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Clinical Cancer Research Vol. 10, 3007-3012, May 1, 2004
© 2004 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Elevated Expression of Valosin-Containing Protein (p97) Is Associated with Poor Prognosis of Prostate Cancer

Yuichi Tsujimoto1, Yasuhiko Tomita1, Yoshihiko Hoshida1, Takuro Kono4, Toshitsugu Oka4, Shinji Yamamoto2, Norio Nonomura3, Akihiko Okuyama3 and Katsuyuki Aozasa1

1 Departments of Pathology, 2 Surgery and Clinical Oncology, and 3 Urology, Osaka University Graduate School of Medicine, Osaka, Japan, and 4 Division of Urology, Osaka National Hospital, Osaka, Japan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: Valosin-containing protein (VCP) has been shown to be associated with metastasis and prognosis in human cancers. In the present study, the correlation of VCP with recurrence and prognosis in patients with prostate cancer (PCA) receiving conservative therapy was examined.

Experimental Design: VCP expression was analyzed immunohistochemically in 136 patients ranging from 46 to 92 years (median, 72 years), who received conservative therapy, including androgen deprivation, radiotherapy, or watchful waiting. Staining intensity of tumor cells was categorized as weaker (level 1) or equal to or stronger (level 2) than that in endothelial cells. The correlation of VCP expression between the mRNA and protein levels was examined in 10 patients.

Results: Thirty-two cases (23.5%) showed level 1 and 100 (76.5%) level 2 VCP expression. Quantitative reverse transcription-PCR analysis revealed greater VCPmRNA expression in level 2 (n = 5) than level 1 cases (n = 5; P < 0.05). A significant difference was observed between VCP level 1 and 2 patients in the positive rate for the digital rectal examination (P < 0.01), serum prostate-specific antigen level (P < 0.0001), cancer volume (P < 0.0001), Gleason score (P < 0.0001), stage (P < 0.0001), and progression-free and overall survival (P < 0.0001 for both). Multivariate analysis revealed VCP expression level, serum prostate-specific antigen level, and Gleason score to be independent prognosticators for progression-free and overall survival. Progression of PCA was found in 9.4% of level 1 but in 64% of level 2 patients.

Conclusions: PCA with level 1 VCP expression could be treated conservatively.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Prostate cancer (PCA) is one of the most common cancers in males: its incidence of mortality is ranked as second in the United States and seventh in Japan (1 , 2) . The annual incidence of PCA in Japan is ~10/100,000 and rapidly increasing possibly because of a change to a Westernized lifestyle (1) . Because PCA usually shows a slowly progressive course, immediate therapy might not always be necessary even in patients with recurrent tumors (3) . Therefore, androgen deprivation has been a commonly used therapy in Japan. Local recurrence and distant metastasis mainly to the bone are common in PCA; thus, radical prostatectomy has been widely used in the United States and is becoming popular in Japan (4 , 5) . Radical prostatectomy, however, occasionally causes severe complications such as life-threatening events at surgery and urinary and sexual incontinence after surgery (5) . Thus, a precise estimation of tumor characteristics is essential in choosing appropriate therapeutic modalities for each patient with PCA.

Previous studies revealed that clinical stage, tumor grade, and serum prostate-specific antigen (PSA) level were prognostic factors for PCA (6, 7, 8) . However, even with use of these prognostic factors, a decision as to whether radical surgery should be used for PCA can be difficult (9) . Therefore, the discovery of new markers with which to estimate the aggressiveness of PCA is essential to establish appropriate therapeutic modalities.

Recently, we have identified the gene encoding valosin-containing protein (VCP; also known as p97) to be associated with metastasis in a murine osteosarcoma cell line (10) . VCP, a member of the ATPases associated with various cellular activities (AAA) superfamily, is known to be involved in the ubiquitin/proteasome degradation pathway (11) , which works in both the up-regulation of cell proliferation and the down-regulation of cell death in human cancer cells (12) . The cell line transfected with VCP showed a decreased rate of apoptosis after tumor necrosis factor {alpha} stimulation and increased metastatic potential (10) . Therefore, it was postulated that the expression level of VCP could be used as a prognosticator for cancers. Indeed, our previous study showed that the VCP expression level in cancer cells was correlated with the rate of recurrence and prognosis of patients with hepatocellular carcinoma and gastric carcinoma (13 , 14) .

The present study was performed to examine whether VCP expression could be a useful indicator of the necessity for radical surgery in cases of PCA. For this purpose, PCA patients treated with nonradical modalities such as watchful waiting, androgen deprivation therapy, and radiation therapy were selected.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients.
One hundred thirty-six patients, who were diagnosed as having PCA at the Urology Division, Osaka National Hospital (Osaka, Japan) from 1986 to 1999, were selected for the present study. The age at admission ranged from 46 to 92 years (median, 72 years). A diagnosis of PCA was made by histological examination of specimens obtained through trans-rectal needle biopsy or transurethral resection of the prostate. Clinical stage was defined based on the American staging system (modified Whitmore-Jewett; Ref. 15 ) through digital rectal examination (DRE), transrectal ultrasonography, X-ray, computed tomography, magnetic resonance imaging, and bone scintigram. Serum PSA levels measured by the immunoenzymatic assay in 101 patients ranged from 0.1 to 5162.0 ng/ml (median, 23.7 ng/ml). Initial therapy performed was watchful waiting in 3 patients, androgen deprivation therapy in 126, and radiation therapy in 7 patients. DRE was not performed on 4 patients. These patients were referred with obvious tumors, and DRE was not performed before treatment. Serum PSA level was not measured in 31 patients. They were diagnosed before 1991 when PSA measurement for PCA was not routinely performed in Japan. Histological specimens were fixed in 10% formalin and routinely processed for paraffin embedding. Histological sections, cut 4-µm thick, were stained with H&E and reviewed by two pathologists (Y. Tsujimoto and K. Aozasa) to determine the following categories: Gleason score based on the Gleason grading system (6) and extent of cancer proliferation in the specimen.

After initial therapy, patients were followed with periodic evaluations of DRE, serum PSA, and imaging findings every 1–3 months in the initial 2 years and every 3–6 months thereafter. Progression of PCA was defined by an elevation in the serum PSA level at three consecutive measurements (PSA failure) or the existence of local or metastatic recurrent tumors.

The present study was approved by the Institutional Review Board of Osaka National Hospital.

Immunohistochemical Analysis.
The immunoperoxidase procedure (avidin-biotin-complex method) was performed with paraffin-embedded sections based on a method described previously (13 , 14) . Positive staining in endothelial cells in each specimen was used as an internal positive control. Stained sections were evaluated in a blinded manner without prior knowledge of the clinicopathological parameters. Staining intensity in the cytoplasm of the tumor cells was shown in comparison to that of endothelial cells and categorized as follows: weaker (level 1) or equal to or stronger (level 2) than that of endothelial cells. When the staining intensity of the tumor cells differed among areas in the same specimen, the predominant pattern was chosen. Cases with negative staining of endothelial cells were regarded as having poor antigen preservation and excluded from additional analysis.

Quantitative Reverse Transcription-PCR Analysis of VCP Expression.
Quantitative RT-PCR was performed using the fresh frozen samples from 10 patients with PCA who underwent radical prostatectomy as described previously (13) . Briefly, 10 serial slices sections were cut 10-µm thick from each frozen sample. Under macroscopic observation, areas containing tumor tissues were chosen and sectioned and were collected into an Eppendolf tube, then total RNA was extracted using TRIzol reagent (Invitrogen, Carlsbad, CA). Ten µg of DNase I-treated total RNA were used for reverse transcription with Superscript II (Invitrogen). An aliquot of 100 ng of input RNA was amplified by quantitative real-time PCR using a TaqMan PCR Reagent Kit (Applied Biosystems, Foster City, CA; Refs. 16 , 17 ). The forward primer 5'-TCACCCACACTGTGCCCATCTACGA-3', reverse primer 5'-CAGCGGAACCGC-TCATTCGCCAATGG-3', and probe 5'-6-caboxyfluorescein (FAM)-ATGCCC-6-carboxytetramethylrhodamine (TAMRA)-CCCCCATGCCATCCTGCGT-3' were used for the amplification of ß-actin and the forward primer 5'-AAACCGTGGTAGAGGTGCCA-3', reverse primer 5'-CTTGGAAGGTGTC-ATGCCAA-3', and probe 5'-(FAM)-CAGTATCCTGTGGA-GCACCCAGACAAATTC-(TAMRA)-3' for VCP. RNA ex-tracted from a noncancerous prostatic sample in 1 patient was used as a standard. After reverse transcription, standard cDNA was serially diluted to obtain five standard solutions for use in PCR to generate the reference curve. The relative amount of cDNA in each sample was measured by interpolation on the standard curve (16) and then the relative ratio of VCP/ß-actin expression was calculated for each PCA sample. One paraffin-embedded section from each sample was used for the immunohistochemistry of VCP.

Statistics.
Statistical analysis was performed using JMP software (SAS Institute, Inc., Cary, NC). The correlation between the expression level of VCP at quantitative RT-PCR and immunohistochemistry was evaluated by one-way ANOVA. Correlation between VCP expression at immunohistochemistry and clinicopathological parameters was evaluated using the {chi}2 test and Fisher’s exact probability test. The follow-up period measured from the date of start of therapy for survivors ranged from 2.7 to 181.5 months (mean, 54.5 months). Progression-free and overall survival rates were calculated using the Kaplan-Meier method (18) , and differences in survival curves were estimated with the log-rank test. Independent prognostic factors were analyzed using the Cox proportional hazards regression model in a stepwise manner (19) . P < 0.05 denoted the presence of a statistically significant difference.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
VCP Expression in PCA.
Four (2.9%) of 136 sections that did not show endothelial staining by immunohistochemistry were regarded as having poor antigen preservation and excluded from additional analysis. The remaining 132 cases showing endothelial staining were evaluated for VCP expression. Twenty-eight cases showed a constant level 1 staining in the cytoplasm in every area of the tumor, whereas 4 cases showed level 2 staining in the peripheral zone but level 1 staining in the larger central area of the tumor (Fig. 1)Citation . In total, 32 cases (23.5%) were regarded as having level 1 VCP expression. The remaining 100 cases (73.5%) showed predominant (14 cases) and constant (86 cases) level 2 staining throughout the tumors and thus were regarded as having level 2 VCP expression.



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  		Fig. 1. A and B, valosin-containing protein (VCP) level 1 prostate cancer. Tumor cells are weakly stained with VCP compared with the endothelial cells. C and D, VCP level 2 prostate cancer. Tumor cells show strong VCP staining similar to that of endothelial cells (magnification, x100).

 
Quantitative RT-PCR analysis was performed in 5 PCA cases with level 1 and 5 with level 2 VCP expression. The relative ratio of VCP/ß-actinexpression in cases with level 1 and 2 expression was 1.8 ± 1.3 and 8.4 ± 5.0 (mean ± SD), respectively (P < 0.05; Fig. 2Citation ). All but 1 of the level 1 cases showed a lower VCP expression than the level 2 cases on RT-PCR analysis.



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  		Fig. 2. Relative ratio of VCP/ß-actinmRNA expression in prostate cancer (PCA) with valosin-containing protein (VCP) level 1 and 2. All but one case of level 1 PCA showed lower ratios than cases of level 2 PCA (P < 0.05). Bars: mean ± SD.

 
Uni- and Multivariate Analysis for Prognostic Factors in PCA.
A significant difference was observed between cases with level 1 and 2 VCP expression in the presence of an elevated serum PSA level (>=20 ng/ml; 25.8% in level 1 and 65.7% in level 2), positive DRE (43.8% in level 1 and 67.7% in level 2), increased cancer volume (7.1% in level 1 and 80.7% in level 2), high Gleason score (>=7; 18.8% in level 1 and 84.0% in level 2), and high stage (C-D; 37.5% in level 1 and 81.0% in level 2; Table 1Citation ). The 5-year progression-free and overall survival rate was 55.1% and 66.2%, respectively. Progression during the course with regard to PSA failure and relapse of tumors was found in 40 and 24 patients, respectively. The significance of VCP expression for progression-free and overall survival was analyzed. Patients with level 1 PCA had better 5-year survival rates than those with level 2 PCA (Fig. 3Citation ; Table 2Citation ). Progression of PCA was found in three (9.4%) of 32 level 1 patients at 42.0 ± 27.1 (mean ± SD) months after initial therapy and in 64 (64.0%) of 100 level 2 patients at 27.0 ± 25.1 months (P < 0.0001).


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  		Table 1 Association between VCPa expression and clinicopathological factors

 


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  		Fig. 3. Progression-free (A) and overall (B) survival of patients with valosin-containing protein (VCP) level 1 and 2 prostate cancer. A significant difference was observed between the two groups.

 

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  		Table 2 Univariate analysis of clinicopathological factors for progression-free and overall survival of patients with prostate cancer

 
Univariate analysis revealed that serum PSA level, stage, Gleason score, and cancer volume also were significant factors for progression-free and overall survival (Table 2)Citation . Positive DRE significantly affected progression-free survival but not overall survival. Multivariate analysis was performed with factors proven to be significant in the univariate analysis, revealing VCP expression level, Gleason score, and serum PSA level to be independent prognostic factors for progression-free and overall survival (Table 3)Citation .


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  		Table 3 Multivariate analysis of clinicopathological factors for progression-free and overall survival of patients with prostate cancer

 
New Grading System.
According to the results of the multivariate analysis, a new grading system was introduced. One point was given for VCP level 2, Gleason score >= 7, and serum PSA level >= 20 ng/ml. The points were summed, and PCA patients were divided into four groups according to the total: grades 0, 1, 2, and 3 for 0, 1, 2, and 3 points, respectively. The 5-year progression-free and overall survival rate for grades 0, 1, 2, and 3 was 100, 100, 54.2, and 27.2% and 100, 100, 61.4, and 52.7%, respectively, (Fig. 4)Citation . A significant difference was observed between grades 0 and 1 and grades 2 and 3 for both progression-free and overall survival (P < 0.0001 and P < 0.01, respectively).



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  		Fig. 4. Five-year survival rate for each grade in the new grading system was 100, 100, 54.2, and 27.2% for progression-free (A, P < 0.0001) and 100, 100, 61.4, and 52.7% for overall survival (B, P < 0.01).

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The natural course of PCA is variable and difficult to predict. Silent PCAs of microscopical size are observed in up to 30% of all men >=50 years throughout the world (20 , 21) . In most instances, tumors remain localized to the prostate and asymptomatic throughout life. Such a PCA is known as a latent cancer. On the other hand, once tumors manifest an aggressive character, local invasiveness and distant metastasis mainly to the bone occur; therefore, PCA could be the main cause of cancer death in males.

The introduction of a method of measuring serum PSA and an increase in public awareness of the disease has enabled early detection of PCA (22 , 23) . Radical prostatectomy became one of the main modalities for the treatment of PCA in the 1990s and was proved to successfully decrease disease-specific mortality compared with watchful waiting (3) . Because PCA usually affects the elderly and often those with other medical complications, it is desirable to avoid radical surgery. Therefore, prediction of the aggressiveness of PCA is essential to adopt the appropriate therapeutic modality for each PCA patient. For this purpose, the prognostic use of several biological markers such as p53 expression (24) and DNA ploidy pattern (25) has been evaluated. The present study was conducted to clarify whether VCP expression could be used to evaluate the necessity of radical prostatectomy for PCA patients. In other words, whether control failure in PCA patients treated with conservative therapy is predictable or not was evaluated.

The present series included 136 patients treated with conservative therapy such as watchful waiting, androgen deprivation, or radiation therapy. The patients’ characteristics such as age, serum PSA level, and 5-year survival rates in the present series were similar to previous studies on patients treated with conservative therapy (26) . Uni- and multivariate analyses revealed a prognostic significance of stage, Gleason score, and serum PSA level, as reported previously (6, 7, 8 , 27) . These findings indicate that the results obtained from the present patients are applicable to PCA in other countries.

VCP is involved in the ubiquitin/proteasome-dependent protein degradation pathway, which plays an essential role in controlling the levels of various cellular proteins and therefore regulates basic cellular processes such as cell cycle progression, signal transduction, and cell transformation (11 , 12 , 28) . Actually, VCP was shown to have a role in a number of cellular activities such as cell cycle transition and growth control (11) and thus is postulated to play a crucial role in tumor invasion and metastasis.

VCP expression at the mRNA and protein level determined by quantitative RT-PCR and immunohistochemical analyses, respectively, was examined in 10 cases, and a clear correlation was found between the two measurements. The present results together with our previous study on hepatocellular carcinomas (13) and the study by Muller et al. (29) on murine tissues indicated the reliability of immunohistochemistry in the measurement of VCP expression.

Among the clinicopathological factors examined, a significant correlation with level 2 VCP expression was observed for increased serum PSA level, positive DRE, increased cancer volume, high Gleason score, and high stage. These findings are consistent with our previous reports showing a correlation of VCP overexpression with increased metastatic potential of tumor cells in an experimental metastasis model (10) and increased recurrence rate and poor prognosis of hepatocellular carcinoma and gastric carcinoma in clinical samples (13 , 14) .

The present uni- and multivariate analyses revealed the VCP expression level to be an independent prognosticator for progression-free and overall survival. Progression of PCA was found in only 9.4% of level 1 patients but in 64% of level 2 patients. In addition, the interval between initial treatment and disease progression was longer in level 1 than level 2 patients. Gleason score and serum PSA level were also independent prognostic factors. The grading system combining these three factors will be useful for choosing the most appropriate therapeutic modality for each patient with PCA. For patients with grade 0–1 PCA, the risk of tumor recurrence after conservative therapy is very low, and therefore, conservative therapy is recommended as an initial treatment. In patients with grade 2–3 PCA, however, a high rate of recurrence is predicted and radical prostatectomy should be the choice.

In conclusion, VCP expression as determined by immunohistochemistry could be used as an indicator in choosing the initial treatment modality. For additional evaluation of the advantages of radical prostatectomy in the treatment of PCA, the prognostic significance of VCP expression among patients who receive radical prostatectomy should be evaluated.


   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.

Requests for reprints: Yasuhiko Tomita, Department of Pathology (C3), Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Phone 81-6-6879-3711; Fax: 81-6-6879-3719; E-mail: yt{at}molpath.med.osaka-u.ac.jp

Received 9/ 9/03; revised 1/ 9/04; accepted 1/20/04.


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 RESULTS
 DISCUSSION
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