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[Cancer Research 63, 7047-7050, November 1, 2003]
© 2003 American Association for Cancer Research

Advances in Brief

Telomere Dysfunction Results in Enhanced Organismal Sensitivity to the Alkylating Agent N-Methyl-N-Nitrosourea1

Eva González-Suárez, Fermín A. Goytisolo, Juana M. Flores and María A. Blasco2

Department of Immunology and Oncology, National Center of Biotechnology [E. G. S., F. A. G., M. A. B.], and Animal Pathology II, Facultad de Veterinaria, Universidad Complutense de Madrid [J. M. F.], Madrid, Spain


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Here, we use telomerase-deficient mice, Terc-/-, to study the impact of telomerase abrogation in response to treatment with the alkylating agent N-Methyl-N-Nitrosourea (MNU), a potent carcinogen in the mouse. Wild-type mice treated with MNU developed lymphomas and carcinomas. In contrast, similarly treated G5 Terc-/- mice with critically short telomeres did not develop tumors and died of acute toxicity to the small intestine. G2 Terc-/- mice, which have long telomeres, were less susceptible to MNU-induced tumors than wild-type mice, as well as less sensitive to MNU toxicity than G5 Terc-/- mice. The results indicate that short telomeres suppress tumor growth and that lack of telomerase retards tumor progression, even in the presence of long telomeres. Finally, G5 Terc-/- hypersensitivity to MNU supports the notion that short telomeres interfere with proper DNA damage repair.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
Telomeres are specialized protective structures at the ends of eukaryotic chromosomes (1) synthesized by telomerase (2) . Dysfunctional telomeres trigger end-to-end chromosome fusions and loss of cell viability (3) . The fact that most cancer cells have high telomerase levels, not observed in somatic cells, and that telomere maintenance above a threshold length is necessary for cell viability make of telomerase an attractive target for cancer therapy. We studied here the tumor susceptibility and cytotoxic sensitivity of mice lacking the RNA component of telomerase (Terc; Ref. 4 ) in response to treatment with the alkylating agent MNU.3 Terc-/- mice lack telomerase activity and show telomere shortening at a rate of 4–5 kb/mouse generation (successive mouse generations are indicated as G1 through G6; Ref. 4 ). Early generation (G1 and G2) Terc-/- mice lack telomerase activity but still show very long telomeres (4) . Fifth generation (G5) Terc-/- mice lack telomerase activity and have a significant loss of telomeric sequences (4) . Telomere shortening in these mice is accompanied by an increase in the number of chromosome ends with no detectable telomeres and in the frequency of end-to-end chromosome fusions (4) . G5 Terc-/- mice have been shown to be hypersensitive to {gamma}-irradiation (5 , 6) , and short telomeres sensitize cells to the chemotherapeutic agent doxorubicin (7) . In addition, telomerase-deficient mice with critically short telomeres are resistant to papilloma formation after chemical carcinogenesis of the skin (8) . To determine whether this resistance to tumor formation and the hypersensitivity to DNA-damaging agents can be extrapolated to other carcinogens and other target tissues, we treated wt, G2 Terc-/-, and G5 Terc-/- mice with the alkylating agent MNU. O6-methylguanine is the preponderant toxic lesion produced by MNU, as it initiates G:C to A:T transition mutations in K-ras and other oncogenes, giving rise to a variety of tumors (9) . O6-methylguanine lesions can be corrected by MMR, or specifically by O6-methylguanine methyltransferase. Alkylant lesions could be repaired by base excision repair, the major DNA repair pathway that protects mammalian cells against single-base DNA damage (10) . Methylation-induced apoptosis appears to be MMR-dependent and to be triggered by secondary lesions, possibly DSBs formed during the MMR process (9) . Alkylating agents, including MNU, are currently used in antitumor therapies (11) ; thus, treatment with MNU allows evaluation of the impact of short telomeres and the absence of telomerase on the murine response to DNA damage induced by this agent.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Mice.
wt, G2 Terc-/-, and G5 Terc-/- mice were generated on a 60% C57BL/6, 37.5% Sv, and 2.5% SJL genetic background (4) .

MNU Treatment.
MNU (Sigma, St. Louis, MO) was dissolved in PBS. Mice received weekly i.p. injections of MNU (30 mg/kg body weight) for 5 consecutive weeks. In experiment I, the first dose was administered to 8 females and 4 males of each genotype at 5 weeks of age. In experiment II, the first dose was administered to 10 males of each genotype (5–7 months of age). Control mice were treated in parallel with PBS.

Histopathological Analysis.
Mice were monitored daily and sacrificed when they showed signs of illness. Survivors were sacrificed at week 92 after the start of treatment. Tissues were fixed in 10% PBS-buffered formalin, embedded in paraffin, 4-µm sections prepared, H&E stained, and examined by light microscopy. Intestinal lesions were classified according to intensity and extension of atrophy and severity of associated lesions (compensatory glandular hyperplasia, inflammation, ulceration, and lymphangiectasias). They were scored as mild (moderate shortening of villi in small intestine and of crypts in the large intestine, with no associated lesions), intermediate (marked reduction in villous/crypt size, with associated lesions of moderate intensity), and severe (disappearance of villi/crypts, with severe associated lesions).

Statistical Analysis.
To calculate the statistical significance of the differences in MNU-induced tumor formation between wt and G2 Terc-/- mice, values on an arbitrary scale were assigned to each mouse according the pathologies present at death [0 = no tumor; 1 = benign tumor (adenoma or hemangioma); and 2 = malignant tumor (carcinoma, sarcoma, or lymphoma)]. Student’s t test was calculated using these values.


   Results
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
G5 Terc-/- and G2 Terc-/- Mice Are Hypersensitive to MNU Genotoxic Damage.
To analyze the impact of short telomeres and lack of telomerase in response to MNU treatment, 5-week-old wt, G2 Terc-/-, and G5 Terc-/- mice were treated with this alkylating agent for 5 weeks (experiment I, see "Materials and Methods"). G5 Terc-/- mice showed a drastic loss of viability after treatment (Fig. 1A)Citation . G5 Terc-/- mice began to die 26 weeks after initiation of treatment; by 54 weeks after the first MNU injection, 75% had died compared with 8.3% of wt and 0% of G2 Terc-/- mice (Fig. 1A)Citation . The mortality rate was higher in G5 Terc-/- males than in females (Fig. 1A)Citation ; by week 34 after the first injection, all males had died, whereas 85% of females remained alive.



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  		Fig. 1. Survival of wt, G2 Terc-/-, and G5 Terc-/- mice after MNU treatment. A, experiment I: 5-week-old mice (8 females and 4 males/genotype) were treated. B, experiment II: 4–7-month-old mice (10 males/genotype) were treated.

 
To determine the cause of death in G5 Terc-/- mice, we performed full-body histopathological analysis of each moribund MNU-treated mouse (Table 1)Citation . All G5 Terc-/- mice showed severe mucosal atrophy of small and large intestine with reduction or disappearance of villi in small intestine and of crypts in the large intestine (Figs. 2Citation and 3Citation , A and C). This was associated with glandular hyperplasia and accompanied in some cases by inflammation, ulceration, enteritis, adenomatous polyp, and peritonitis. This mucosal abnormality typically results in reduced nutrient absorption, a possible cause of the premature death of these mice (all 4 males died from weeks 26–34 after start of treatment and all 8 females from weeks 33–77). Intermediate intestinal atrophy was detected in 11 of 12 (91.7%) MNU-treated G2 Terc-/- mice, which died or were sacrificed at weeks 69–92 (Figs. 2Citation and 3, A and C)Citation ; no significant differences in mortality were found between G2 Terc-/- males and females (Fig. 1A)Citation . Some PBS-treated G5 Terc-/- and G2 Terc-/- control mice also showed mild to intermediate intestinal atrophy at death (72 and 92 weeks, respectively; Ref. 12 ). No intestinal atrophy was found in any of the PBS- or MNU-treated wt mice.


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  		Table 1 Pathology observed in MNU-treated wt, G2 Terc-/- and G5 Terc-/- mice

The number of mice is indicated that showed a given lesion at necropsy.

 


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  		Fig. 2. H&E staining of representative intestinal sections of moribund MNU-treated G5 Terc-/-, G2 Terc-/-, and wt mice (experiment I). A and B, transverse section of small intestine from a G5 Terc-/- mouse (death at week 64) showing shortened villi and thick mucosa because of compensatory glandular hyperplasia. The enlargement in b shows marked villous atrophy in G5 Terc-/- mouse intestine. Note the decrease in the number of villi associated with inflammation and lymphangiectasia. C and D, transverse section of small intestine from a G2 Terc-/- mouse (sacrificed at week 92). Note shortened villi and their abnormal distribution. The enlargement in D shows moderate atrophy of ileal mucosa associated with underlying inflammation in a G2 Terc-/- mouse. E and F, transverse sections of small intestine from a wt mouse (death at week 58). Note normal number and distribution of the villi. A, C, and E, x20; B, D, and F, x100.

 


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  		Fig. 3. A and B, MNU-induced intestinal atrophy (A) and tumors (B) at death in wt, G2 Terc-/-, and G5 Terc-/- mice. Each symbol represents a single mouse. Note that survivors were sacrificed at week 92, although they did not show signs of suffering. C and D, percentage of MNU-treated mice that showed intestinal atrophy or malignant tumors at death (C) experiment I; (D) experiment II.

 
In a second experiment (experiment II, see "Materials and Methods") using 5–7-month-old males, MNU toxicity in G5 and G2 Terc-/- mice intestines was even higher than in young animals. G5 Terc-/- mice began to die after the third MNU injection and 80% had died by week 26 (Fig. 1B)Citation . Death in 100% of MNU-treated G5 Terc-/- animals (from weeks 3 to 43 after the first injection) was related to severe abnormal mucosal structure in intestine and the associated lesions (Fig. 3A and D)Citation . Severe intestinal atrophy was also detected in all MNU-treated G2 Terc-/- but not in wt mice (death in both groups occurred at weeks 50–80; Fig. 3, A and DCitation ). This indicates that the degenerative intestinal lesions are due specifically to either telomere shortening or lack of telomerase. Other senile lesions detected in wt and G2 Terc-/- mice, including atrophy of the kidney, testis, and spleen, may contribute to animal death (Table 1)Citation . All together, the results indicate that mice with critically short telomeres are hypersensitive to MNU-induced DNA damage, concurring with the response described to ionizing agents (5 , 6) . In addition, absence of telomerase, independent of telomere length, also sensitizes mice to MNU cytotoxic effects.

G5 and G2 Terc-/- Mice Are more Resistant to MNU-Induced Tumors Than wt Mice.
No tumors were detected in MNU-treated G5 Terc-/- mice from experiment I, except for a single 82-week-old female that showed an incipient hemangioma in one lymph node at week 77 (experiment I; Fig. 3BCitation , Table 1Citation ). In contrast, MNU-treated wt and G2 Terc-/- mice developed various benign and malignant tumors (experiment I; Fig. 3, B and CCitation ; Table 1Citation ), concurring with previous descriptions of MNU as a potent carcinogen (13) . Malignant tumors, including lymphomas, sarcomas, osteosarcomas, adenocarcinomas, and carcinomas, were detected in 58% (7 of 12) of wt mice after MNU treatment (experiment I). None of the G5 Terc-/- mice developed malignant tumors, even those surviving to 77 weeks after the start of MNU treatment, by which time 87% of wt mice had died of tumors (experiment I; Fig. 3, B and CCitation ). In contrast to MNU-treated wt mice, only 25% (3 of 12) of G2 Terc-/- mice developed malignant tumors after MNU treatment, whereas most G2 Terc-/- mice (75%; 9 of 12) showed only benign adenomas or hemangiomas (experiment I; Fig. 3, B and CCitation ). In addition, tumor latency was longer in G2 Terc-/- than in wt mice after the start of MNU treatment (69 and 50 weeks, respectively). This tumor resistance of G2 Terc-/- mice resulted in prolonged survival compared with wt animals (Fig. 1A)Citation ; 75% of G2 mice were thus alive at week 77, whereas only 33% of wt mice remained alive at this time.

MNU treatment of older (experiment II; 4–7-month-old) G5 Terc-/- mice did not result in tumor formation, except for an 80-week-old male that showed an incipient follicular lymphoma in spleen at week 43 (experiment II; Table 1Citation , Fig. 3BCitation ). Nevertheless, malignant tumors were detected in 50% of wt and 20% of G2 Terc-/- mice (Fig. 3, B and D)Citation . Whereas in wt mice, malignant tumors included adenocarcinomas, carcinomas, sarcomas, hemangiosarcomas, and lymphomas, only hemangiosarcomas were detected in G2 Terc-/- mice (Table 1)Citation . Most MNU-treated wt mice (90%; 9 of 10) showed benign hemangiomas or adenomas in different tissues (liver, lung, and testis), whereas only one G2 Terc-/- mouse presented a bronchioloalveolar adenoma (Fig. 3, B and D)Citation . No differences in survival were detected between wt and G2 Terc-/- mice, probably because of the acute intestinal lesions that affected G2 Terc-/- mice (Fig. 1B)Citation .

To calculate the statistical significance of the intergenotype differences in tumor incidence after MNU treatment, we assigned an arbitrary tumor severity value to each mouse depending on the presence of benign or malignant tumors at death ("Materials and Methods"). Student’s t test analysis (P = 0.003, experiment I; P = 0.006, experiment II) indicated that tumor severity was significantly reduced in G2 Terc-/- compared with wt mice.

The fact that MNU-treated G5 Terc-/- mice with critically short telomeres were tumor resistant compared with the similarly treated wt or G2 Terc-/- mice (Fig. 3b)Citation indicates that critically short telomeres act as potent tumor suppressors after carcinogen treatment. In addition, independent of telomere length, lack of telomerase diminishes tumor development after MNU treatment of G2 Terc-/- mice.


   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
Inhibition of telomerase activity in tumor cells or in the context of telomerase-deficient mice triggers telomere shortening and limits viability (12 , 14 , 15) . The fact that telomerase is expressed in most tumor cells but not in normal cells, together with the fact that telomeres are generally shorter in tumor than in normal cells, suggests that telomerase inhibitors would mainly affect cancer cells (16) . The telomerase-deficient mouse has served to study the impact of telomerase abrogation in a physiological context (3 , 8 , 12 , 15) . Short telomeres in these mice act as potent tumor suppressors in a p53-dependent manner (3 , 8 , 16) . Here, we show that this tumor suppressor effect of short telomeres is maintained in MNU-induced tumorigenesis because G5 Terc-/- mice do not develop tumors after treatment with this carcinogen compared with similarly treated wt mice. In addition, we show here that lack of telomerase retards MNU-induced tumor progression, even in the presence of long telomeres, in the MNU-treated G2 Terc-/- mice. This finding suggests that telomerase activity has novel roles in promoting tumorigenesis independent of its role in net telomere elongation (8 , 17 , 18) . In agreement with this, mice with constitutive telomerase expression show a predisposition to tumor formation compared with wt mice in the absence of significant differences in telomere length (19 , 20) .

The tumor resistance of mice with short telomeres after MNU treatment could be also related to the fact that short telomeres may interfere with DSB repair, thus resulting in increased cell death in response to DNA-damaging agents (5 , 6 , 21) . In particular, mice with short telomeres are hypersensitive to treatment with agents that provoke DNA strand breaks such as {gamma}-irradiation (5, 6, 7) . This hypersensitivity of late generation Terc-/- mice to {gamma}-irradiation is not a direct consequence of a defect in the DNA DSB repair pathway but rather of short telomeres interfering with the proper repair of radiation-induced DSB (5 , 6 , 21) . Here, we observed a drastic increase in mortality of MNU-treated mice with short telomeres, which was more evident in males than in females, as also observed in {gamma}-irradiated and untreated G5 Terc-/- mice (Ref. 6 and unpublished observations). The earlier death of G5 Terc-/- males compared with females upon MNU treatment suggests a differential impact of short telomeres depending on the sex of the animal. Although the basis of this difference is currently unknown, it could be related to the fact that male rodents have significantly shorter telomeres than females (22) . Similar differences between males and females have been observed in response other cytotoxic agents (23) . Interestingly, G2 Terc-/- mice, whose telomeres remain within the normal range for this genetic background, were also more sensitive to MNU treatment than the wt controls, suggesting that telomerase activity itself may influence the response to MNU-induced lesions independently of telomere length.

In summary, the results presented here show that short telomeres in the absence of telomerase are potent suppressors of MNU-induced tumorigenesis in the context of the organism. In addition, we show that short telomeres enhance the sensitivity to the genotoxic effects of MNU treatment, thus reinforcing the notion that short telomeres interfere with proper DNA repair (21) . Finally, we show that telomerase deficiency, even in the presence of long telomeres, significantly delays MNU-induced tumorigenesis and increases MNU cytotoxic effects in vivo. All together, these results suggest that combined telomerase inhibition and MNU treatment could have synergistic effects in killing cells with short telomeres such as cancer cells.


   ACKNOWLEDGMENTS
 
We thank Rosa Serrano and Elisa Santos for mouse care and genotyping, and we also thank Catherine Mark for proofreading the manuscript.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 E. G-S. received a predoctoral fellowship from the Spanish Fondo de Investigaciones Sanitarias. Research at the laboratory of M. A. B. is funded by grants from the Ministry of Science and Technology, the Regional Government of Madrid (Comunidad Autonoma de Madrid), the European Union, and by The Department of Immunology and Oncology (DIO). The DIO was founded and is supported by the Spanish Council for Scientific Research (Consejo Superior de Investigaciones Cientificas) and by Pfizer. Back

2 To whom requests for reprints should be addressed, at Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Spanish National Cancer Centre, Madrid, E28029, Spain. Phone: 917328031; E-mail: mblasco{at}cnio.es Back

3 The abbreviations used are: MNU, N-methyl-N-nitrosourea; BER, base excision repair; DSB, double strand break; MMR, mismatch repair; Terc, telomerase RNA; wt, wild type. Back

Received 6/27/03. Revised 9/11/03. Accepted 9/12/03.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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