Incidence Of Spontaneous Tumors Research Articles

Effect of Epitalon on biomarkers of aging, life span and spontaneous tumor incidence in female Swiss-derived SHR mice.

From the age of 3 months until their natural deaths, female outbred Swiss-derived SHR mice were subcutaneously injected on 5 consecutive days every month with 0.1 ml of normal saline (control) or with 1.0 microg/mouse (approximately 30-40 microg/kg) of tetrapeptide Epitalon (Ala-Glu-Asp-Gly) dissolved in 0.1 ml saline. There were 54 mice in each group. The results of this study show that treatment with Epitalon did not influence food consumption, body weight or mean life span of mice. However, it slowed down the age-related switching-off of estrous function and decreased the frequency of chromosome aberrations in bone marrow cells (by 17.1%, P<0.05). It also increased by 13.3% the life span of the last 10% of the survivors (P<0.01) and by 12.3% the maximum life span in comparison with the control group. We also found that treatment with Epitalon did not influence total spontaneous tumor incidence, but inhibited the development of leukemia (6.0-fold), as compared with the control group. The data obtained suggest a geroprotector activity of Epitalon and the safety of its long-term administration in mice.

Life span and spontaneous tumors incidence of the Wistar Mishima (WM/MsNrs) rat.

The life spans and spontaneous tumors in a total of 1960 Wistar Mishima (WM/MsNrs) rats, inbred strain, from the 80-130th generations were examined. The average life span (mean +/- SD) was 731 +/- 173 days (n = 1053) in the males and 813 +/- 214 days (n = 907) in the females (p < 0.0001). The average life span of tumor-afflicted females was significantly longer than that of the non-tumor group (p < 0.0001), while no such difference was observed in males. Tumors were observed in 33 males (3.1%) and 246 females (27.1%). In the males, tumors were often observed under the skin (2.2%). Frequencies of tumors in lung and liver, bones and intestine were less than 0.5%. In the females, incidence of mammary tumor was 20.1%, and various organs such as ovaries, uterus, bones, lung, and liver had tumor incidence frequencies of less than 3.5%. It was concluded that WM/MsNrs rats might be suitable for life span and age-related studies because of their characteristics of length of longevity and the low incidence of spontaneous tumors in both sexes.

Chemical Carcinogens as Foreign Bodies and Some Pitfalls Regarding Cancer Immune Surveillance

Interferon-gamma-receptor (IFN-gammaR)-deficient mice are more susceptible to tumor induction by methylcholanthrene (MCA) in comparison to control littermates. The cellular source of IFNgamma is not known, but the absence of T cells does not significantly increase the incidence of MCA-induced tumors. However, it appears that the presence of T cells in combination with unknown, perhaps environmental, factors can decrease MCA-induced tumor incidence, indicating that IFN-gamma of unknown origin contributes to the protective response. The current knowledge of cancer biology, immune regulation, and tumor-promoting effects of inflammation are difficult to reconcile with the concept of immune surveillance against non-virus-associated cancer. Analysis of the primary MCA-treated mouse indicates, as one protective mechanism, a tissue repair response against MCA-induced damage, in the course of which MCA is encapsulated and persists for long time in tumor-free mice, termed foreign-body reaction. The protection from DNA damage could simultaneously diminish tissue injury and malignant transformation. We argue that inhibition of MCA-induced carcinogenesis is mechanistically different from tumor transplantation immunity and that a longer latency in MCA-treated mice is unlikely due to T cell-mediated tumor recognition and selection of less immunogenic variants. We discuss that the IFNgammaR-dependent mechanism against MCA is unrelated to the original concept of T cell-mediated immune surveillance and that the increased spontaneous tumor incidence observed in some immune-deficient mice is likely to be explained by opportunistic infection and tumor-promoting chronic inflammation.

A low molecular weight antioxidant decreases weight and lowers tumor incidence.

Stable free radical nitroxides are potent antioxidants possessing superoxide dismutase- and catalase-mimetic activity that protect cells and animals against a variety of oxidative insults. Tempol, as a representative nitroxide, was evaluated for its influence on weight maintenance and spontaneous tumor incidence in C3H mice. Tempol administered in either the drinking water or food did not show any untoward effects and prevented animals from becoming obese. Tempol-treated animals' leptin levels were reduced. Long-term treatment with Tempol significantly decreased tumorigenesis when compared to controls (10 vs. 40%, respectively). Selected tissues from Tempol-treated animals exhibited elevated levels of mitochrondrial uncoupling protein-2 (UCP-2) and HSP70. The present data suggest that nitroxides upregulate UCP-2, obviate weight gain, and decrease age-related spontaneous tumor incidence. As a class, nitroxides may provide overall health benefits by contributing to decreased obesity and tumor incidence.

Dose-dependent effect of melatonin on life span and spontaneous tumor incidence in female SHR mice

From the age of 3 months until their natural death, female Swiss-derived SHR mice were given melatonin with their drinking water (2 or 20 mg/l) for 5 consecutive days every month. Intact mice served as controls. There were 54 mice in each group. The results of this study show that the treatment of melatonin did not significantly influence food consumption, but its administration at lower doses did decrease the body weight of mice; it slowed down the age-related switching-off of estrous function; it did not influence the frequency of chromosome aberrations in bone marrow cells; it did not influence mean life span; and it increased life span of the last 10% of the survivors in comparison to controls. We also found that treatment with low dose melatonin (2 mg/l) significantly decreased spontaneous tumor incidence (by 1,9-fold), mainly mammary carcinomas, in mice whereas higher doses (20 mg/l) failed to influence tumor incidence as compared to controls. For this reason, we conclude that the effect of melatonin as a geroprotector is dose-dependent.

A Wistar Rat Strain Prone to Spontaneous Liver Tumor Development: Implications for Carcinogenic Risk Assessment

The European Union legislation considers nongenotoxic substances that only cause liver tumors in certain sensitive strains of mice as raising no concern for man. The EU legislation, however, also clearly stipulates that cases where the only available tumor data are the occurrence of neoplasms at sites and in strains where they are well known to occur spontaneously with a high incidence are relevant arguments which exclude a concern for man. We have analyzed the spontaneous liver tumor incidence in Wistar rats and in B6C3F 1 and C57Bl mice used in carcinogenicity trials at the BASF facility in Ludwigshafen, Germany, over the past 15 years and compared the spontaneous liver tumor incidence in BASF Wistar rats with those observed in rat strains employed in major European contract research organizations (CROs). The results of these analyses indicate that the incidence of spontaneous liver tumors in the BASF Wistar rat strain is very high, similar to that seen in the B6C3F 1 mouse and much higher than that seen in the C57Bl mouse and other commonly used strains of rat. The analyses also revealed signs of increasing variability and liver tumor drift in several rat strains. Moreover, the incidence of spontaneous preneoplastic liver cell foci was far higher in the BASF Wistar rat strain than reported for other rat strains in the literature. The analyses provide relevant arguments which exclude a concern for man for nongenotoxic chemicals that only tested positive for liver tumors in this sensitive rat strain.

Characterization of mice deficient in the Src family nonreceptor tyrosine kinase Frk/rak.

Frk/rak belongs to a novel family of Src kinases with epithelial tissue-specific expression. Although developmental expression patterns and functional overexpression in vitro have associated these kinases with growth suppression and differentiation, their physiological functions remain largely unknown. We therefore generated mice carrying a null mutation in iyk, the mouse homolog of Frk/rak. We report here that frk/rak(-/-) mice are viable, show similar growth rates to wild-type animals, and are fertile. Furthermore, a 2-year study of health and survival did not identify differences in the incidence and spectrum of spontaneous tumors or provide evidence of hyperplasias in frk/rak(-/-) epithelial tissues. Histological analysis of organs failed to reveal any morphological changes in epithelial tissues that normally express high levels of Frk/rak. Ultrastructural analysis of intestinal enterocytes did not identify defects in brush border morphology or structural polarization, demonstrating that Frk/rak is dispensable for intestinal cytodifferentiation. Additionally, frk/rak-null mice do not display altered sensitivity to intestinal damage induced by ionizing radiation. cDNA microarray analysis revealed an increase in c-src expression and identified subtle changes in the expression of genes regulated by thyroid hormones. Significant decreases in the circulating levels of T3 but not T4 hormone are consistent with this observation and reminiscent of euthyroid sick syndrome, a stress-associated clinical condition.

On the occurrence of Leydig cell tumors in the F344 rat

Dunning began inbreeding, what is now the Fischer F344 rat, in 1931. Because of her publications showing a low incidence of spontaneous tumors to 35 months of age, we selected the F344 rat for most of the studies in the National Cancer Institute (NCI) Bioassay Program, beginning in 1964. We were surprised by the finding that untreated male F344 rats displayed a high incidence of Leydig cell tumors of the testes beginning at about 17 months of age. The key difference between the results of Dunning and the NCI Bioassay Program was that her animals were retired breeders, whereas the NCI studies utilized virgin rats. The question of breeding was, therefore, examined as a possible protective factor. Groups of male F344 CDF/Crl rats were kept as virgin animals, or permitted access to bilaterally tube ligated female F344/Crl rats that were replaced twice over a 52-week period. At that time, all males from both groups were housed three per cage to 85 weeks when they were killed in a CO 2 atmosphere and necropsied. Sections were prepared from the fixed tissues, stained and studied by histopathology. The results were evaluated by appropriate statistical methods. Virgin and sexually active F344 rats displayed monolateral or bilateral Leydig cell tumors. There was no statistical difference between the two groups. Despite the early difference between breeding and virgin F344 rats, a control experiment failed to disclose an effect of sexual activity on the occurrence of Leydig cell cancers. This disease displays some difference in incidence in various parts of the world, with the higher socioeconomic groups having a greater incidence. Etiological factors on the occurrence of this disease in animals and in humans remain to be discovered.

Unsymmetrical methylene derivatives of indoles as antiproliferative agents

Indole-3-carbinol is a natural product which has been shown to reduce the incidence of spontaneous and carcinogen-induced mammary tumours in animals. Eighteen unsymmetrical methylene derivatives of indoles were prepared by reaction of Mannich bases of 7-hydroxycoumarins with substituted indoles in acetic or propionic anhydride. The synthesised molecules were tested in vitro against the MCF7 and MDA-MB-231 breast cancer cell lines by MTT and cell count assays. Results from 16 tested compounds showed that 60% of them exerted some effects against the MDA-MB-231 compared to about 30% towards the MCF7. Among all, the 3-(7′-acetoxy-4-methylcoumarin-8′-yl)methyl-2-methylindole resulted the most effective in both cell lines, compared to indole-3-carbinol. In conclusion, these preliminary results report that some of these compounds might be promising potential antiproliferative agents.

Xpa and Xpa/p53 +/- Knockout Mice: Overview of Available Data

DNA repair deficient Xpa-/- and Xpa-/-/p53+/- knock-out mice in a C57BL/6 genetic background, referred to as respectively the XPA and XPA/p53 model, were investigated in the international collaborative research program coordinated by International Life Sciences Institute (ILSI)/Health and Environmental Science Institute. From the selected list of 21 ILSI compounds, 13 were tested in the XPA model, and 10 in the XPA/p53 model. With one exception, all studies had a duration of 9 months (39 weeks). The observed spontaneous tumor incidence for the XPA model after 9 months was comparable to that of wild-type mice (total 6%). For the XPA/p53 model, this was somewhat higher (9%/13% for males/females). The 3 positive control compounds used, B[a]P, p-cresidine, and 2-AAF, gave positive and consistent tumor responses in both the XPA and XPA/p53 model, but no or lower responses in wild-type mice. From the 13 ILSI compounds tested, the single genotoxic carcinogen (phenacetin) was negative in both the XPA and XPA/p53 model. Positive tumor responses were observed for 4 compounds, the immunosuppressant cyclosporin A, the hormone carcinogens DES and estradiol, and the peroxisome proliferator WY-14,643. Negative results were obtained with 5 other nongenotoxic rodent carcinogens, and 2 noncarcinogens tested. As expected, both DNA repair deficient models respond to genotoxic carcinogens. Combined with previous results, 6 out of 7 (86%) of the genotoxic human and/or rodent carcinogens tested are positive in the XPA model. The positive results obtained with the 4 mentioned nongenotoxic ILSI compounds may point to other carcinogenic mechanisms involved, or may raise some doubts about their true nongenotoxic nature. In general. the XPA/p53 model appears to be more sensitive to carcinogens than the XPA model.

Melatonin increases both life span and tumor incidence in female CBA mice.

From the age of 6 months until their natural deaths, female CBA mice were given melatonin with their drinking water (20 mg/l) for 5 consecutive days every month. Intact mice served as controls. The results of this study show that the consumption of melatonin did not significantly influence food consumption, but it did increase the body weight of older mice; it did not influence physical strength or the presence of fatigue; it decreased locomotor activity and body temperature; it inhibited free radical processes in serum, brain, and liver; it slowed down the age-related switching-off of estrous function; and it increased life span. However, we also found that treatment with the used dose of melatonin increased spontaneous tumor incidence in mice. For this reason, we concluded that it would be premature to recommend melatonin as a geroprotector for long-term use.

J-Shaped Dose-Response Relationship for Tumor Induction by Caffeic Acid in the Rat Forestomach, Modeled by Non-Monotonic Dose Response for DNA Damage and Cell Proliferation

Dose-response relationships for chemical tumor induction can be described with stochastic carcinogenesis models by incorporation of dose-dependent parameters. We used a two-stage mutational model with clonal expansion of intermediate cells to mimic the observed U-shaped (more precisely: J-shaped) dose response for cell division in the forestomach of rats treated with caffeic acid. The question was whether biologically acceptable model parameters for the rates of mutation and cell turnover could be found to fit the experimental data, including tumor incidence in controls and at high dose. Using rates of cell turnover in proportion to the experimental labeling indices for DNA replication, model parameters could fit the tumor incidences within the 95% confidence limits of the experimental data, and the J-shape was retained quantitatively. However, when the smaller confidence limits derived from historical data on the spontaneous forestomach tumor incidence were taken into account, the original model could no longer accommodate all data and had to be expanded. For that, mutation rates were considered to be proportional to both the level of DNA damage and the rate of cell division, and both factors were allowed to be dose dependent. For the DNA damage, an increment over background was used at the higher, cytotoxic dose levels. This model improvement resulted in biologically acceptable parameters to fit all available data, demonstrating its usefulness for further analyses of hormetic dose response.

Fumonisin B1 Promotes Aflatoxin B1 and N-Methyl-N′-nitro-nitrosoguanidine-Initiated Liver Tumors in Rainbow Trout

Laboratory studies have described the carcinogenicity of fumonisin B1 (FB1) in rodents and epidemiological evidence suggests an association between FB1 (a mycotoxin produced by Fusarium moniliforme) and cancer in humans. This study was designed to reveal in rainbow trout, a species with very low spontaneous tumor incidence, if FB1 was (i) a complete carcinogen, in the absence of an initiator; (ii) a promoter of liver tumors in fish initiated as fry with aflatoxin B1 (AFB1); and (iii) a promoter of liver, kidney, stomach, or swim bladder tumors in fish initiated as fry with N-methyl-N′-nitro-nitrosoguanidine (MNNG). FB1 was not a complete carcinogen in trout. No tumors were observed in any tissue of fish fed diets containing 0, 3.2, 23, or 104 ppm FB1 for a total of 34 weeks (4 weeks FB1 exposure, 2 weeks outgrowth on control diet, followed by 30 weeks FB1 diet) in the absence of a known initiator. FB1 promoted AFB1 initiated liver tumors in fish fed ≥23 ppm FB1 for 42 weeks. A 1-week pretreatment of FB1 did not alter the amount of liver [3H]AFB1 DNA adducts, which suggests that short-term exposure to FB1 will not alter phase I or phase II metabolism of AFB1. In MNNG-initiated fish, liver tumors were promoted in the 104 ppm FB1 treatment (42 weeks), but FB1 did not promote tumors in any other tissue. Tumor incidence decreased in kidney and stomach in the 104 ppm FB1 treatment of MNNG-initiated trout. The FB1 promotional activity in AFB1-initiated fish was correlated with disruption of sphingolipid metabolism, suggesting that alterations in associated sphingolipid signaling pathways are potentially responsible for the promotional activity of FB1 in AFB1-initiated fish.

Spectrum and age-related incidence of spontaneous tumours in a colony of Han:AURA hamsters

One-hundred-and-forty-four male and 184 female untreated Syrian golden hamsters (strain Han:AURA) were kept for life under standard laboratory conditions. They were examined with regard to spontaneously occurring tumours in relation to their survival periods. The mean survival rate of the males was 106 +/- 26 weeks and that of the females 97 +/- 20 weeks. Tumours were found in 71% of males and 67% of females. Adenomas and carcinomas of the adrenal glands were the most frequently observed tumours in both sexes (male: 66%; female: 38%) and in the early stages of life. Malignant lymphoma (8%), adenomas and carcinomas of pancreatic islet-cells (8%) and papillomatous benign and malignant squamous cell tumours of the forestomach (7%) showed relatively high incidences in males, whilst in females, leiomyoma (10%) and endometrial adenocarcinoma (7%) of the uterus and adenomas and carcinomas in the pars distalis of the pituitary gland (9%) occurred frequently.

Final report on the safety assessment of Hydrogenated Cottonseed Oil, Cottonseed (Gossypium) Oil, Cottonseed Acid, Cottonseed Glyceride, and Hydrogenated Cottonseed Glyceride.

Hydrogenated Cottonseed Oil, Cottonseed (Gossypium) Oil, Cottonseed Acid, Cottonseed Glyceride, and Hydrogenated Cottonseed Glyceride are cosmetic ingredients derived from Cottonseed Oil and used as skin-conditioning agents and surfactants. Nonoils known to be toxic that may be found in cottonseed oils include gossypol, aflatoxin, and cyclopropenoid fatty acids (CPFA). Toxic heavy metal and/or polychlorinated biphenyl (PCB) or other pesticide contamination is also possible. Cottonseed Oil was nontoxic in acute oral toxicity studies in rats. In a short-term study, rabbits that had been fed 2% Cottonseed Oil for 7 weeks had significantly lower blood chemistry parameters (compared to wheat bran controls) and significantly more stored hepatic vitamin A (compared to rabbits fed other fats). Cottonseed Oil controls used as vehicles in two parenteral studies produced negative results. Hydrogenated Cottonseed Oil tested in formulation did not produce dermal or ocular irritation in rabbits. An oral-dose reproductive study tested up to 30% Cottonseed Oil (with 1% CPFAs) and reported no adverse effects on sexual maturity and reproductive performance of the F0 generation; changes were noted in the F1 generation but reproductive capacity was not altered. Parenteral-dose reproductive studies reported no adverse effects. Cottonseed Oil was not mutagenic. Cottonseed Oil did not induce aberrant crypt foci when given orally to mice, but in other studies, it increased the incidence of spontaneous mammary tumors in rats and mice. Mice fed 20% Hydrogenated Cottonseed Oil during induction and promotion of photocarcinogenesis had significantly lower tumor incidence compared to mice fed 20% sunflower oil. Hydrogenated Cottonseed Oil in formulation (up to approximately 21%) was neither an irritant nor sensitizer in clinical studies. Limited clinical data indicated that Cottonseed Oil does not contain allergic protein. Based on the available data, it was concluded that these ingredients may be used safely in cosmetic formulations if established limits on gossypol, heavy metals, and pesticide concentrations are not exceeded.

Effect of synthetic thymic and pineal peptides on biomarkers of ageing, survival and spontaneous tumour incidence in female CBA mice

Fifty female CBA mice were injected s.c. either with 0.1 ml saline, or with synthetic thymic dipeptide Lys–Glu or with synthetic pineal tetrapeptide Ala–Glu–Asp–Gly both in a single dose of 0.1 μg/animal monthly for five consecutive days from the age of 6 months until natural death. Lys–Glu did not significantly influence the body weight and food consumption, free radical processes and estrus function in mice and did increase their physical activity with the subsequent decrease in spontaneous lung adenomas incidence. The pineal peptide treatment was failed to modify the food consumption and physical strength of mice, and was followed by the increase in the body weight, mean survival (by 5.3%, P < 0.05) and maximum (by 10 months), by slow down of the ageing of estrus function, by the decrease in body temperature, physical activity, free radical processes and spontaneous tumor incidence (mainly, lung adenomas) in mice. These data suggest the geroprotector potential of the pineal peptide.

Final Report on the Safety Assessment of Hydrogenated Cottonseed Oil, Cottonseed (Gossypium) Oil, Cottonseed Acid, Cottonseed Glyceride, and Hydrogenated Cottonseed Glyceride

Hydrogenated Cottonseed Oil, Cottonseed (Gossypium) Oil, Cottonseed Acid, Cottonseed Glyceride, and Hydrogenated Cottonseed Glyceride are cosmetic ingredients derived from Cottonseed Oil and used as skin-conditioning agents and surfactants. Non-oils known to be toxic that may be found in cottonseed oils include gossypol, aflatoxin, and cyclopropenoid fatty acids (CPFA). Toxic heavy metal and/or polychlorinated biphenyl (PCB) or other pesticide contamination is also possible. Cottonseed Oil was nontoxic in acute oral toxicity studies in rats. In a short-term study, rabbits that had been fed 2% Cottonseed Oil for 7 weeks had significantly lower blood chemistry parameters (compared to wheat bran controls) and significantly more stored hepatic vitamin A (compared to rabbits fed other fats). Cottonseed Oil controls used as vehicles in two parenteral studies produced negative results. Hydrogenated Cottonseed Oil tested in formulation did not produce dermal or ocular irritation in rabbits. An oral-dose reproductive study tested up to 30% Cottonseed Oil (with 1% CPFAs) and reported no adverse effects on sexual maturity and reproductive performance of the F0 generation; changes were noted in the F1 generation but reproductive capacity was not altered. Parenteral-dose reproductive studies reported no adverse effects. Cottonseed Oil was not mutagenic. Cottonseed Oil did not induce aberrant crypt foci when given orally to mice, but in other studies, it increased the incidence of spontaneous mammary tumors in rats and mice. Mice fed 20% Hydrogenated Cottonseed Oil during induction and promotion of photocarcinogenesis had significantly lower tumor incidence compared to mice fed 20 % sunflower oil. Hydrogenated Cottonseed Oil in formulation (up to 21 %) was neither an irritant nor sensitizer in clinical studies. Limited clinical data indicated that Cottonseed Oil does not contain allergic protein. Based on the available data, it was concluded that these ingredients may be used safely in cosmetic formulations if established limits on gossypol, heavy metals, and pesticide concentrations are not exceeded.

The Tg.AC (v-Ha-ras) Transgenic Mouse: Nature of the Model

The Tg.AC (v-Ha-ras) transgenic mouse model provides a reporter phenotype of skin papillomas in response to either genotoxic or nongenotoxic carcinogens. In common with the conventional bioassay, the Tg.AC model responds to known human carcinogens and does not respond to noncarcinogens. It also does not respond to most chemicals that are positive in conventional bioassays principally at sites of high spontaneous tumor incidence. The mechanism of response of the Tg.AC model is related to the structure and genomic position of the transgene and the induction of transgene expression through specific mediated interactions between the chemicals and target cells in the skin.

Systemic deficits in transporter for antigen presentation (TAP)-1 or proteasome subunit LMP2 have little or no effect on tumor incidence.

Some tumor cells have deficits in class I MHC antigen processing, suggesting that T cells exert selective pressure on tumor cells. Previous studies have not revealed increased tumor incidence in mice with deficits in T-cell immunity, including mice lacking TAP1 (a subunit of the transporter for antigen presentation) or LMP2 (a regulated subunit of the 20S proteasome). The incidence of spontaneous tumors in these mice, however, is too low to assess differences in host resistance to tumors. To increase tumor incidence and better assess the role of systemic expression of TAP1 and LMP2 in responses to tumors, TAP1-/- and LMP2-/- mice were bred with p53-/- mice to create TAP1-/-p53-/- and LMP2-/-p53-/- double knockout mice. Lymphomas and sarcomas (malignant fibrous histiocytoma and angiosarcoma) occurred with high incidence in all p53-deficient populations. Tumor incidence and death rate were similar in TAP1-/-p53-/- mice and closely matched control TAP1+/+p53-/- mice. Tumor incidence and death rate were slightly accelerated in LMP2-/-p53-/- mice relative to control LMP2+/+p53-/- mice, but the biological significance of this difference was unclear. The relative incidence of lymphomas vs. sarcomas was not significantly altered by variation in TAP1 or LMP2. In conclusion, systemic absence of TAP1 did not alter tumor incidence, while absence of LMP2 was associated with only a slight acceleration of tumor incidence of uncertain significance. These observations are consistent with other evidence that normal T-cell responses do not effectively limit tumorigenesis. Even though T cells can attack some tumor cells, the ability of tumors to alter their immunogenicity and evade T-cell surveillance may render the native immune system ineffective at providing a rate-limiting barrier to tumorigenesis and preventing cancer.

Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis.

Inhibition of telomerase is proposed to limit the growth of cancer cells by triggering telomere shortening and cell death. Telomere maintenance by telomerase is sufficient, in some cell types, to allow immortal growth. Telomerase has been shown to cooperate with oncogenes in transforming cultured primary human cells into neoplastic cells, suggesting that telomerase activation contributes to malignant transformation. Moreover, telomerase inhibition in human tumour cell lines using dominant-negative versions of TERT leads to telomere shortening and cell death. These findings have led to the proposition that telomerase inhibition may result in cessation of tumour growth. The absence of telomerase from most normal cells supports the potential efficacy of anti-telomerase drugs for tumour therapy, as its inhibition is unlikely to have toxic effects. Mice deficient for Terc RNA (encoding telomerase) lack telomerase activity, and constitute a model for evaluating the role of telomerase and telomeres in tumourigenesis. Late-generation Terc-/- mice show defects in proliferative tissues and a moderate increase in the incidence of spontaneous tumours in highly proliferative cell types (lymphomas, teratocarcinomas). The appearance of these tumours is thought to be a consequence of chromosomal instability in these mice. These observations have challenged the expected effectiveness of anti-telomerase-based cancer therapies. Different cell types may nonetheless vary in their sensitivity to the chromosomal instability produced by telomere loss or to the activation of telomere-rescue mechanisms. Here we show that late-generation Terc-/- mice, which have short telomeres and are telomerase-deficient, are resistant to tumour development in multi-stage skin carcinogenesis. Our results predict that an anti-telomerase-based tumour therapy may be effective in epithelial tumours.