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1 Department of Surgery and the Siteman Cancer Center and 2 Division of Comparative Medicine, Washington University School of Medicine, St. Louis, Missouri; 3 Department of Pathology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio; and 4 Chemoprevention Agent Development Research Group, National Cancer Institute, Rockville, Maryland
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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It has been difficult to establish a mouse lung SCC model (10, 11, 12, 13, 14, 15) . Previous studies, now almost 25 years old, showed a high incidence of mouse SCCs induced by direct tracheal instillation of benzo(a)pyrene (77%) or 3-methylcholanthrene (85%; Refs. 12, 13, 14 ). These studies were technically difficult, and the results were rarely reproduced by others. Subsequently, a report described that preneoplastic and neoplastic lesions including Lscc were induced by skin painting of N-nitroso-tris-chloroethylurea (NTCU) and of N-nitroso-methyl-bis-chloroethylurea (15) . A prior attempt to repeat this study failed.5 Thus, neither of these two mouse lung SCC models has been fully characterized or routinely used for mechanistic, genetic, or preclinical cancer therapeutic or chemoprevention studies. Because the majority of phase II clinical chemoprevention trials are performed on patients with bronchial squamous precancerous lesions, development of a mouse model to screen for potential chemopreventive or chemotherapeutic agents for human SCC becomes one of the highest priorities for cancer chemoprevention of lung cancer.
In addition to being useful in delineating mechanisms of tumor development and for use in studying therapeutic or preventive agents, mouse SCC models can help define genetic modifiers related to susceptibility or resistance. Quantitative trait loci mapping has revealed loci on several mouse chromosomes related to susceptibility and resistance to lung adenomas and adenocarcinomas. For example, pulmonary adenoma susceptibility (Pas) 1 locus is on chromosome 6 between markers D6Mit54 and D6Mit304. It is the major locus affecting inherited predisposition to lung tumor development in mice (16 , 17) . Several quantitative trait loci of pulmonary adenoma resistances (Par) have been reported: for example, Par1 locus was mapped to mouse chromosome 11, near the Rara locus, with a 5.3 logarithm of odds score (18) . In Pas1/+ mice, Par1 accounts for 23% of the phenotypic variance and 10-fold reduction in total tumor volume (18) . Linkage disequilibrium (LD) is defined as the better than chance association of alleles at one locus with alleles at another nearby locus in the population. It is the basis of quantitative trait loci mapping of complex disease loci through whole-genome association studies (19 , 20) .
In this study, we characterized the premalignant and malignant squamous lesions in inbred strains of mice induced by skin painting with NTCU. We also observed that different strains of mice exhibited different sensitivities to the induction of SCCs after treatment with NTCU. Finally, we conducted whole-genome LD analysis in seven strains of mice with known susceptibility for SCC using 6,128 markers to define regions of the genome that modify SCC induction. Our results provide a systematic histological characterization of a mouse lung SCC model that should be useful for examining both therapeutic and preventive agents.
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MATERIALS AND METHODS |
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Mice.
Female A/J, SWR/J, 129/svJ, FVB/J, AKR/J, C57BL/6J, and BALB/cJ mice were purchased from the Jackson Laboratory (Bar Harbor, ME). Female NIH Swiss mice were obtained from the Charles River Laboratories (Wilmington, MA).
Bioassay.
Female mice were used because they tend to be less aggressive. Seven-week-old mice were randomized into two groups. Forty-eight h before initial treatment, the dorsal skin of the mice was shaved. One group of mice was treated topically with NTCU, as follows: 25-microliter drop of 0.04 M, twice a week, with a 3-day interval. The second group of mice was treated with acetone, which is the solvent for the NTCU. All mice had their backs shaved weekly. Eight months after the initial treatment with NTCU, the animals were euthanized by CO2 asphyxiation. After termination, the lung was removed and fixed in 10% buffered formalin for 48 h and then transferred to 70% ethanol until embedded in paraffin.
Histopathology Analysis.
More than 100 serial tissue sections (5-µm each) were made from formalin-fixed lung, and 1 in every 20 sections (approximately 100 µm apart) was stained with H&E and examined histologically under a light microscope. The lesions, including invasive SCC, SCC in situ, and the bronchial hyperplasia/metaplasia, were scored from the H&E-stained sections of each lung. When the hyperplasia occurs (Fig. 1
, B1), single layer of bronchiolar epithelial cells becomes multiple layers. The cells maintain their normal look. Mitosis is rare. In bronchiolar metaplasia (Fig. 1
, B2), the normal columnar epithelium is replaced by flattened squamous epithelium with increased keratin production (increased red staining in H&E). The premalignant lesions described in this paper are the combination of bronchiolar hyperplasia and bronchiolar metaplasia. In carcinoma in situ, atypical cells (irregular shape, increased nucleus/cytoplasm ratio, and so forth) with mitosis and loss of orderly differentiation replaced the entire thickened epithelium. The bronchiole base membrane is intact. There is no tumor cell in the surrounding stroma. In invasive carcinoma, general features of SCC such as keratin pearl, multiple nuclei, and increasing mitotic index can be seen. The normal architecture of the lung is disrupted. Cords and nests of tumors can be seen in the subepithelial stroma. The board-certified veterinary pathologist, Marie La Regina, DVM, at Washington University School of Medicine in St. Louis, performed histopathological diagnosis of the mouse lesions.
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Analysis of Ras Mutations by PCR-Direct Sequencing.
Sequences of PCR primers for the exon 1 and 2 for all three ras genes (K-ras, N-ras, and H-ras) were described previously (21)
. Briefly, 100 µl of reaction mixture containing 100 ng of genomic DNA, 10 mM Tris-HCl (pH 8.5), 50 mM KCl, 2.5 mM MgCl2, 100 µM of each deoxyribonucleoside triphosphate (dATP, dCTP, dGTP, dTTP), 1.0 unit of TaqDNA polymerase (Promega, Madison, WI), and 40 pmol of each primer were overlaid with sterile mineral oil and subjected to 35 cycles of PCR amplification. Each cycle consisted of 1 min each at 94°C, 55°C, and 72°C. The 12th codon mutations were analyzed with an ABI Prism 3700 DNA analyzer (PE Applied Biosystems, Foster City, CA).
Genome-Wide LD Analysis.
Genotype information for 6,128 markers was compiled by merging publicly available databases provided by The Jackson Laboratory (http://aretha.jax.org/pub-cgi/phenome), MIT (http://www-genome.wi.mit.edu), Center for Inherited Disease Research (http://www.cidr.jhmi.edu/downloads/CIDR_mouse.xls), and Research Genetics (ftp://ftp.resgen.com/pub/mappairs/mouse/STR129.TXT). Markers showing inconsistent strain-allele correspondence across data sources were discarded. Specifically, if in one dataset two mouse strains shared the same allele at a marker, whereas in another dataset they had different alleles at the same marker, the marker was discarded.
Mouse strains were divided into three phenotype categories according to susceptibility to chemically induced SCC: resistant (C57BL/6J, AKR/J, 129X1/SvJ); intermediate (BALB/cJ, FVB/J); and susceptible (A/J, SWR/J). Genotype information was not available for NIH Swiss mice, so this strain was necessarily excluded. Linkage disequilibrium between markers and these phenotype categories was assessed using Fisher’s exact test (22) . On the basis of the number of reported alleles, approximately 280 markers had the capacity to show significance.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and 2
). The shape and size of the neoplastic cells are polygonal to round with reduced amounts of cytoplasm. The nuclei are irregularly shaped with coarsely clumped chromatin. The presence of uniform gaps between cells is clearly observed (Fig. 1F)
, although the intercellular bridges are somewhat less variable in SCCs, both confirm the squamous identity of the tumor. Bronchiolar hyperplasia/metaplasia and premalignant lesions of Lscc were also observed (Tables 1
and 2
; Fig. 1
). Bronchial hyperplasia is diagnosed when there is >1 layer of bronchiolar epithelial cells in a bronchiole (Fig. 1, A and B)
. Bronchial metaplasia is diagnosed when bronchiolar epithelial cells show abnormalities in cytoplasmic and nuclear morphology (Fig. 1
, B2). Fig. 1, C and D
, demonstrates typical lung SCC in situ, because the epithelial cells restricted within the bronchiole show the malignant features. Fig. 1, E and F
, illustrate the classical profile of mouse Lscc.
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. Tumor growth pattern was usually firm-nonencapsulated masses. As shown in Fig. 2
, SCC appears as an area of stratified squamous cells with hyperchromatic nuclei. The squamous cells exhibiting loss of polarity and intercellular bridges are prominent. The tumors form irregularly shaped sheets and nests of cells. The shape and size of the neoplastic cells is polygonal to round with at least moderate amounts of cytoplasm. The nuclei are irregularly shaped with coarsely clumped chromatin, typically as keratin pearl formation (Fig. 2A
, human lung SCC; Fig. 2C
, mouse lung SCC). Furthermore, positive staining of CK5/6 has been seen in these tumors (Fig. 2, B and D)
. Immunohistochemical staining of keratins is one of the useful tools in making the diagnosis of SCC in humans (23
, 24)
. We show that CK5/6 is expressed in the cytoplasm of both human and mouse Lscc cells (Fig. 2D)
. We also searched activating mutations in all three members of the ras gene family: K-ras, H-ras, and N-ras. Mutation analysis of the ras genes was performed on a total of 20 Lsccs (10 from NIH Swiss mice and 10 from A/J mice that were treated with NTCU). Direct sequence analysis showed that none of the tumors harbored mutations in the 12th or 61st codons of K-ras, H-ras, or N-ras (data not shown). This result is consistent with some reports showing the lack of ras mutations found in human lung SCCs (25, 26, 27) , although other studies suggested that mutations of the K-ras oncogene plays a role in lung adenocarcinomas (37%) as well as in a subset (about 8%) of SCCs (28 , 29) .
As shown in Table 1
, lung SCC was seen in five of the eight strains tested, whereas the Lscc in situ was seen in seven of eight strains with NTCU treatment. Premalignant lesions, including lung hyperplasia and metaplasia, were seen in all of the mouse strains tested (Table 1)
. NIH Swiss, SWR/J, and A/J mice had a greater neoplastic burden compared with that from FVB/J or BALB/cJ mice (Table 1)
. The lower susceptibility of AKR/J, 129/svJ, and C57BL/6J mice might appear partially because of fewer treated mice. However, these differences are readily apparent when considering the high multiplicity of tumors in the various susceptible strains (Table 2)
. SCCs were observed in 75–100% of NIH Swiss, SWR/J, and A/J mice. An SCC tumor incidence of 40–45% was observed in BALB/cJ and FVB/J mice, respectively. Finally, AKR/J, 129/svJ, and C57BL/6J mice are resistant to the SCC induction in lung by NTCU skin painting. An adenoma, with adenocarcinoma arising in its center, was observed in two of eight BALB/cJ mice and two of nine FVB/J mice (data not shown).
Our study shows striking genetic differences in susceptibility of these mouse strains toward NTCU-induced lung premalignant and malignant lesions (Table 2)
. In this study, we have shown that the AKR/J, 129/svJ, and C57BL/6J mice are highly resistant; NIH Swiss, A/J, and SWR/J mice are highly susceptible to the induction of lung SCC by NTCU skin treatment whereas FVB/J and BALB/cJ mice are intermediate strains in this matter. Eight months after the initial treatment with NTCU, the resistant strains of mice did not develop any SCC, the strains with intermediate susceptibility FVB and BALB/c developed roughly four SCCs per mouse whereas the susceptible strains (SWR/J, A/J and NIH Swiss) developed 21, 53, and 71 SCCs on average, respectively. The intermediate strains of mice (FVB/J and BALB/cJ) have shown only a few SCC lesions. In the present study, we have also demonstrated that the levels of bronchiolar hyperplasia, metaplasia, and SCC in situ are correlated with the degree of their susceptibility to SCC (Tables 1
and 2)
. SCC in situ is an early malignant lesion seen in all mouse strains tested, except in AKR/J mice (Tables 1
and 2
). The frequency of SCC in situ paralleled the incidence of SCCs in these same strains. Bronchiolar hyperplasias are common premalignant lesions, having been seen in all mouse strains tested with an incidence that paralleled the final SCC incidence for most of the strains (Tables 1
and 2)
.
To conduct LD genetic mapping for lung SSC susceptibility, approximately 6,128 markers were compiled by merging publicly available databases provided by The Jackson Laboratory, MIT, The Center for Inherited Disease Research, and Research Genetics. LD analysis revealed the following three markers associated with SCC at the P < 0.05 level: D1Mit169, D3Mit178, and D18Mit91 (Fig. 3)
. Neighboring regions were named Lscc (lung squamous cell carcinoma) 1 for the locus near D1Mit169, Lscc2 for the locus near D3Mit178, and Lscc3 for the locus near D18Mit91 (Fig. 4)
. Candidate genes were defined as those within 2.5 cM proximal and distal to the three markers. In chromosome 1 (Lscc1), we extended the searching range based on the position of D1Mit169 (15 cM, 24,365 kbp) with franking markers D1Mit52 (12 cM, 20,757 kbp) and D1Mit526 (17.8 cM, 30,574 kbp; Table 3
). The candidate genes include Il17, Il17F, Mcm3, Gsta3, and Bai3. For chromosome 3 (Lscc2), we searched the range from D3Mit203 (11.2 cM, 26735 kbp) to D3Mit167 (16.5 cM, 32112 kbp) covering the significant marker D3Mit178 (13.8 cM, 30193 kbp; Table 4
). Candidate genes for Lscc2 include Ect2, Ghsr, PLD1, Slc2a2, Evi1, Mds1, Prkcl, Skil, Tnfsf10, and Cldn11. For chromosome 18 (Lscc3), the region we searched ranged from D18Mit10 (26 cM, 53424 kbp) to D18Mit52 (32 cM, 58714 kbp) covering the marker D18Mit91 (29 cM, 55743 kbp; Table 5
). Candidates for Lscc3 include Lmnb1 and Slc12a2.
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DISCUSSION |
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We have compared the mouse Lscc to human Lscc histologically and found that the mouse SCCs (Fig. 2, C and D)
have many similarities to histopathological features observed in human Lscc (Fig. 2, A and B)
. The histogenesis of human SCC may be related to inflammation and injury of the bronchial epithelium mediated in part by exposure to cigarette smoke, which leads to metaplasia by replacing the normal ciliated columnar epithelium by a squamous epithelium. We have seen lymphocyte infiltration (Fig. 1A
, top portion) along with numerous macrophages infiltration in the surrounding area of the lesions (Fig. 1C)
. The increased lymphocyte is one of the indicators for inflammation. Increased macrophages are possible because of increased production of surfactant by the hyperplastic cells (31)
. We have noticed many lesions, including bronchial hyperplasia, metaplasia, and even SCC in situ, arising in an area with macrophage infiltration (Fig. 1, A and C)
. Histological and cytological studies have revealed a series of changes that occur over many years and represent a morphological progression to bronchogenic carcinoma. Early changes include bronchiale basal cell hyperplasia, followed by a squamous metaplasia, eventually progressing to carcinoma in situ, and finally to invasive SCC. Similar changes are observed in the mouse Lsccs including hyperplasia, metaplasia, SCC in situ, and SCCs (Fig. 1)
. In human, SCC of the lung is generally believed to arise from the bronchial metaplastic/dysplastic epithelium through the hyperplasia-carcinoma sequence, which is a well-known carcinogenic process similar to that observed in uterine cervical neoplasia (32)
. During this carcinogenic process, SCC in situ, a noninvasive carcinoma with no metastatic potential, is the earliest stage in the progression of SCC. Once carcinoma in situ penetrates the basement membrane to involve the lamina propria, it is invasive carcinoma and capable of widespread dissemination. However, there is no sign of metastasis of Lscc to any distant location(s) in our NTCU-treated mice similar to what was found by Lijinsky et al. (Refs. 15
and 30
). In human, most Lsccs arise from the bronchi: about two-thirds of human Lscc originated from the central portion of the lung (C-type), whereas the remaining one-third does so from the periphery (P-type; 33
). In this study, we observed that C-type and P-type SCCs occurred in almost an equal proportion in the NTCU-treated mice.
As shown in the results, we failed to observe K-ras mutations in SCCs from either NIH Swiss or A/J mice. This is in agreement with the fact that human SCCs of the lung rarely have K-ras mutations. Interestingly, the preponderance of lung adenocarcinomas induced in A/J mice by a wide variety of chemical carcinogens exhibit mutations in the K-ras oncogene. This is in line with the fact that human lung adenocarcinomas frequently have mutations in K-ras oncogene. These data show the striking cell specificity in terms of mutation induction in the same strain with adenocarcinomas showing high levels of K-ras mutations and SCCs showing no mutations.
These results show the exquisite specificity of NTCU in inducing SCCs. One might have expected such a result with intratracheal administration of a carcinogen that would result in very high levels of carcinogen in the trachea and associated bronchi. In contrast, the NTCU that was administered topically, but which failed to induce skin tumors and was therefore administered systemically to the lung, results almost only in SCCs even in A/J mice that are highly susceptible to adenoma formation by hundreds of agents.
Different inbred mouse strains show widely different susceptibilities to both spontaneous and chemically induced lung adenoma and adenocarcinoma formation and thus serve as models for research in lung cancer genetics. The multiplicity of mouse lung tumors is a quantitative trait controlled by multiple genetic loci (10
, 11
, 34)
. Linkage studies have been conducted on these mice and have identified Pas and Par loci by us and the other investigators (16
, 22
, 35
, 36)
. A major susceptibility locus was mapped in (A/J x C3H/HeJ) F2 mice to distal chromosome 6 near K-ras locus and was termed the Pas1 locus (16)
. In the present study, we used whole-genome LD analysis to identify the following three markers associated with susceptibility to SCC and have named the surrounding regions Lscc1–3: D1Mit169 (Lscc1), D3Mit178 (Lscc2), D18Mit91 (Lscc3). For initial identification of candidate genes, we selected the regions 2.5 cM proximal and distal to these markers. The Lssc1 locus surrounding D1Mit169 is approximately 4.5 cM from Sluc 15 (37)
. A number of genes listed in Table 3
are involved in transforming growth factor/3 signaling; cell cycle and the p53 pathway are located in this region. The Lscc2 locus surrounding D3Mit178 is syntenic with human 3q26, which has been linked with SCC in humans (38)
. This appears to be the first report of association of this region with cancer in mouse. Numerous oncogenes and putative tumor suppressor genes are located in this region, as seen in Table 4
. Locus Lssc3 surrounding D18Mit91 is approximately 9 cM from Sluc 14 and 5 cM from SCC5 (39)
. This region contains genes implicated in cell proliferation and transformation (Table 5)
.
This is the first study in rodents to determine the genetic susceptibility to lung SCC. This study brings up two additional questions with regard to SCC induction. The first question deals with what additional studies can be performed to understand the genetics of susceptibility in this model. The second concerns what potential manipulations might be made to facilitate use of this model for screening for potential preventive or therapeutic agents. To improve our understanding of the association of these regions with SCC, a number of future steps are in order. First, the NIH Swiss mouse can be genotyped for these markers and confirmatory analysis performed. Second, single-nucleotide polymorphisms within these regions can be genotyped for these strains, and doing so will permit a high-resolution analysis of association within these regions. Because it has been shown in both human and mouse that LD extends different distances in different regions, it is difficult to assess how far from an associated marker one might find a causal gene. We chose to extend 2.5 cM as a reasonable, conservative distance. Third, we are conducting further genetic mapping studies of these loci using F2 and congenic populations of mice. Thus, we conclude that these are candidate regions, with Lssc2 especially intriguing, that will be more precisely characterized and confirmed in future studies.
In conclusion, our findings demonstrate that Lscc and precancerous lesions (hyperplasia and metaplasia) can be readily induced by NTCU treatment. These lesions closely resemble the SCC in human lung both with regard to histology and expression of keratins. Furthermore, different strains of mice exhibited strikingly different responses to SCC induction by NTCU that led to the mapping of Lscc1–3. Further characterization of these novel loci and genes identified by LD analysis and further single-nucleotide polymorphism genotyping will assist greatly in the delineation of the genetic basis of mouse Lscc susceptibility in mice and, possibly, in humans. Thus, this mouse Lscc model is a promising model for mechanistic studies examining SCC development for preclinical screening of potential therapeutic or preventive agents and for the study of genetic susceptibility to Lscc induction.
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FOOTNOTES |
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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.
Note: Y. Wang and Z. Zhang and their laboratories contributed equally to this paper.
Requests for reprints: Ming You, Department of Surgery, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110. E-mail: youm{at}msnotes.wustl.edu
5 S. Rehm, personal communication. 
Received 10/17/03. Revised 12/18/03. Accepted 12/22/03.
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