = 12), and 0.261 (N = 5), respectively, for murine RCC, rat RCC, human CCRCC, and human PRCC. Notably, gain/loss ratio was remarkably different as indicated by 0.0820, 0.161, 0.821, and 4.44, respectively. These data suggest that higher species require more genomic alterations with amplification preference for renal carcinogenesis. Further studies are necessary to identify the molecular mechanisms whether the present results depend on cellular functional differences, etiology of carcinogenesis or the target cells in carcinogenesis.

Cancer Is An Adaptation Mechanism of the Aged Stem Cell against Stress

Although many theories have been proposed for carcinogenesis, no one hypothesis seems adequate to explain all the phenomena associated with cancer. Cancers have been shown to be clonally derived from a single cell, and so it does seem that stem cells are target cells for carcinogenesis. Several examples might support the stem cell theory, but the underlying mechanism is unclear. The hypothesis presented here, which is a radical departure from all previous theories of cancer, explicitly states that cancer is the adaptation of the aged stem cell against sustained stress.

Cancer stem cell hypothesis in thyroid cancer

There is increasing evidence that many types of cancer contain their own stem cells: cancer stem cells, which are characterized by their self-renewing capacity and differentiation ability. Cancer could be regarded as an abnormal organ initiated by cancer stem cells, and cancer stem cells might play a decisive role in tumor initiation and progression. Dysregulation of stem cell self-renewal is a likely requirement for the development of cancer, and stem cells seem more likely to be the transformed target cells in carcinogenesis. This cancer stem cell model has great implications for understanding of oncogenesis and treatment for cancer. Abundant evidence suggests that, parallel to other solid tumors, cancer stem cells also exist in thyroid cancer, although their characteristics are largely unknown to date. The present review will discuss the potential traits of cancer stem cells in thyroid cancer and their transformation targets: stem cells in the thyroid gland.

The role of stem cells and gap junctions as targets for cancer chemoprevention and chemotherapy

Since carcinogenesis is a multi-stage, multi-mechanism process, involving mutagenic, cell death and epigenetic mechanisms, during the “initiation/promotion/and progression” phases, chemoprevention must be based on understanding the mechanism(s) of each phase. Prevention of each phase could reduce the risk to cancer. Because reducing the initiation phase to a zero level is impossible, the most effective intervention would be at the promotion phase. Assuming the “target” cells for carcinogenesis are the pluri-potent stem cells and their early progenitor or transit cells, chemoprevention strategies for inhibiting the promotion of these two types of pre-malignant “initiated” cells will require different agents. A hypothesis will be proposed that involves stem cells, which lack gap junctional intercellular communication (GJIC-) or their early progenitor daughter cells, which express GJIC+ and are partially-differentiated, if initiated, will be promoted by agents that either inhibit secreted negative growth regulators or by inhibitors of GJIC. Chemopreventing agents to each of these two types of initiated cells must have different mechanisms of action. Assuming stem cells are target cells for carcinogenesis, an alternative method of chemoprevention would be to reduce the stem cell pool. Anti-tumor promoter chemopreventive agents, such as green tea components, resveratrol, caffeic acid phenethylene ester, that either up-regulate GJIC in stem cells or prevent the down regulation of GJIC by tumor promoters in early progenitor cells, will be provided. Human pluri-potent stem cell systems, that can be induced to form 3-dimensional “organoid” structures, will be discussed as a more realistic model system to screen for relevant chemopreventive agents.

The role of human adult stem cells and cell–cell communication in cancer chemoprevention and chemotherapy strategies

Since carcinogenesis is a multi-stage, multi-mechanism process, involving mutagenic, cell death and epigenetic mechanisms, during the “initiation/promotion/and progression” phases, chemoprevention must be based on understanding the underlying mechanism(s) of each phase, In principle, prevention of each of these phases could reduce the risk to cancer. However, because reducing the mutagenic/initiation phase to a zero level is impossible, the most efficacious intervention would be at the promotion phase that requires a sustained exposure to promoting conditions/agents. In addition, assuming the “target” cells for carcinogenesis are the pluri-potent stem cells and their early progenitor or transit cells, chemoprevention strategies for inhibiting the promotion of these two types of pre-malignant “initiated” cells will require different kinds of agents. A hypothesis will be proposed that involves adult stem cells, which express Oct-4 gene and lack gap junctional intercellular communication (GJIC−) or the early progenitor cells which express GJIC+ and are partially-differentiated, if initiated, will be promoted by agents that either inhibit secreted negative growth regulators or by inhibitors of GJIC. Consequently, anti-tumor promoting chemopreventing agents to each of these two types of initiated cells must have different mechanisms of action and work on different target cells. Assuming stem cells are target cells for carcinogenesis, an alternative method of chemoprevention would be to reduce the stem cell pool. Many classes of anti-tumor promoter chemopreventive agents, such as green tea components, resveratrol, caffeic acid phenethylene ester, either up-regulate GJIC in stem cells or prevent the down regulation of GJIC by tumor promoters in early progenitor cells.

Premalignancy in the human breast: how is it defined, is morphology good enough?

With increasing sensitivity of methods of detection, microscopic lesions are being identified which produce a diagnostic dilemma for the pathologist. This is because their natural history is largely unknown. Some postmortem studies would suggest that what a pathologist would call a potential precursor lesion for invasive breast cancer may be present with an incidence as high as 40% in some age groups. Although we are now beginning to understand the spectrum of protein, RNA expression, gene mutations and epigenetic changes in breast cancer, this is a long way from being able to predict from a single lesion what its potential is to invade or metastasise. It is, however, reassuring that the recent advances in stem cell biology in the breast may assist in the identification of the potential target cells for carcinogenesis. These studies have relied on the use of classical markers for fully differentiated luminal and myoepithelial/basal cells. The current vogue to classify tumours on the basis of microarray data as 'basal-like' or lumenal may be leading us into assumptions about histogenesis that are not proven. Whether these studies will assist in identifing preneoplasia will be discussed in relation to our current knowledge on the evidence for myoepithelial and lumenal cell differentiation in human breast cancer.

A human breast epithelial cell type with stem cell characteristics as target cells for carcinogenesis.

Two types of human breast epithelial cells (HBEC) have been characterized. In contrast to Type II HBEC, which express basal epithelial cell phenotypes, Type I HBEC are deficient in gap junctional intercellular communication and are capable of anchorage-independent growth and of expressing luminal epithelial cell markers, estrogen receptors, and stem cell characteristics (i.e. the ability to differentiate into other cell types and to form budding/ductal organoids on Matrigel). A comparative study of these two types of cells has revealed a high susceptibility of Type I HBEC to immortalization by SV40 large T antigen, although both types of cells are equally capable of acquiring an extended life span (bypassing senescence) after transfection with SV40. The immortalization was accompanied by elevation of a low level of telomerase activity in the parental cells after mid-passage ( approximately 60 cumulative population doubling levels). Thus HBEC do have a low level of telomerase activity, and Type I HBEC with stem cell characteristics are more susceptible to telomerase activation and immortalization, a mechanism which might qualify them as target cells for breast carcinogenesis. The immortalized Type I HBEC can be converted to highly tumorigenic cells by further treatment with X rays (2 Gy x 2) and transfection with a mutated ERBB2 (also known as NEU) oncogene, resulting in the expression of p185(ERBB2) which is tyrosine phosphorylated.

Nickel subsulfide is genotoxic in vitro but shows no mutagenic potential in respiratory tract tissues of BigBlue™ rats and Muta™Mouse mice in vivo after inhalation

Carcinogenic nickel compounds are known to induce promutagenic DNA lesions such as DNA strand breaks and DNA adducts in cultured mammalian cells. In standard mutation assays, in contrast, they were found to be either inactive or weakly active. In our in vitro mutation studies in a lacI transgenic embryonic fibroblast cell line, nickel subsulfide (Ni 3S 2) increased mutation frequency up to 4.5-fold. We subsequently applied the comet assay and transgenic rodent mutation assays to investigate the DNA damaging effect and mutagenic potential of nickel subsulfide in target cells of carcinogenesis. A 2-h in vitro treatment of freshly isolated mouse nasal mucosa and lung cells with nickel subsulfide clearly induced DNA fragmentation in a concentration dependent manner. The strong effect was not seen in the same cell types following inhalative treatment of mice and rats, leading only in the mouse nasal mucosa to high DNA damage. When the same inhalative treatment was applied to lacZ and lacI transgenic mice and rats, the spontaneous mutation frequency of these target genes in the respiratory tissues was not increased. These results support a recently proposed non-genotoxic model of nickel carcinogenesis, which acts through gene silencing via DNA methylation and chromatin condensation. This model may also explain our in vitro mutation data in the lacI transgenic cell line, in which nickel subsulfide increased mutation frequency, but in about one-third of the mutants, molecular analysis did not reveal any DNA sequence change in the coding region of the lacI gene despite of the phenotypic loss of its function.

The role of aromatic hydrocarbons in the genesis of breast cancer

The incidence of breast cancer in women has increased dramatically over the last decade. Epidemiological markers of this increased incidence include: endocrine related phenomena (early menarche, age of first parity and age of menopause); exposure of the breast to X-radiation; and a group of seemingly disparate factors—urban residence, dietary selection and alcohol consumption. Although experimental breast cancer may be induced by estrogenic hormones, X-radiation and aromatic hydrocarbons, only aromatic hydrocarbons have not been previously implicated in human mammary carcinogenesis. The seemingly unrelated human factors can best be understood by examining the role of breast tissue in aromatic hydrocarbon metabolism. Aromatic hydrocarbons are important environmental chemicals produced by the incomplete combustion of hydrocarbons for use in energy production. Benzene, benz(a)pyrene, dibenz(ah)anthracene and 1-nitropyrene, known experimental breast carcinogens, are produced in this way. Human exposure to aromatic hydrocarbon metabolites induces and promotes altered DNA by mechanisms described as increased intracellular pro-oxidant production as well as direct adduction to DNA. The breast is anatomically embedded in a major fat depot which stores and concentrates aromatic hydrocarbons and can metabolize these hydrocarbons to carcinogenic metabolites. Ductal cells concentrate these metabolites and themselves become target cells for carcinogenesis. Some lifestyle factors increase the amount of carcinogens produced or enhance their activity. A unitary model for mammary carcinogenesis in humans as well as in experimental carcinogenesis is hypothesized. If correct, the hypothesis would account for some of the increase in breast cancer incidence in industrial countries—and would suggest environmental and dietary modifications that would inhibit hydrocarbon induced mammary carcinogenesis.

Normal human breast xenografts activate N-nitrosodimethylamine: identification of potential target cells for an environmental nitrosamine

Normal human breast tissue maintained as xenografts in female Balb/c (nu/nu) athymic mice is capable of metabolising N-nitrosodimethylamine (NDMA) to active intermediates that will react with DNA. Administration of NDMA to mice with slow-release implants of 17 beta-oestradiol which provide human physiological (luteal phase) circulating oestrogen levels and increase cell proliferation in the xenograft (Laidlaw et al., 1992), leads to an apparent increase in the extent of reaction with DNA compared to controls without oestrogen implants. In mice with oestrogen implants, measurements of the amounts of the promutagenic lesion, O6-methyl-2'-deoxyguanosine formed in DNA clearly indicated a dose related increase in the extent of reaction. Detection of O6-methyl-2'-deoxyguanosine using immunohistochemical procedures revealed that the nuclei of cells of the glandular epithelium, supportive tissue and adipose tissue, in decreasing order of prevalence, were positively stained for the presence of this DNA lesion. Epithelial cells, which are the putative target cells for carcinogenesis in the breast, are therefore prone to promutagenic damage as a result of exposure to an environmental nitrosamine.