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Clinical Cancer Research Vol. 5, 2520-2525, September 1999
© 1999 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Decreased Expression of Transforming Growth Factor ß Receptor Type I Is Associated with Poor Prognosis in Bladder Transitional Cell Carcinoma Patients1

Hideo Tokunaga, Dong-Hyeon Lee, Isaac Yi Kim, Thomas M. Wheeler and Seth P. Lerner2

Scott Department of Urology [H. T., D. H. L., I. Y. K., S. P. L.] and Department of Pathology [T. M. W.], Baylor College of Medicine, Houston, Texas 77030


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Transforming growth factor (TGF) ß, a potent growth inhibitor of proliferation in most cells, usually exerts its effects through an interaction with membrane receptors, type I (TßR-I) and type II (TßR-II). In the present study, the expression of TGF-ß receptors was correlated with tumor grade, pathological stage, and probability of progression and survival in patients with bladder transitional cell carcinoma (TCC). To this end, immunohistochemistry was carried out in specimens obtained from 59 patients who underwent either radical cystectomy or transurethral resection of bladder tumor. Among these patients, 18 (30.5%) had loss of TßR-I expression, whereas 27 (44.0%) had loss of TßR-II expression. There was a correlation between the loss of expression of TßR-I and TßR-II and the tumor grade (P = 0.041 and P = 0.026, respectively). In addition, both pathological and lymph node status also were associated with the loss of TßR-I and TßR-II expression (P = 0.025 and P = 0.004, respectively). Interestingly though, only the loss of expression of TßR-I was associated with an increased probability of tumor progression and a decreased probability of survival (P = 0.0046 and P = 0.0022, respectively). These results suggest that the status of TßR-I expression may be a potential prognostic marker in patients with bladder TCC.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Bladder cancer is the second most common urological malignancy in the United States. There were ~54,500 new cases and 11,700 deaths in 1997 (1) . Approximately 90% of bladder cancers in the United States are TCCs.3 Radical cystectomy is widely used as definitive therapy for muscle invasive bladder cancer and for superficial bladder cancer that is refractory to chemo- or immunotherapy. For deep-muscle invasive and lymph node-positive cancers, adjuvant and neoadjuvant chemotherapy may improve cancer control rates and long-term survival (2, 3, 4) . With such varying treatment options, identification of patients at high risk for tumor progression after the initial treatment will permit a more appropriate selection of patients for early cystectomy, while providing a more conservative approach in patients whose tumors are less likely to progress. In this regard, molecular markers may aid in identifying bladder cancer patients who have higher risk of tumor progression after the definitive treatment. One such group of potential molecular markers are TßRs.

TGF-ß is a Mr 25,000 pleiotropic growth factor that is expressed by many cell lines and tissue types. There are three ubiquitously expressed TßRs: types I, II, and III (TßR-I, TßR-II, and TßR-III, respectively). TßR-III is a membrane proteoglycan that has a very short cytoplasmic tail and lacks any signaling motif, whereas TßR-I and TßR-II are serine/threonine kinases (5 , 6) . The present theory concerning the mechanism of action of TßRs states that both TßR-I and TßR-II are required for TGF-ß signal transduction (7 , 8) .

TGF-ß usually acts as a potent growth inhibitor in most cells, especially those of the epithelial lineage (reviewed in Ref. 9 ). However, malignant cells are frequently resistant to the growth-inhibitory effects of TGF-ß (10, 11, 12, 13) . An accumulating body of evidence suggests that alteration in the expression of TßRs may play a critical role in rendering malignant cells resistant to TGF-ß (14, 15, 16, 17) . Specifically, loss of expression of TßRs has been demonstrated in prostate, colon, and stomach cancer (13, 14, 15) . Moreover, TßR-II has been suggested as a tumor suppressor in a subset of colon cancers (15 , 16) .

In bladder cancer, it has been demonstrated that the serum level of TGF-ß is elevated in TCC patients (18) . Among bladder cancer cell lines, loss of TßR-I has been reported (19) . Moreover, transfection of TßR-I into these cells that lack TßR-I expression results in a decreased tumorigenic potential. These results suggest that the loss of TßR expression may be an important event during bladder carcinogenesis. Therefore, the prognostic value of the expression of TßR-I and TßR-II in 59 patients with bladder TCCs was investigated in the present study. We observed that the loss of TßR-I expression was associated with increased risk of progression and death in these patients.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Population.
Fifty-nine patients with bladder TCCs who underwent radical cystectomy (n = 55) or transurethral resection of the bladder tumor were included in the study. Table 1Citation shows the tumor grade, pathological stage, lymph node status, and surgical treatment in these patients. Patients who had received radiotherapy or systemic chemotherapy previously were excluded from this study. Of the 59 patients, 46 were men and 13 were women; ages ranged from 39 to 94 years (median age, 66 years). The pathological stage was determined according to the 1997 American Joint Committee on Cancer classification (20) . No patient had evidence of distant metastatic disease at the time of the surgery. The median follow-up was 41.6 months (range, 1.8–132.1) for patients who were alive at the time of analysis.


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  		Table 1 Tumor grade, pathological stage, lymph node status, and surgical treatment in 59 patients with bladder TCC

 
Immunohistochemistry.
All H&E-stained slides were reviewed by one pathologist (T. M. W.) to confirm stage and grade. Five µm sections were cut from paraffin-embedded tissue blocks and mounted on poly-L-lysine-coated slides. These slides were stored at 4°C until staining. The sections were dewaxed in xylene and rehydrated with graded alcohols. Endogenous peroxidase activity was inactivated by incubating in 3% H2O2 for 25 min. The antigen retrieval procedure using a microwave technique was used (21) . The tissue sections were immersed in 0.1 M citrate buffer (pH 6.0) and microwaved at 800W for 10 min. Subsequently, the sections were incubated with primary antibodies in a humidified chamber for 24 h at 4°C. Anti-TßR-I and anti-TßR-II antibodies (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) were used at a concentration of 2 µg/ml. The specificity of this antibody was demonstrated previously (22 , 23) . The following day, the sections were washed three times in fresh PBS, and the secondary antibody was applied at a dilution of 1:400. Visualization of the reactivity was accomplished with an avidin-biotin complex immunoperoxidase system (Vector, Burlingame, CA), according to the manufacturer’s recommendations. Diaminobenzidine (0.03%) was used as a chromogen. The sections were counterstained with Mayer’s Hematoxylin (Sigma Diagnostics).

Negative control sections were processed in an identical manner by substitution of primary antibody with a normal rabbit IgG. No negative control sections showed any color reactions. Because immunohistochemistry is not quantitative, all sections were categorized as either positive or negative staining for TßRs. Specimens were classified as negative if the staining level was comparable with that of the negative control slides. All negative cases were confirmed with at least two indepen-dent staining experiments. All slides were reviewed indepen-dently by two individuals.

Statistics.
Survival was calculated on the basis of the date of death due to bladder TCC or the date of the last follow-up contact (either a clinical visit or information provided by the patient’s referring physician). Time to progression was calculated from the date of surgery to the date of the first documented clinical recurrence or the last follow-up. Patients whose disease never recurred and died of other causes were censored at their death. Times to progression and survival were analyzed using the Kaplan-Meier method, and the log-rank test was used to assess the difference between the negative and positive groups. The {chi}2 test was used to evaluate the association between the expression of TßRs and histological grade, pathological stage, and the lymph node status. For multivariate analysis, a Cox proportional hazard model was used. P < 0.05 was considered statistically significant. Statistical analyses were performed using the STATA statistics package (Stata Corp., College Station, TX).


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Expression of TßRs in Normal Bladder and Bladder TCC.
A representative result of the immunohistochemistry for TßR-I and TßR-II in normal and malignant bladder tissues is shown in Figs. 1Citation and 2Citation , respectively. As shown, the expression of TßR-I and TßR-II was predominantly localized in the epithelial cells in normal bladder tissues. In bladder cancer cells though, the expression of TßRs was frequently decreased with increasing tumor grade. In the 59 cases investigated in this study, 18 (30.5%) had loss of TßR-I expression, and 27 (44.0%) had loss of TßR-II expression.



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  		Fig. 1. Immunohistochemistry for TßR-I in normal and malignant bladder tissues. Note the positive brown staining cells. TßR-I was predominantly expressed by epithelial cells. In addition, there was a significant decrease in the level of expression of TßR-I with increasing grade of bladder cancer

 


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  		Fig. 2. Immunohistochemistry for TßR-II in normal and malignant bladder tissues. Note the positive brown staining cells. TßR-II was predominantly expressed by epithelial cells. In addition, there was a significant decrease in the level of expression of TßR-II with increasing grade of bladder cancer

 
Expression of TßRs and Tumor Grade and Pathological Stage.
The {chi}2 test showed a statistically significant relationship between TßR-I expression and tumor grade (Table 2)Citation . TßR-I expression was detectable in 100 and 87% of grades 1 and 2 tumors, respectively. In contrast, only 60% of grade 3 tumors were positive for TßR-I expression (P = 0.041). Similarly, the expression of TßR-II also correlated with tumor grade (Table 3)Citation . In grade 1 tumors, 100% had positive TßR-II expression, whereas 50 and 46% of grades 2 and 3 tumors had detectable levels of TßR-II expression, respectively (P = 0.026). To investigate the relationship between expression of TßRs and pathological stage, patients were classified into three groups: (a) those with positive lymph node metastasis; (b) those with organ-confined tumors with no evidence of lymph node metastasis; and (c) those with extravesical tumor with no evidence of lymph node metastasis. The results revealed that the expression status of both TßR-I and TßR-II was associated with tumor stage (P = 0.025 and P = 0.004, respectively; Tables 2Citation and 3Citation ).


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  		Table 2 TßR-I expression, tumor grade, and pathological stage in bladder TCC patients

 

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  		Table 3 TßR-II expression, tumor grade, and pathological stage in bladder TCC patients

 
TßR Expression and Probability of Progression.
As an initial attempt to determine the potential role of the expression of TßRs as a prognostic marker in bladder TCC patients, we investigated the relationship between the expression of TßRs and the probability of progression. Of 59 patients, 22 patients had progressed, with the median time to progression of 39.1 months. As shown in Fig. 3ACitation , the rate of progression after surgery for patients with loss of TßR-I expression was significantly higher than for those with normal expression (P = 0.0046). A multivariate analysis also demonstrated that the loss of TßR-I expression was significantly associated with tumor progression (Table 4)Citation . There was no statistically significant association between TßR-II expression and probability of progression (Fig. 3B)Citation .



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  		Fig. 3. Kaplan-Meier estimated probability of progression related to expression of TßRs in bladder cancer tissues. A, TßR-I (P = 0.0046); B, TßR-II (P = 0.1931)

 

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  		Table 4 Cox proportional model for progression

 
TßR Expression and Probability of Survival.
To further study the role of the expression of TßR status as a potential prognostic indicator, we investigated the relationship between the expression of TßRs and the probability of survival after surgery. Of 59 patients, 30 were dead at the time of analysis. Of these patients, 21 died of metastatic bladder TCCs, and 9 died without evidence of recurrence. As shown in Fig. 4ACitation , the loss of TßR-I expression was associated with the decreased probability of cancer specific survival (P = 0.0022). A multivariate analysis also demonstrated that the loss of TßR-I expression was significantly associated with tumor recurrence (Table 5)Citation . There was no statistically significant association between TßR-II expression and probability of survival (Fig. 4B)Citation .



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  		Fig. 4. Kaplan-Meier estimated cancer-specific survival related to expression of TßRs in bladder cancer tissues. A, TßR-I (P = 0.0022); B, TßR-II (P = 0.0912)

 

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  		Table 5 Cox proportional model for cancer-specific death

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The results of the present study have demonstrated that the expression of TßR-I is associated with tumor grade, pathological stage, increased probability of progression, and decreased probability of survival after surgery. In contrast, the status of TßR-II expression was associated with only the tumor grade and pathological stage and not with the probability of progression and survival. Taken together, these observations suggest that the status of TßR-I expression is a potential prognostic marker in bladder TCC patients.

TGF-ß is pleiotropic growth factor that regulates cellular proliferation, angiogenesis, and chemotaxis (24 , 25) . In cells of epithelial lineage, TGF-ß is a potent growth inhibitor. Nevertheless, it has been demonstrated that malignant epithelial cells frequently have elevated levels of TGF-ß expression and a loss of its receptor expression. Because overexpression of TGF-ß renders survival advantage by suppressing immune response and enhancing angiogenesis, the loss of expression of TßRs may be a critical event during carcinogenesis because resistance to the growth-inhibitory effect of TGF-ß likely will enable overexpression of TGF-ß. This concept is consistent with the results of the present study in which the loss of TßRs was seen most frequently in high-grade tumors. In addition, loss of expression of TßRs was associated with higher pathological stage. With respect to probability of tumor progression and survival, only the loss of TßR-I expression showed a significant association by univariate analysis and was independently associated with both clinical end points by multivariate analysis. These results suggest that the loss of expression of TßRs, especially of TßR-I, may be an important event during bladder TCC carcinogenesis.

Because both TßR-I and TßR-II are required for TGF-ß signaling, the loss of TßR-I should have the same biological effects as the loss of TßR-II. Yet, in the present study, only TßR-I expression status was significantly associated with prognosis. It is possible that the sample size in the present study may not have been large enough to demonstrate a correlation between the loss of TßR-II expression and prognosis. However, the possibility exists that in bladder cancer cells, the biological consequence of the loss of TßR-I expression may not be the same as the loss of TßR-II expression. Interestingly, TßR-I is mapped to human chromosome 9q23-24 (26) ; loss of heterozygosity of chromosome 9q has been shown in >50% of bladder cancer (27) . Therefore, TßR-I may be a tumor suppressor in bladder cancer. Further work is under way to verify this concept.

In conclusion, results of the present study have demonstrated that the status of TßR-I expression is a potential prognostic marker in bladder TCC patients. In the future, the specific role of TßR-I in bladder TCC cells will be investigated.


   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 This work was supported in part by Hankamer Research Fund. Back

2 To whom requests for reprints should be addressed, at Scott Department of Urology, 6560 Fannin Street, Suite 2100, Houston, TX 77030. Phone: (713) 798-6841; Fax: (713) 798-5553; E-mail: slerner{at}bcm.tmc.edu Back

3 The abbreviations used are: TCC, transitional cell carcinoma; TGF, transforming growth factor; TßR, TGF-ß receptor. Back

Received 11/ 2/98; revised 5/25/99; accepted 6/14/99.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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