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Overexpression of c-met as a Prognostic Indicator for Transitional Cell Carcinoma of the Urinary Bladder: A Comparison With p53 Nuclear Accumulation

From the Departments of Urology, Microbiology and Immunology, and Pathology, College of Medicine, and Department of Statistics, National Cheng Kung University, Tainan, Taiwan, Republic of China, and Department of Otolaryngology, Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD.

Address reprint requests to Nan-Haw Chow, MD, Department of Pathology, National Cheng Kung University Hospital, 138 Sheng-Li Rd, Tainan 704, Taiwan, Republic of China; email: chownh@ mail.ncku.edu.tw.

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: The c-met proto-oncogene encodes a receptor tyrosine kinase (Met) and has been shown to play a role in oncogenesis. Given that high titers of hepatocyte growth factor, the specific ligand for Met, are excreted in the urine and tend to reflect disease activity of bladder cancer, we performed this study to examine the clinical significance of Met in human bladder cancer.

MATERIALS AND METHODS: We studied the mRNA expression and genomic alteration of c-met in five bladder cancer cell lines. Significance of Met overexpression was then compared with p53 nuclear accumulation (TP53) in primary bladder cancer (n = 142 patients).

RESULTS: Expression of c-met mRNA tended to positively correlate with differentiation of cancer cell lines in the absence of point mutation. High expression of Met was found in seven cases (4.9%), low expression in 32 cases (22.5%), and negative expression in 103 cases (72.5%). Expression of Met was positively associated with histologic grade, stage classification, tumor size, and nodular tumor growth (P < .05, respectively); however, it was not related to TP53 status. Factors that predicted disease progression were tumor stage, Met status, and TP53 accumulation (P < .05, respectively). Indicators for poor long-term survival were invasive cancer, multiple tumors, and Met overexpression (P = .0006, .01, and .04, respectively).

CONCLUSION: The c-met proto-oncogene plays a more important role in the progression of bladder carcinogenesis than p53. Evaluation of Met expression could identify a subset of bladder cancer patients who may require a more intensive treatment strategy.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
PROTEIN TYROSINE kinases (PTKs) are a major class of proto-oncogenes and play a crucial role in many cell regulatory processes, such as proliferation, migration, adhesion, and, potentially, cellular transformation.¹ Currently, most of the established proto-oncogenes in solid tumors are PTKs. Epidermal growth factor receptor and ErbB2 (c-erbB-2, HER-2/neu) are well known examples.² Some of the receptor-type PTKs have been chosen as a target for anticancer therapy in vitro and are currently being tested clinically because of these observations.

The c-met proto-oncogene encodes a trans-membrane tyrosine kinase receptor (Met) for the hepatocyte growth factor/scatter factor (HGF/SF). HGF/SF-Met signaling clearly plays a role in a variety of normal cellular processes, such as cell motility, proliferation, epithelial morphogenesis,³ and normal embryogenesis.⁴ In addition, there is a substantial body of experimental evidence supporting an oncogenic role for the HGF/SF-Met signaling pathway.^5-7 High levels of Met expression have been correlated with the metastatic spread of tumors and poor survival in patients with breast carcinoma,^8,9 extrahepatic biliary tract cancer,¹⁰ gastric cancer,^11,12 endometrial carcinoma,¹³ hepatocellular carcinoma,¹⁴ colorectal cancer,¹⁵ and renal cell carcinoma.¹⁶

In urothelial cancer, Natali et al¹⁶ found no expression of Met in normal urothelium as well as in five cases of transitional cell carcinoma (TCC) of the kidney. However, there is evidence supporting a role for Met in the tumorigenesis of human bladder.^17-19 Strong expression of Met was demonstrated in four cases of invasive bladder carcinomas,¹⁷ while varying levels of MET immunostaining were consistently detected in TCC of the bladder.¹⁸ In our molecular profiling of PTKs in bladder cancer, c-met was among the most frequently detected receptor-type PTKs.¹⁹ However, Li et al¹⁸ suggested that Met expression did not significantly correlate with tumor stage and grade, or with overall patient survival. The disparities described above suggest that the clinical relevance of c-met for TCC of the bladder remains to be clarified.

The p53 tumor suppressor gene, located on chromosome 17p13.1, encodes for a 53-kd nuclear phosphoprotein. The wild-type protein functions to arrest cells in the G₁-S phase of the cell cycle when DNA is damaged, thus allowing cellular repair of DNA or programmed cell death.²⁰ Mutations in the p53 gene result in an extended half-life of the p53 protein (TP53), which becomes detectable in the cell nucleus by immunostaining. However, the wild-type p53 gene product has a very short half-life in normal cells and thus is not detectable. Accumulation of nuclear TP53 has been reported to be an independent prognostic indicator for TCC of the urinary bladder,²¹ as well as in the subset of superficial (pTa-pT1) or T1 bladder tumors.^22-24 As a result, we performed this study to examine the expression of c-met and genomic alteration in cancer cell lines. The significance of Met overexpression was analyzed in the progression of human bladder cancer compared with TP53 accumulation.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Cell Lines and Culture
Five human bladder cancer cell lines (RT4, TSGH-8301, TCC-SUP, J82, and T24) were propagated for use, as previously described.²⁵ They were maintained in Dulbecco’s modified Eagle’s medium (DMEM) (Gibco BRL, Grand Island, NY) supplemented with 10% fetal calf serum (Gibco), L-glutamine 2 mmol/L, sodium pyruvate 110 mg/L, penicillin (100 U/mL), and streptomycin (50 g/mL) at 37°C in a 5% CO₂-humidified atmosphere. The E6 cell line was an immortalized human uroepithelium (general gift from C.A. Reznikoff, MD, Department of Human Oncology, University of Wisconsin Medical School, Madison, WI).

Northern Blot Hybridization of mRNA Expression
RNA preparation and Northern blotting were performed as previously described.²⁶ Briefly, a total of 20 µg of RNA from each cell were resolved by 1% agarose gel electrophoresis and then transferred to GeneScreen nylon membranes (New England Nuclear, Boston, MA). The membrane was hybridized with a c-met cDNA probe labeled with [-³²P]-dCTP by using a random primer labeling kit (Gibco) at 42°C for 18 hours. It was then exposed to Kodak X-OMAT films (Eastman Kodak Co, Rochester, NY) at -80°C. The resulting autoradiographs were evaluated by a scanning densitometer (Molecular Dynamics, Sunnyvale, CA). A complete digital image of each sample was scanned and measured as units of optical density x cm³ (OD x cm³). Both c-met and beta (ß)-actin signals were measured for each cell line and expressed as ratios of c-met to ß-actin.

Mutation Analysis of the c-met Gene
First strands of cDNA were prepared by reverse transcription of 1 µg of RNA, according to the instructions for the SuperScript preamplification system (Gibco). The primers used for amplification of c-met exons for polymerase chain reaction (PCR) were chosen from a prior report.²⁷ We sequenced exons 5 to 7 (encoding the cysteine-rich extracellular region) and 13 to 20 (encoding the kinase domain of the intracellular portion) by direct sequencing of PCR products. Exons 14 to 19 were analyzed both by direct sequencing and by PCR-based single-strand conformation polymorphism, as previously described.²⁸ Each sequence was confirmed by two independent PCR reactions.

Clinicopathologic Characteristics
For this study, archival blocks were collected from a total of 142 patients with primary TCC of the urinary bladder treated between July 1, 1988, and July 31, 1994, in the National Cheng Kung University Hospital, Tainan, Taiwan. There were 95 men and 47 women, ranging in age from 29 to 90 years old (mean age, 63 ± 11 years). All cases were reviewed for histologic grade according to the World Health Organization classification (1973). Clinical staging was determined according to the tumor-node-metastasis staging protocol of the American Joint Committee on Cancer (1983) by survey of the clinical details, image studies, and pathologic data.

The treatment and follow-up of patients were conducted according to the standard strategy previously described in detail.²⁹ Briefly, all patients with superficial bladder cancer received transurethral resection and postoperative intravesical chemotherapeutic agent instillation with either thiotepa (30 mg in 30 mL of normal saline for 70 patients) or epirubicin (40 mg in 40 mL of normal saline for 34 patients) weekly for 8 consecutive weeks. Those patients who received intravesical bacillus Calmette-Guerin therapy or neoadjuvant chemotherapy were not included in this study. The patients were followed up every 3 months for the first 2 years, then every 6 months for another 2 years, and yearly thereafter. Each recurrence was confirmed by biopsy. Whenever recurrent tumors were found, they were treated by repeated transurethral operation followed by another 8-week course of intravesical chemotherapeutic instillation therapy or by radical/partial cystectomy if disease progression was noted. Disease progression at recurrence was defined as being at a higher stage than the previous result. For those with muscle-invasive tumors (n = 38), a radical operation was the standard procedure. Systemic chemotherapy with methotrexate, cisplatin, doxorubicin, and vinblastine was given in 29 patients. The survival status was determined by outpatient clinic records and/or confirmed by interview with patients’ families. Clinical follow-up ranged from 24 to 95 months (median, 54 months).

Immunohistochemistry of Expression for Met and TP53
We used immunostaining procedures described in detail previously.²⁶ Briefly, tissue sections were incubated with monoclonal anti–c-met antibody (Santa Cruz Biotechnology, Inc, Santa Cruz, CA) raised against cytoplasmic domain human Met protein for 2 hours at room temperature. The optimal dilution (1/50) was determined by using human kidney as a positive control.³⁰ Expression of TP53 was analyzed by using anti-p53 mouse monoclonal antibody Pab1801 (BioGenex, San Ramon, CA) based on its advantage in predicting clinical outcome.³¹ The StrAviGen Super Sensitive MultiLink kit (BioGenex) was used to detect the resulting immune complex. Peroxidase activity was visualized by an aminoethyl carbazole substrate kit (Zymed Laboratory, Inc, San Francisco, CA). Finally, sections were counterstained with hematoxylin. For the negative control, nonimmune mouse immunoglobulin (Ig) G was substituted for the primary antibody in the incubation.

When evaluating the staining results (by N.-H.C. and C.-L.H.), the pathologists were blinded to the clinical outcomes. We used three-category scoring systems for Met according to the proportion of tumor cells stained.³² "High Met expression" indicates that more than 50% of tumor cells exhibited immunostaining; "low Met expression," between 5% and 50% of reactivity; and "negative," less than 5%% or absent staining for Met. Nuclear staining for TP53 was also graded using three categories, as previously described.³¹ Those showing positive staining in less than 20% of tumor cells were classified as negative (-); between 20% and 50%, as positive (+); and greater than 50%, as double-positive (++).

Statistics
Correlations of Met or TP53 and clinicopathologic indicators of bladder cancer were examined, where suitable, by analysis of variance, Fisher’s exact test, or ² test. The relationships between immunostaining results and clinical parameters were analyzed by logistic regression. Overall survival was calculated by Kaplan-Meier analysis, and the Cochran-Mantel-Haenszel test (log-rank test) was used to assess the significance of Met or TP53 expression in relation to tumor recurrence or patient survival. Only those variables with a P value of less than .05 were considered significant.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
c-met mRNA was expressed in E6 cells and all cancer cell lines except for T24 cells (Fig 1). The ratio of c-met in relation to ß-actin mRNA expression tended to positively correlate with tumor differentiation from RT4 cells (original histologic grade 1) through J82 cells (original histologic grade 3). Mutational screening of the coding region of c-met did not reveal any point mutations in the cancer cell lines. Taken together, these results indicate that c-met overexpression seems to play a positive role in the development of human bladder cancer in the absence of mutation. Furthermore, the absence of c-met mRNA in T24 cells indicates that at least some bladder tumors harbor an alternative pathway to growth development.

View larger version (36K): [in this window] [in a new window]   Fig 1. Expression of c-met and ß-actin in E6 and cancer cell lines. (A) E6 and all bladder cancer cells express abundant c-met mRNA, except for T24 cells. (B) The ratio of c-met in relation to ß-actin mRNA expression tended to positively correlate with original differentiation of cancer cell lines.

Protein expression of Met in normal urothelium was examined by immunohistochemistry (IHC) staining in 20 cases of nonneoplastic bladder tissue with inflammatory disease. There was weak and occasional staining in the basal cells of the mucosa. For bladder cancer (n = 142 patients), Met expression was assessed by IHC and correlated with clinicopathologic factors (summarized in Table 1): in seven patients (4.9%), tumors showed high Met expression (Fig 2); in 32 patients (22.5%), low expression; and in 103 patients (72.5%), no expression. Met expression, analyzed by a three-category scoring system, was positively associated with histologic grade, stage classification, tumor size, and nodular tumor growth (P = .002, .004, .01, and .02, respectively).

View larger version (142K): [in this window] [in a new window]   Fig 2. Immunohistochemical Met expression of human bladder cancer. Most of the cancer cells showed strong membranous staining for Met, thus the grade of high Met expression (original magnification x300).

View larger version (130K): [in this window] [in a new window]   Fig 3. Nuclear accumulation of TP53 in human bladder cancer. Most of the invasive carcinoma cells showed strong nuclear staining for TP53, representative of the double-positive (++) grade in our scoring system (original magnification x300).

View larger version (18K): [in this window] [in a new window]   Fig 4. Kaplan-Meier analysis of Met expression in relation to clinical outcome. Significance of Met in association with patient survival was assessed by log-rank test. Patients with high Met tumors had a worse prognosis than those with negative or low Met bladder cancer (P = .005).

Disease progression was observed in 34 patients (23.9%) in our series. Six of seven patients whose primary tumors had high Met expression experienced disease progression or death caused by cancer. In contrast, disease progression was observed in eight (25%) of 32 patients with low Met tumors and in 20 (19.4%) of 103 patients whose tumors showed no Met expression during follow-up. Thus, patients with high Met bladder cancer had a significantly higher chance of disease progression (P = .001) (Table 4). Likewise, the proportion of TP53 nuclear accumulation in patients with disease progression (11 of 34 patients, 32.4%) was significantly higher than that in disease-free patients during follow-up (16 of 108 patients, 14.8%) (P = .02). In addition, histologic grade, staging classification, tumor size, and nodular shape were also important risk factors for disease progression (P < .05). In the multivariate model, tumor stage, Met overexpression, and TP53 nuclear accumulation were important predictors for disease progression (P = .002, .02, and .05, respectively).

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

The direct genetic link between c-met and human cancer was, in fact, established by the identification of germline and somatic mutations in papillary renal carcinoma,^28,33 childhood hepatocellular carcinoma,³⁴ and a small portion of squamous cell carcinoma of the head and neck.³⁵ In all reported cases, mutations were located in the kinase domain, either in the N-terminal lobe, which includes the adenosine triphosphate binding site, or in the C-terminal lobe, which includes the catalytic and activation loops. These mutations seem to be activating, albeit to different degrees, and are among the most effective in inducing phosphorylation of target molecules.^36-38 In this investigation, all five cancer cell lines tested revealed no evidence of mutation. Moreover, there was no evidence of mutation in 80 tumors examined, which supports the idea that c-met could be expressed in human bladder cancer cells in the absence of mutation as opposed to papillary renal cell carcinoma.^28,33

Previous studies have demonstrated that HGF can be overproduced in bladder carcinoma tissue.^17,18 In addition to deregulation of the growth factors in tumor cells, positive staining for HGF was also observed in fibroblast-like cells, smooth muscle cells of the bladder wall, and even endothelial cells.¹⁷ Indeed, there is evidence that tumor cells can influence neighboring cells to release abundant growth-stimulating signals.³⁹ Eventually, these cooperating cells may coevolve and express independent growth signals.⁴⁰ Urinary HGF titers are significantly elevated in bladder cancer patients (mean creatinine 40 pg/mg) compared with normal control and tend to reflect disease activity of bladder cancer.¹⁷ On this basis, Met expression on the surface of cancer cells seems to be activated by paracrine and/or autocrine mechanisms in vivo. Given that Met is positively associated with biologic indicators (such as histologic grade, cancer stage, and solid growth pattern) and disease progression, HGF/SF-Met signaling molecules may serve as important therapeutic targets for human bladder cancer.

In this study, TP53 nuclear accumulation showed a positive relationship to histologic grade and invasive growth of bladder cancer. However, we failed to prove its value as an independent predictor of tumor recurrence or overall survival, as previously reported.²¹ The conclusion is in agreement with recent reports showing a limited prognostic significance of TP53 nuclear accumulation for human bladder cancer.^41-43 Nevertheless, the association of TP53 with disease progression supports a role for p53 in the progression of bladder cancer.^21-24 Taken together with the prognostic importance of Met compared with TP53, HGF/SF-Met signaling plays an even more important role in the carcinogenesis of human bladder.

In conclusion, the current study supports the importance of c-met in the progression of bladder cancer compared with p53. Evaluation of Met expression could identify a subset of bladder cancer patients who may require a more intensive treatment strategy. As a result, HGF/SF-Met signaling molecules deserve further investigation as important therapeutic targets for human bladder cancer.

	ACKNOWLEDGMENTS

 
Supported by grant nos. NSC-88-2314-B006-075 and NSC-89-2314-B-006-027 from the National Science Council of the Republic of China and grant no. NCKUH 89-051 from the National Cheng Kung University Hospital, Tainan, Taiwan, Republic of China.

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Submitted January 25, 2001; accepted December 3, 2001.

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