Carcinogenesis Advance Access originally published online on March 16, 2006
Carcinogenesis 2006 27(7):1489-1496; doi:10.1093/carcin/bgl012
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Zinc deficiency potentiates induction and progression of lingual and esophageal tumors in p53-deficient mice
Department of Molecular Virology, Immunology and Medical Genetics 1 Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA and 2 Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
* To whom correspondence should be addressed at: Comprehensive Cancer Center, Ohio State University, Room 388A, Tzagournis Medical Research Facility, 420 W. 12th Avenue, Columbus, OH 43210, USA. Tel: +1 614 688 5914; Fax: +1 614 688 4020; Email: Louise.Fong{at}osumc.edu
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Abstract |
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Upper aerodigestive tract (UADT) cancer, including oral and esophageal cancer, is an important cause of cancer deaths worldwide. Patients with UADT cancer are frequently zinc deficient (ZD) and show a loss of function of the pivotal tumor suppressor gene p53. The present study examined whether zinc deficiency in collaboration with p53 insufficiency (p53+/–) promotes lingual and esophageal tumorigenesis in mice exposed to low doses of the carcinogen 4-nitroquinoline 1-oxide. In wild-type mice, ZD significantly increased the incidence of lingual and esophageal tumors from 0% in zinc sufficient (ZS) ZS:p53+/+ mice to
40%. On the p53+/– background, ZD:p53+/– mice had significantly greater tumor incidence and multiplicity than ZS:p53+/– and ZD:p53+/+ mice, with a high frequency of progression to malignancy. Sixty-nine and 31% of ZD:p53+/– lingual and esophageal tumors, respectively, were squamous cell carcinoma versus 19 and 0% of ZS:p53+/– tumors (tongue, P = 0.003; esophagus, P = 0.005). Immunohistochemical analysis revealed that the increased cellular proliferation observed in preneoplastic lingual and esophageal lesions, as well as invasive carcinomas, was accompanied by overexpression of cytokeratin 14, cyclooxygenase-2 and metallothionein. In summary, a new UADT cancer model is developed in ZD:p53+/– mouse that recapitulates aspects of the human cancer and provides opportunities to probe the genetic changes intrinsic to UADT carcinogenesis and to test strategies for prevention and reversal of this deadly cancer.
Abbreviations: COX, cyclooxygenase; DAB, 3,3'-diaminobenzidine tetrahydrochloride; H&E, hematoxylin and eosin; KRT14, keratin 14; MT, metallothionein; NQO, 4-nitroquinoline 1-oxide; NMBA, N-nitrosomethylbenzylamine; PCNA, proliferating cell nuclear antigen; SCC, squamous cell carcinoma; UADT, upper aerodigestive tract; ZD, zinc deficient; ZS, zinc sufficient
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Introduction |
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Upper aerodigestive tract (UADT) cancer, including esophageal and tongue tumors, is an important cause of morbidity and mortality worldwide (1). The incidence of UADT cancer is increasing worldwide, including that in young adults and those without the known risk factors of tobacco and alcohol use (2). The prognosis of esophageal cancer is poor, with a 5-year survival rate of only 10%. The survival with oral cancer, the major site being the tongue, is equally dismal. Patients with oral cancer have a high mortality rate, because of field cancerization effects that result in second primary tumors, particularly in the esophagus (3,4). In addition, patients with oral cancer are frequently zinc deficient (ZD) (5,6), a condition associated with an increased risk for esophageal squamous cell cancer (ESCC) (7,8). Abnet et al. (9) established a direct connection between zinc deficiency and human ESCC, by using X-ray fluorescence spectroscopy to measure zinc, copper, iron, nickel and sulfur in esophageal biopsy samples obtained from residents in a high ESCC incidence area in China. Subjects were matched on baseline histology and followed for 16 years: 90% of subjects in the highest zinc quartile versus 65% in the lowest quartile were cancer-free for 16 years. No associations with ESCC cancer risk were found for any of the other elements studied. These findings in humans are consistent with our conclusion from rodent model studies that zinc deficiency promotes esophageal cancer (10–12).
We have developed ZD rodent cancer models and found that zinc deficiency creates a precancerous condition in the rat UADT by causing unrestrained cell proliferation (11–13) and extensive changes in gene expression, including upregulated expression of cyclooxygenase-2 (COX-2), keratin 14 (KRT14) and metallothionein-1 (MT-1) (13,14). Overexpression of COX-2 has been reported in a variety of human premalignant and malignant lesions, including UADT cancer (15–17). MT protein is overexpressed in human squamous cell carcinoma (SCC) of the esophagus (18) and tongue (19). KRT14 is a biomarker of human and rodent esophageal carcinogenesis (20,21). A ZD diet in rats accelerates carcinogenesis in the esophagus and forestomach that results from a single exposure to the carcinogen of N-nitrosomethylbenzylamine (NMBA) (22,23) and at multiple sites in the UADT with continuous exposure to the carcinogen 4-nitroquinoline 1-oxide (NQO) (13). On the other hand, zinc replenishment rapidly reverses cell proliferation, stimulates apoptosis, corrects abnormal gene expression in esophageal epithelium and inhibits tumorigenesis (13,14,24).
The p53 tumor suppressor protein plays a pivotal role in preventing uncontrolled cellular proliferation. A loss of function of the TP53 tumor suppressor gene is demonstrated in over 50% of all human cancers, including oral and esophageal cancer (25). Our previous work shows that zinc deficiency modulates the enhanced genetic susceptibility to esophageal cancer by NMBA in p53-deficient mice (21).
The mouse tongue is not sensitive to chemical carcinogenesis. Mice exposed to 10 p.p.m. NQO in the drinking water for 50 weeks (26) or 20 p.p.m. for 8 weeks and killed at week 24 (27) did not develop any lesions in the tongue. NQO at high concentrations of 50 and 100 p.p.m. in the drinking water, however, induced both esophageal and tongue tumors in mice, with progression to malignancy (27). In the present study, we tested the hypothesis that zinc deficiency increases cellular proliferation in the murine tongue, as it does in the rat tongue (13), and that zinc deficiency in collaboration with p53 insufficiency (p53+/–) promotes lingual and esophageal tumorigenesis in ZD:p53+/– mice exposed to low doses of NQO in the drinking water (26,27). In addition, we examined whether an association exists between increased cellular proliferation and overexpression of the tumor markers KRT14, COX-2 and MT in premalignant and malignant lesions during UADT carcinogenesis.
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Materials and methods |
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Chemicals and diets
NQO was from Wako Chemicals, USA (Richmond, VA). Custom-formulated, egg white-based ZD and zinc sufficient (ZS) diets containing 1.5 and 70 p.p.m. zinc, respectively, were prepared by Teklad (Madison, WI). The deficient diet is nutritionally complete and is identical to ZS diet except for the concentration of elemental zinc (21).
P53-deficient mice
Breeder pairs, homozygous C57BL/6J-Trp53 males and heterozygous C57BL/6J-Trp53 females that have been backcrossed for 11 generations, were purchased from The Jackson Laboratory (Bar Harbor, ME) to generate p53–/– and p53+/– mice for this study. The p53+/– and p53–/– offsprings were differentiated by genotyping of tail DNA using a PCR-based method (28). Wild-type C57BL/6J controls were obtained from The Jackson Laboratory.
Experimental design
This study was approved by the Institutional Laboratory Animal Care of and Use Committee of the Thomas Jefferson University, Philadelphia, PA and conducted under National Institutes of Health guidelines. The experiment was conducted in three batches when the animals became available from our breeding colonies. Each batch contained all treatment groups listed below. Four-week-old mice were housed 3–5 to a polycarbonate cage with a stainless-steel wire floor. The animals had free access to deionized drinking water. The mice were randomized into two dietary groups and were fed ad libitum a ZD or control ZS diet, forming six experimental groups: ZD:p53–/– (n = 15), ZS:p53–/– (n = 14), ZD:p53+/– (n = 16), ZS:p53+/– (n = 26), ZD:p53+/+ (n = 14) and ZS:p53+/+ (n = 12). After 3 weeks, all animals were switched to drinking water containing 20–10 p.p.m. NQO for 21 weeks: 20 p.p.m. for the first 3 weeks and 10 p.p.m. for the remaining 18 weeks. NQO was freshly prepared every week and administered in light-shielded water bottles. The animals were monitored daily for signs of ill health. Moribund mice were killed and autopsied. For the analysis of tumor incidence, all mice were killed at week 21.
Tumor analysis
After anesthetization with isoflurane (Abbott Laboratories, North Chicago, IL), the animals were subjected to complete autopsies, with particular attention to tongue, esophagus and forestomach. Tumors >0.5 mm were mapped and counted. Tongue, esophagus and forestomach were fixed in phosphate-buffered formalin and embedded in paraffin and 4-µm sections were cut. Hematoxylin and eosin (H&E) staining for histopathology and immunohistochemical analyses of the biomarkers were performed on sections from all animals.
Immunohistochemical detection of cell proliferation
Esophagus and tongue sections were deparaffinized and rehydrated in a graded alcohol series and then incubated with mouse anti-proliferating cell nuclear antigen (anti-PCNA) monoclonal antibodies (Santa Cruz Biotechnology Inc., Santa Cruz, CA) at a 1:250 dilution overnight at 37°C in a humidified chamber, followed by incubation with biotinylated goat anti-mouse antibodies (DakoCytomation, Carpinteria, CA) at 1:750 dilution and streptavidin horseradish peroxidase (DakoCytomation). PCNA staining was visualized by incubation with the chromogen 3-amino-9-ethylcarbazole (DakoCytomation). Cells with a red reaction product in the nucleus were defined as positive for PCNA.
Immunohistochemical analysis of KRT14, COX-2 and MT protein expression
Following deparaffinization and rehydration in a graded alcohol series, esophageal and lingual sections were heated in citrate buffer (0.01 M, pH 6.0) in a microwave oven (85–90°C, 3 x 5 min) and non-specific binding sites were then blocked with goat or rabbit serum. Sections were incubated overnight at 37°C in a humidified chamber with one of the following primary antibodies: mouse anti-KRT14 monoclonal antiserum (Clone LL002, Novocastra Lab., Newcastle upon Tyne, UK) at a 1:100 dilution, rabbit anti-COX-2 polyclonal antiserum (Caymen Chemical, Ann Harbor, MI) at a 1:50 dilution or mouse anti-MT monoclonal antiserum (Clone E9; DakoCytomation) at a 1:50 dilution. Sections were then incubated with the appropriate biotinylated secondary antibodies (DakoCytomation) and streptavidin horseradish peroxidase (DakoCytomation). Staining of individual proteins was visualized by incubating sections with 3,3'-diaminobenzidine tetrahydrochloride (DAB) and lightly counterstaining them with hematoxylin.
Zinc determination
The testes were removed from male and hair from female animals at necropsy. Samples of testis or hair were dried to constant weight at 90°C and ashed in a furnace. Ashed samples were dissolved in 0.1 N HCl, and the zinc content determined by atomic absorption spectrometry as described (11). Zinc content was expressed as µg/g dry weight of testis or hair. The well-described overt signs of zinc deficiency for rats (11), including foci of alopecia, skin lesions and retarded growth, were not evident in ZD:WT mice, which had similar body weights at endpoint (data not shown). Zinc content in the testis (male) and hair (female), however, was significantly lower in ZD than ZS mice, regardless of genotype. For example, zinc content of testis and hair was significantly lower in ZD:p53+/– than ZS:p53+/– mice (testis, 113 ± 11 versus 153 ± 8 µg/g; hair, 129 ± 11 versus 192 ± 16 µg/g, P < 0.001), a result consistent with previous studies (21).
Statistical analysis
Data on tumor multiplicity were analyzed by two-way analysis of variance (ANOVA), followed by Tukey's highest significant difference test. Tumor incidence differences were analyzed by Fisher's exact test, two-tailed. All statistical tests were two-sided and were considered statistically significant at P < 0.05.
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UADT tumorigenesis in ZD:p53+/– mice
In order to determine whether the combined deficiency of zinc and p53 promotes UADT carcinogenesis, p53–/–, p53+/– and p53+/+ mice on ZD or ZS diet were given for 21 weeks drinking water containing 20 to 10 p.p.m. NQO. While all heterozygous p53+/– and wild-type p53+/+ mice survived for 21 weeks, only 2 of 15 (13%) nullizygous ZD:p53–/– mice and 10 of 14 (71%) ZS:p53–/– and were alive after 15 weeks (Table I). Among the heterozygous and wild-type mice, only 2 of 16 ZD:p53+/– mice had spontaneous (non-UADT) splenic lymphomas at week 21. In contrast, ZD:p53–/– mice succumbed to the rapid development of spontaneous tumors (29), in addition to induced lingual and esophageal lesions (Table I). These NQO-induced lesions appeared to occur earlier in ZD:p53–/– than in ZS:p53–/– mice, a finding in agreement with our previous studies with NMBA-induced forestomach tumors in ZD:p53–/– mice (21).
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Leukoplakia, the most common oral intraepithelial neoplasia in humans and a precursor of SCC, were consistently found on the ZD:p53–/– tongue between 2 and 8 weeks after NQO exposure. By week 13, ZD:p53–/– mice typically harbored tumors at multiple sites in the UADT. For example, ZD:p53–/– mouse no. 15 showed multiple tumors in tongue, esophagus, forestomach and hard palate at week 21 (Figure 1A, lower panel, forestomach tumor data not shown). Histopathological examination revealed progression to malignancy in ZD:p53–/– tongue and esophagus at week 11 (Figure 2B and D) but mostly hyperplasia in ZS:p53–/– tongue and esophagus at week 12 (Figure 2A and C). By 20 weeks, however, malignant changes in tongues became evident in ZS:p53–/– mice (data not shown). These data demonstrate that in the absence of both p53 alleles, zinc deficiency greatly accelerates the induction and progression of UADT tumors in mice.
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ZD:p53+/– versus ZS:p53+/–, P = 0.029;
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Wild-type ZS mice did not develop lingual or esophageal lesions (0%) after exposure for 21 weeks to low levels of NQO, a result consistent with previous reports (26,27). Zinc deficiency, however, significantly enhanced the development of tumors at multiples sites in wild-type mice, with a tumor incidence of 50, 36 and 43% in tongue, esophagus and forestomach, respectively (Figure 1B; ZD:p53+/+ versus ZS:p53+/+: tongue, P = 0.006; esophagus, P = 0.04). These results demonstrate that in wild-type mice, zinc deficiency increases the incidence of NQO-induced UADT tumors as it does in rats (13).
Haploinsufficiency for p53 alone enhanced the induction of lingual and esophageal tumors in ZS mice, resulting in a significantly higher incidence of lingual (62%) and esophageal (38%) tumors in ZS:p53+/– than wild-type ZS:p53+/+ mice (tongue, P = 0.0003; esophagus, P = 0.02; Figure 1B). Haploinsufficiency for p53 alone, however, had no effects on tumor progression (Figure 1B–D). In contrast, combination of p53 haploinsufficiency and zinc deficiency led to a significantly greater tumor incidence/multiplicity and frequency of tumor progression, as compared with heterozygous ZS:p53+/– or wild-type ZD:p53+/+ mice (Figure 1B–D). Fifty-six percent of ZD:p53+/– mice harbored tumors in all three sites (Figure 1A, upper panel), as compared with 23% of ZS:p53+/– (P = 0.047), 14% of ZD:p53+/+ (P = 0.026) and none of the ZS:p53+/+ mice (P = 0.0028). In addition, ZD:p53+/– mice had a higher incidence of SCC, with 69% of lingual and 31% of esophageal tumors presenting as SCC versus 19% of lingual and 0% of esophageal tumors from ZS:p53+/– mice (tongue, P = 0.003; esophagus, P = 0.005; Figure 1C). These results demonstrate that zinc deficiency or p53 haploinsufficiency acting alone increases UADT tumors induction by low levels of NQO and acting together greatly enhances tumor induction with rapid progression to malignancy.
Cell proliferation and marker gene expression in tongue and esophagus of NQO-treated wild-type mice
Histopathological examination revealed that esophagus and tongue from wild-type ZS:p53+/+ mice at week 21 showed a moderately thickened epithelium, with PCNA-positive nuclei largely restricted to the basal cell layer (esophagus, Figure 3C and G) and in focal hyperplastic lesions (tongue, Figure 3A and E). In contrast, similarly treated ZD:p53+/+ esophagi were highly proliferative, with PCNA-positive nuclei in many cell layers and in focal hyperplastic lesions (Figure 3D and H). ZD:p53+/+ lingual epithelia were typically hyperplastic, showing dysplastic changes or early carcinoma in situ (Figure 3B), with abundant PCNA-positive nuclei in dysplastic areas (Figure 3F).
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Immunohistochemistry was then used to determine whether these early precancerous lesions in the ZD:p53+/+ mice are accompanied by overexpression of the tumor markers KRT14, COX-2 and MT. ZS:p53+/+ esophagus and tongue displayed moderate immunostaining of KRT14 and MT, mostly confined to the basal cell layers (KRT14: esophagus, Figure 3K, tongue, Figure 3I; MT: esophagus, Figure 3S, tongue, Figure 3Q). Invariably, COX-2 staining was weak and diffuse in both tissues of these mice (esophagus, Figure 3O, tongue, Figure 3M). In contrast, early precancerous ZD:p53+/+ lesions showed strong expression of all three markers. For example, intense cytoplasmic staining of KRT14 was found in hyperplastic esophagus (Figure 3L) and dysplastic tongue with early cancerous changes (Figure 3J) and strong to intense nuclear and cytoplasmic expression of MT occurred in proliferative esophagus (Figure 3T) and in lingual focal hyperplastic lesions (Figure 3R). These same lesions also displayed moderate to strong cytoplasmic COX-2 expression (esophagus, Figure 3P; tongue, Figure 3N). These results in NQO-treated ZD wild-type mice are in agreement with our findings in precancerous ZD rat esophagus and tongue (13,14).
Cell proliferation and marker gene expression in lingual SCC and ESCC of ZD:p53+/– mice
After 21 weeks, ZS:p53+/– esophagus and tongue showed mostly basal cell hyperplasia, focal cell hyperplasia and papillomas, with a very low incidence of tumor progression only in the tongue (Figure 1D). An example of a ZS:p53+/– tongue showing dysplasia with microinvasion is presented in Figure 4A. In combination, p53 insufficiency and zinc deficiency led to high incidence of SCC in both tongue and esophagus in ZD:p53+/– mice (Figure 1D). Examples of invasive lingual SCC and ESCC are shown in Figure 4F and K. ZD:p53+/– carcinomas were highly proliferative with abundant PCNA-positive nuclei in the tumors and in adjacent hyperplastic epithelia (lingual SCC, Figure 4G; ESCC, Figure 4L). A high correlation was evident between the spatial localization of KRT14, COX-2 or MT and that of PCNA in serial lingual sections of early cancerous lesions of ZS:p53+/– and in lingual SCC and ESCC of ZD:p53+/– mice (lingual early cancerous lesion, compare Figure 4C–E with Figure 4B; lingual SCC, compare Figure 4H–J with Figure 4G; ESCC, compare Figure 4M–O with Figure 4L). Together, these results show an association between the cell proliferation marker PCNA and tumor markers KRT14, COX-2 or MT in hyperplasia (Figure 3), dysplasia (Figure 4) and invasive carcinomas (Figure 4). They provide evidence that all three markers, MT, in particular, are highly relevant intermediate and endpoint biomarkers in UADT carcinogenesis.
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Discussion |
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The data presented above show that with combined deficiency of zinc and p53, the mouse tongue and esophagus become exquisitely sensitive to the carcinogenicity of low concentrations of NQO (Figure 1). In addition, the results document that zinc deficiency and haploinsufficiency acting alone increases the yield of NQO-induced UADT benign tumors, whereas the combined action drives tumor progression to malignancy. Although UADT tumor induction and progression occurred earlier in nullizygous ZD:p53–/– mice than heterozygous ZD:p53+/– mice, the nullizygous mouse is not a feasible cancer model for UADT cancer because it succumbs to induced and spontaneous tumorigenesis at an early age (Table I). In contrast, Ide et al. (31) reported that p53+/– and p53–/– mice, on a mixed genetic background of C3H/HeN, C57BL/6 and CBA, were tumor-free with exposure to drinking water containing 10 p.p.m. NQO for 50 and 20 weeks, respectively. It is possible that p53-deficient mice on a C57BL/6 background, as in the case of the present study, are more sensitive to the tumorigenic activity of NQO than those on a mixed genetic background.
Complex genetic mouse models provide a useful framework for understanding the interrelationship of p53 deficiency and specific genes in oral–esophageal cancer development, for example, the collaboration of p53 deficiency and overexpression of cyclin D1 (30), or p53 deficiency and xeroderma pigmentosum group A (XPA) gene deficiency (31). The L2D1+/p53+/– model that overexpresses cyclin D1 in the oral–esophageal epithelium of p53-deficient mice develops invasive oral–esophageal cancer, whereas control cyclin D1 L2D1+ mice exhibit only oral–esophageal dysplasia (30). XPA–/–p53+/– mice generated by crossing XPA–/– mice with p53+/– mice demonstrate that p53 haploinsufficiency greatly accelerates the onset of lingual tumors in XPA–/– mice with continuous exposure to 10 p.p.m. NQO in the drinking water (31). In either model, the remaining p53 allele was not lost during tumor formation (30–33) and p53 deficiency acting alone did not bring about progression to malignancy. These genetic models support the concept that p53 plays an important role in oral–esophageal epithelial carcinogenesis.
The growing list of genes in human cancers with aberrant expression, however, points toward a more complex view of the carcinogenesis process. In this regard, our UADT cancer model in ZD:p53+/– mouse has obvious benefits. By rendering the p53+/– mice nutritionally deficient in zinc, this model mimics aspects of human UADT cancers. Both zinc deficiency (5–9) and a loss of function of the tumor suppressor gene TP53 (25) are associated with human UADT carcinogenesis. Zinc deficiency causes substantial cell proliferation in the squamous epithelium of the UADT, as well as extensive changes in gene expression (13,14). On the other hand, loss of p53 function results in genetic instability and increased cell cycle progression (34,35). Thus, the grave biological consequences of combining zinc deficiency and p53 deficiency are rapid UADT tumor induction and progression to malignancy (Figure 1D, Table I).
The sequence of histopathologic events of human oral and ESCC is well characterized and proceeds from hyperplasia to focal hyperplastic lesions, dysplasia and finally invasive carcinoma. Although many molecular alterations have been reported in UADT carcinogenesis, intermediate biomarkers that accurately predict the risk of developing cancer, prognosis and effect of therapeutic treatment have not been clearly defined. In human cancers, MT overexpression is often positively correlated with the metastatic and proliferative activities of ESCC (18) and a worse prognosis for oral SCC (36). KRT14 is an indicator of tumor progression in human ESCC (20) and oral dysplasia-SCC sequence (37,38). COX-2 expression is correlated with the proliferation activity in esophageal dysplasia (39) and with early stage carcinogenesis in the oral dysplasia-carcinoma sequence (40).
Recent data from our laboratory (13,14) show that (i) the hyperplastic esophagus and tongue of ZD rats overexpressed COX-2 protein and mRNA; (ii) the zinc sensitive gene MT-1 and tumor marker KRT14 are upregulated >6-fold in hyperplastic ZD rat esophagus; and (iii) upon zinc replenishment, the overexpression of all three markers, as well as the hyperplastic phenotype of the esophagus were rapidly reduced. The present study examined whether the sequence of histopathologic events in UADT carcinogenesis after 21 weeks of NQO treatment is accompanied by overexpression of these three biomarkers, KRT14, COX-2 and MT. Our results demonstrate in a mouse UADT cancer model that expression of biomarkers KRT14, MT and COX-2 in lingual and esophageal carcinogenesis is correlated with cell proliferation and the histopathologic hyperplasia-dysplasia-carcinoma sequence (Figures 3 and 4).
In summary, we have developed an in vivo UADT cancer model in ZD:p53+/– mouse that reproduces features of human oral–esophageal cancer. This model will be useful to study the molecular mechanisms of UADT carcinogenesis and to test novel strategies for prevention and reversal of this deadly cancer.
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Acknowledgments |
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This work was supported by grant no. 04B106-REN from the American Institute for Cancer Research (LYYF). We thank Mr Karl Smalley, Kimmel Cancer Institute, Thomas Jefferson University for help with statistical analysis of data.
Conflict of Interest Statement: None declared.
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