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[Cancer Research 65, 1207-1212, February 15, 2005]
© 2005 American Association for Cancer Research

Molecular Biology, Pathobiology and Genetics

Reduced FEZ1/LZTS1 Expression and Outcome Prediction in Lung Cancer

Daisuke Nonaka1, Alessandra Fabbri1, Luca Roz2, Luigi Mariani3, Andrea Vecchione5,6, G. William Moore7, Luca Tavecchio4, Carlo M. Croce5 and Gabriella Sozzi2

Departments of 1 Pathology and 2 Experimental Oncology, Units of 3 Medical Statistics and Biometry and 4 Thoracic Surgery, Istituto Nazionale Tumori, Milan, Italy; 5 Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania; 6 Division of Surgical Pathology, II Faculty of Medicine, University La Sapienza, Hospital Sant'Andrea, Rome, Italy; and 7 Baltimore Veterans' Administration Maryland Health Care System, University of Maryland Medical System and Johns Hopkins Medical Institutions, Baltimore, Maryland

Request for reprints: Gabriella Sozzi, Cytogenetics and Molecular Cytogenetics Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy. Phone: 39-02-23902232; Fax: 39-02-23902764; E-mail: gabriella.sozzi{at}istitutotumori.mi.it.


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Chromosomal deletions are often observed in lung cancers suggesting that inactivation of tumor suppressor genes plays an important role in the development of this neoplasm. The region around chromosome 8p22 is a frequent and early target of these deletions and has therefore been investigated for the presence of candidate genes. The FEZ1/LZTS1 gene, located at 8p22, is inactivated in many cancers with 8p deletions, including prostate, esophageal, gastric, bladder, and breast cancer and the Fez1 protein has been shown to suppress growth of cancer cells and to regulate mitosis. To elucidate the role of FEZ1 in lung cancer, we have analyzed its expression by immunohistochemistry in 103 primary lung cancer specimens including 98 non–small cell lung cancers (57 adenocarcinomas, 32 squamous cell carcinomas, 7 large cell carcinomas, and 2 others) and five small cell carcinomas. Absence of Fez1 protein expression was observed in 27 cases (26%) and additional 43 cases (42%) showed strong reduction in immunoreactivity. There was a positive association between loss of FEZ1 expression and tumor grading (P = 0.0345) and a tendency toward a reduction in the mortality rate in subjects with strong FEZ1 expression. Overall, these data indicate an important role for FEZ1 in lung cancer and suggest the possibility that it may serve as a novel prognostic indicator.

Key Words: Lung cancer • FEZ1/LZTS1 • cell cycle control • p34cdc2


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Inactivation of tumor suppressor genes is one of the most common genetic alteration underlying the development of many human carcinomas and frequently results in the insensitivity to antigrowth signals that is considered one of the "hallmarks" of cancer (1). Loss-of-function of these genes may be the result of different molecular events (either genetic or epigenetic) that often include deletion of the chromosomal region harboring at least one of their alleles (2). Hotspots of genomic deletion may therefore indicate the areas where tumor suppressor genes are more likely to reside. Chromosome 8p deletions are frequently observed in many human cancers including prostate, colorectal, bladder, head and neck, breast, and gastric carcinomas (3–8) and the 8p22 region has been shown to possess oncosuppressive properties in chromosome transfer experiments (9–11). Genes isolated from this area include N33 (12, 13), PRLTS (14, 15), NAT1, NAT2 (16–18) etc., but there is little functional evidence for their involvement in human cancer. The FEZ1 gene (subsequently renamed LZTS1) was isolated from 8p22 and it was shown to be inactivated in a large fraction of prostate, esophageal, and breast cancers (19). Although the mechanisms of inactivation are not completely elucidated and somatic mutations are uncommon, reduced expression has been reported in gastric (20), bladder (21), and oral cancers (22). More importantly, restoration of its expression was shown to slow the growth of breast (MCF7), prostate (AT6.2), and bladder (SW780) cancer cells (21, 23, 24) and to reduce their tumorigenicity in vivo giving support to the hypothesis that it may function as a tumor suppressor gene. The product of the FEZ1 gene is a 67-kDa cytoplasmic protein that binds to microtubules and has been implicated in cell cycle control through its interaction with the p34 cdc2/cyclinB1 complex (23). Its frequent inactivation in many human cancers and its proposed mechanism of action make it therefore a good candidate as a tumor suppressor gene.

The 8p21-23 region is also frequently deleted in lung cancers and this genetic alteration seems to be an early event in the development of all the different histologic types of this neoplasm (25). A previous analysis of FEZ1 expression in lung cancer done on cell lines from non–small cell lung cancers (NSCLC), small cell lung cancers (SCLC), and short-term cultures of resected NSCLC revealed loss of expression especially in NSCLC (76% of cell lines and 50% of short-term cultures), indicating that FEZ1 may be involved in lung cancer (26). In the present study, to clarify the role of FEZ1 in lung cancer, we carried out the first immunohistochemical analysis of its expression in 103 primary lung cancer specimens and analyzed its possible association with the histopathologic features of the tumors as well as with patients' survival over an observation time of >4 years.


   Materials and Methods
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 Materials and Methods
Results
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Tissue Samples and Immunohistochemistry. This is a retrospective study of primary lung cancers diagnosed and treated between 1998 and 2000 at the Istituto Nazionale Tumori (National Cancer Institute), Milan, Italy. Cases included in this study were those that were diagnosed as primary lung carcinomas and treated by surgical intervention for initial treatment and had adequate paraffin blocks for histologic and immunohistochemical analysis as well as complete clinicopathologic data. A total of 103 lesions (from 100 patients) were studied. H&E-stained slides were reviewed (available slides ranging from 2 to 36) and the histologic subtype was classified according to the latest WHO classification.

A representative paraffin block of each case was selected and all sections that were mounted on positively charged slides were deparaffinized according to the standard procedures followed by rehydration through serial ethanol treatments. The slides were immersed in citrate buffer [0.005 mol/L sodium citrate (pH 6.0)] and heated in an autoclave at 95°C for 30 minutes to enhance antigen retrieval. Endogenous peroxidase was blocked with 0.3% hydrogen peroxide in methanol for 30 minutes. Sections were immunostained with a 1:1,000 dilution of the polyclonal rabbit anti-Fez1 antibody overnight at 4°C. As previously reported (20), this antibody was raised in rabbits against glutathione S-transferase fusion Fez1 protein corresponding with nucleotides 1 to 1,128, which was expressed in Escherichia coli and purified with a glutathione column (Amersham Pharmacia, Piscataway, NJ). The specificity of the antibody was tested by Western Blot analysis and confirmed in immunohistochemical analyses of gastric and bladder carcinomas (20, 21).

The primary antibody was omitted and replaced with preimmune serum in the negative controls. Sections were then reacted with biotinylated anti-rabbit antibody and streptavidin-biotin-peroxidase. Diaminobenzidine was used as a chromogen substrate. Finally sections were washed in distilled water and weakly counterstained with Carazi hematoxylin. All sections were examined independently by two pathologists (D.N. and A.F.), and agreement was reached for the grade of Fez1 immunostaining. Fez-1 immunoreactivity was classified into four groups using the previously reported scoring method (20): +/+ or strong (96-100% Fez1-positive cells), +/– or moderate (51-95% Fez-1 positive cells), –/+ or weak (2-50% Fez1-positive cells), and –/– or absent (<2% Fez1-positive cells). The tumors were graded as low grade (well to moderately differentiated) and high grade (poorly differentiated). All cases of small cell carcinoma and large cell carcinoma were categorized as high grade.

Statistical Methods. Associations of Fez1 expression with clinicopathologic variables, including age, sex, disease stage, histology, tumor grade, necrosis, and survival were computed using a two-tailed {chi}2 statistic or Fisher's exact test where appropriate.

An exponential model was fit to individual disease-specific survival times to estimate and compare death rates according to FEZ1 expression, with or without adjustment for tumor grade. The mortality rates so obtained correspond to the ratio between the number of events (cancer deaths) and the sum of observation times (in years) over all subjects belonging to the same group (low or high expression). The model, however, allows direct calculation of rate ratios and corresponding confidence limits.

P ≤ 0.05 was considered statistically significant.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
This study included 87 males and 13 females (M/F = 6.7:1) with ages ranging from 39 to 81 years (median 64 years).

Overall, 103 tumor samples were investigated. Out of these, there were 98 NSCLCs (57 adenocarcinomas, including 4 bronchioalveolar, 32 squamous cell carcinomas, 7 large cell carcinomas, 1 adenosquamous carcinoma, and 1 salivary gland type adenocarcinoma) and five SCLCs (with one case of mixed SCLC and poorly differentiated squamous cell carcinoma). Fifty-five lesions (53%) were stage I, 20 (19%) stage II, and 28 (27%) stage IIIA. The grading was grade 1 for six samples (6%), grade 2 for 33 samples (32%), and grade 3 for 64 samples (62%).

Table 1 summarizes the data of FEZ1 immunostaining on individual lesions and the association with the clinicopathologic information. Fez1 immunostaining was strong (+/+, 96-100% of positive cells) in 15 lesions (15%), moderate (+/–, 51-95% of positive cells) in 18 lesions (17%), weak (–/+, 2-50% of positive cells) in 43 lesions (42%), and absent (–/–, <2% of positive cells) in 27 lesions (26%). Overall, 70 samples (68%) showed a considerable reduction in FEZ1 expression. Representative examples of Fez1 immunostaining in lung tumors of different histologic subtype are shown in Figs. 1 and 2.


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  		Table 1. Fez1 expression according to clinicopathologic features

 


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  		Figure 1. Immunohistochemical analysis of Fez1 expression in normal bronchial epithelium, precancerous lesions, and squamous cell carcinomas of the lung. A, strong Fez1 immunoreactivity in normal bronchial epithelium. Staining is also detected in stroma and lymphocytes. B, squamous intraepithelial neoplasia and poorly differentiated squamous cell carcinoma showing negative immunostaining (Fez1 –/–, same case as A). C, negative Fez1 staining in a poorly differentiated squamous cell carcinoma (Fez1 –/–). Fez1 staining is detected in infiltrating lymphocytes and stromal tissue. D, poorly differentiated squamous cell carcinoma with strong Fez1 cytoplasmic immunoreactivity (Fez1 +/+).

 


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  		Figure 2. Immunohistochemical analysis of Fez1 expression in lung adenocarcinomas. A, poorly differentiated adenocarcinoma negative for Fez1 expression (Fez1 –/–) with adjacent normal bronchial epithelium with strong cytoplasmic immunoreactivity. B, reduced Fez1 expression in a poorly differentiated adenocarcinoma (Fez1 –/–) compared with the normal bronchial epithelium. C, poorly differentiated adenocarcinoma showing some residual Fez1 staining (Fez1 –/+). D, positive Fez1 immunoreactivity in a poorly differentiated adenocarcinoma with prominent bronchioloalveolar pattern (Fez1 +/+).

 
Statistical analysis showed a significant association between Fez1 expression and tumor grade (P = 0.0345; Table 2). To avoid sparse data, grade 1 and 2 lesions and Fez +/+ and +/– (high expressers) were grouped in the statistical analysis. In particular, the frequency of high expressers in the grade 1 to 2 lesions was 46% versus only the 23% in the grade 3 lesions. No associations were found between Fez1 expression and the other clinicopathologic variables tested, such as age, sex, tumor histology, or necrosis.


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  		Table 2. Association between Fez1 expression and tumor grade

 
Three cases of high-grade squamous intraepithelial neoplasia (SIN3) were detected either adjacent or in the same section of the tumor sample. All three cases showed that whereas positive Fez1 immunostaining was present in the normal bronchial mucosa cells Fez1 expression was absent (two cases) or reduced (one case) in the high-grade precancerous lesions and perfectly matched the type of immunostaining observed in the associated tumor. Figure 1A and B shows representative Fez1 immunostaining in a sample containing normal bronchial epithelium, high-grade squamous intraepithelial neoplasia and tumor areas.

Follow-up information was available for all the cases with a period ranging from 2 to 68 months (median 52 months). Overall, 54 deaths were recorded in the study cohort and of these 48 were due to lung cancer. The median disease-specific survival was 50 months.

Table 3 shows the number of cancer related deaths according to Fez1 expression. The lowest death rate of 12.6 per 100 person-years at risk was observed in the group with strong Fez1 immunostaining (+/+), versus a death rate of 17.8 per 100 person-years at risk in the remaining patients. The corresponding death rate ratio was 0.711 (P = 0.47) or 0.771 (P = 0.58) after adjusting for tumor grade. Such findings denote a relative mortality reduction around 20% to 30% in subjects with very strong Fez1 expression. The lack of statistical significance is compatible with the low study power (around 20%) to detect such a survival difference in the small series under investigation.


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  		Table 3. Cancer-related deaths according to Fez1 expression

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Lung cancer still remains the leading cause of cancer-related deaths in industrialized countries (27). Current treatment protocols have little efficacy on advanced disease where the 5 years survival rate is <20% (28). A better knowledge of the molecular mechanisms underlying the development of this deadly neoplasm is therefore needed to devise novel prevention and intervention strategies. In particular, identification of the genes that are altered during cancer initiation and progression can provide valuable tools as therapeutic targets or prognostic indicators. In this respect, the analysis of the genomic changes associated with cancer specimens has helped in the identification of the chromosomal regions where genes involved in cancer formation and progression are located (29).

The 8p21-23 region is frequently deleted in many cancers, including lung cancer and the FEZ1 gene located at 8p22 has been investigated as a potential tumor suppressor gene in breast (23), prostate (24), and bladder carcinomas (21). Functional support for its oncosuppressive role has been provided by gene transfer experiments using plasmids or adenoviral vectors that resulted in inhibition of colony forming potential of transfected cancer cells and reduction of in vivo tumorigenicity in the nude mouse model (21, 23, 24). Immunohistochemical analyses of primary tumors have shown absent or reduced expression in 62% (37 of 60) of transitional cell carcinoma of the urinary bladder (21) and in 44% (39 of 88) of gastric carcinomas (20) indicating that the gene might play an important role in different cancers.

The only previous study of the expression FEZ1 in lung cancer was done by reverse transcription-PCR in cell lines from 17 NSCLCs and 19 SCLCs with a reported loss of expression in 76% of NSCLC and 16% of SCLC (26). Similar frequencies were also observed by Western blot analysis of a subset of 18 cell lines representing both histologic subtypes. The same study also showed loss of expression in three of six primary cultures of resected NSCLCs.

To clarify the role of FEZ1 in the development of lung carcinomas, we have done the first immunohistochemical characterization of FEZ1 expression in primary lung cancers. In our study, 27 samples (26%) were completely negative for FEZ1 expression and 43 (42%) displayed a significant reduction of the protein. Overall, 68% of the tested specimens showed highly reduced FEZ1 expression indicating a central role for FEZ1 inactivation in lung cancer. A significant association was found between lack of FEZ1 expression and tumor grade (grade 1 to grade 2 versus grade 3; P = 0.0345) revealing that a less differentiated phenotype might be related to loss of FEZ1 function. Interestingly, the same association was also reported for bladder carcinomas (P < 0.005), and in the analysis of gastric carcinomas a very strong correlation was found with the diffuse histotype (P < 0.001) which may occur without well-defined glandular structures.

It has been reported that FEZ1 interacts with microtubules, binds the mitotic kinase p34cdc2 and regulates its activity in the complex with cyclinB1, a crucial modulator of the G2-M transition (23). The function of FEZ1 as a player in G2-M checkpoint of the cell cycle has led to the hypothesis that loss of FEZ1 activity could lead to early exit from mitosis and accumulation of chromosomal aberrations. In particular murine Fez1–/– cells cultured in the presence of taxol or nocodazole fail to arrest in the G2-M phase of the cell cycle and have a higher tendency to develop aneuploidy than Fez +/+ controls indicating a direct link between gene loss-of-function and a cancer-related phenotype.8 This observation also provides insights into how a molecular alteration (Fez1 inactivation) may affect cancer treatment (taxol administration) and therefore on its possible use as a predictor of therapeutic outcome.

The possibility that Fez1-negative tumors might have a defined biological behavior is also suggested by the analysis of cancer related deaths according to Fez1 expression in our cohort. Patients with tumors with high Fez1 expression had a 20% to 30% relative mortality reduction compared with those whose tumors had absent or strongly reduced expression, a trend that remained evident even after adjusting for tumor grade. Although the low study power doesn't allow drawing firm conclusions it is possible therefore that lack of Fez1 expression might turn out to be a negative prognostic factor in lung cancer. This is a promising observation because although many markers, including p53, bcl-2, Rb, K-ras, and c-erbB-2 have been investigated as predictors of outcome in lung cancer (30–32), their clinical significance is often controversial (33), and a definitive role seems firmly established only for few of them (e.g., p53 mutations in stage I NSCLC; ref. 34).

The mechanism of inactivation of the gene that can be inferred from previous studies describing the down-regulation of Fez1 expression in cancer seems to be complex, involving DNA deletions, promoter methylation and, uncommonly, point mutations. The residual expression in a low percentage of cancer cells in some tumors raises the question of whether complete loss of the protein is needed to abrogate the function of the gene or not. The animal model provides some insights into this issue in that both Fez –/– and +/– animals are similarly susceptible to the development of carcinogen-induced tumors indicating that loss of one Fez1 allele is sufficient to predispose to cancer.9 The haploinsufficient behavior of Fez1 in the mouse indicates therefore that in tumors with 2% to 50% expressing cells (–/+ class in our scoring system) the function of Fez1 could be totally impaired.

In conclusion, our analysis of 103 primary lung cancer samples provides evidence of an important role for Fez1 in lung cancer. The association of loss of expression with high-grade tumors and worst death rate ratio warrant further investigation on the possible use of Fez1 as a prognostic tool and as a determinant of therapeutic intervention outcome.


   Acknowledgments
 
Grant support: Italian Association for Cancer Research, Italian Foundation for Cancer Research (G. Sozzi).

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.


   Footnotes
 
8 A. Vecchione et al., submitted for publication. Back

9 A. Vecchione et al., submitted for publication. Back

Received 9/24/04. Revised 12/ 2/04. Accepted 12/13/04.


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 Introduction
 Materials and Methods
 Results
 Discussion
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