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Clinical Cancer Research Vol. 10, 651-657, January 2004
© 2004 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Expression of Valosin-Containing Protein in Colorectal Carcinomas as a Predictor for Disease Recurrence and Prognosis

Shinji Yamamoto1, Yasuhiko Tomita2, Yoshihiko Hoshida2, Masato Sakon1, Masao Kameyama3, Shingi Imaoka3, Mitsugu Sekimoto1, Shoji Nakamori1, Morito Monden1 and Katsuyuki Aozasa2

1 Departments of Surgery and Clinical Oncology and 2 Pathology, Osaka University Graduate School of Medicine, Osaka, and 3 Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Osaka, Japan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: Valosin-containing protein (VCP or p97) is associated with antiapoptotic function and metastasis via activation of the nuclear factor-{kappa}B signaling pathway. The present study was designed to investigate the prognostic significance of VCP expression in colorectal adenocarcinoma.

Experimental Design: We analyzed VCP expression immunohistochemically in 129 patients with colorectal carcinoma ages 35–84 years. The staining intensity of tumor cells was categorized as either weaker-to-equal (low VCP expression) or stronger (high expression) than that in noncancerous colonic mucosa. We also analyzed 8 colorectal adenomas and 10 metastatic foci.

Results: Low VCP expression was noted in 41 (31.8%) cases and high expression in 88 (68.2%) cases. A low level of VCP expression was noted in all adenomas, whereas a high level was seen in all metastatic tumors. A significant difference was observed in depth of invasion (T1–2 versus T3–4, P < 0.05), presence or absence of venous invasion (P < 0.05), and tumor stage (I and II versus III and IV; P < 0.05) between adenocarcinomas with low and high VCP expression. Patients with high VCP-expressing tumors had a higher recurrence rate (P < 0.001) and poorer disease-free and overall survival (P < 0.01 and P < 0.05, respectively) compared with the low expression group. Multivariate analysis revealed VCP expression level to be an independent prognosticator for both disease-free and overall survival. VCP level was an indicator of disease-free survival in both stage II and III (pathological Tumor-Node-Metastasis classification, P < 0.05 and <0.01, respectively).

Conclusions: A high expression level of VCP in tumors is a poor prognostic marker in patients with colorectal carcinomas.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Colorectal carcinoma is one of the most common cancers worldwide and is the second leading cause of cancer mortality in the United States (1) . The prognosis of patients with colorectal carcinomas has improved during the last decade because of advances in screening and early detection; however, ~30% of patients who undergo curative resection die within a few years after surgery (2) . The main cause of the unfavorable prognosis is tumor metastasis, mainly to the liver (3) . It has been reported that tumor cell metastasis is not a random event but that it arises from a tumor cell subpopulation with higher metastatic potential, which has a variety of specific biological characteristics (4) . Therefore, identification of novel informative indices to apply at the time of surgery for primary colorectal carcinomas may aid in identifying tumors with higher metastatic potential. This could lead to improved prognostication and hence more appropriate therapeutic approaches with adjuvant treatments.

At present, the pathological stage of tumors according to the Tumor-Node-Metastasis staging system (pTNM stage; Ref. 5 ) is regarded as one of the most important predictors of risk of recurrence after potentially curative resection for colorectal adenocarcinoma (2) . However, prognoses of patients with colorectal carcinomas vary, even within tumors of the same stage (3) , and therefore identification of additional factors predicting recurrence of the tumor would be advantageous.

Recently, we have applied the mRNA subtraction technique and identified the gene encoding valosin-containing protein (VCP; also known as p97) as being associated with metastasis of a murine osteosarcoma cell line (6) . VCP, a member of the "ATPases associated with various cellular activities" superfamily, plays a key role in the ubiquitin-dependent proteasome degradation pathway (7) . In particular, VCP inhibits apoptosis after stimulation with cytokines such as tumor necrosis factor via degradation of inhibitor {kappa}B{alpha}, an inhibitor of nuclear factor-{kappa}B (NF-{kappa}B; Ref. 7 ). Murine osteosarcoma cells transfected with the VCP gene exhibited constant activation of NF-{kappa}B, rapid degradation of phosphorylated-inhibitor {kappa}B{alpha}, decreased apoptosis rates after tumor necrosis factor {alpha} stimulation, and increased metastatic potential (6) . These results indicated the importance of VCP in the metastatic process in experimental models.

In the present study, we analyzed the expression level of VCP in human colorectal carcinomas by immunohistochemistry and assessed its correlation with tumor recurrence and prognosis.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients.
A total of 129 patients who underwent surgery for primary colorectal carcinomas at the Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases (Osaka, Japan), during the period from August 1984 to September 1992, was selected for the present study. Patients who had undergone preoperative chemotherapy or radiotherapy were not included in the present study. A total of 107 patients was treated with curative resection on the basis of clinical and pathological findings, and 22 were treated with noncurative resection because of the presence of unresectable metastatic tumors in distant organs. The study group consisted of 82 males and 47 females with ages ranging from 35 to 84 (median, 61) years. All of the resected primary tumors were examined macroscopically to determine location, size, and extent and mode of invasion. Tumors were located in the proximal colon in 26 patients and either the distal colon or rectum in 103 patients. Tumor size ranged from 0.7 to 11 cm (4.7 ± 2.0 cm). Samples obtained at surgery were fixed in 10% formalin and routinely processed for paraffin embedding. Histological sections cut at 4 µm were stained with H&E and immunoperoxidase procedures (avidin-biotin complex method). Histological sections were reviewed to define extent and mode of cancer invasion in the colorectum, lymph node metastasis, and histological subtype. The stage of the disease was classified according to the pTNM staging system (5) .

All patients received standardized follow-up examinations, including laboratory tests such as routine blood count and serum carcinoembryonic antigen level at 1–6-month intervals, chest X-ray, liver ultrasound, computerized tomographic scan of the abdomen and pelvis at 6-month intervals, and endoscopic colonoscopy at 1-year intervals during the first 3 postoperative years and at 6–12-month intervals thereafter. Postoperative adjuvant chemotherapy with fluorouracil was performed on all of the stage III and IV patients but was not applied to stage I and II patients. The mean observation time for survivors was 63.8 months.

Immunohistochemical Analysis.
Immunohistochemistry was performed using paraffin-embedded tissue sections with an immunoperoxidase procedure (avidin-biotin complex method). Briefly, antigen retrieval was performed by heating the deparaffinized rehydrated sections in 10 mM citrate buffer for 5 min. Mouse monoclonal anti-VCP (p97) antibody (PROGEN Biotechnik, Heidelberg, Germany) was used as the primary antibody at a final dilution of 1:3000. Sections were lightly counterstained using methylgreen. For negative controls, nonimmunized mouse IgG (Vector Laboratories, Burlingame, CA) was used as the primary antibody. Stained sections were evaluated in a blinded manner without prior knowledge of the clinicopathological features of patients. Staining intensity in the cytoplasm of tumor cells was categorized as follows: weaker-to-equal (low VCP expression) or stronger (high expression) than that in noncancerous colonic mucosa, which was determined as the positive control. Cases showing combined high- and low-intensity staining in different areas of the tumors were classified into the high-intensity group. Immunohistochemical analysis for VCP expression was performed in 129 primary colorectal carcinomas together with 10 cases of its metastatic foci in the liver and 8 cases of colorectal adenomas resected by polypectomy.

Statistical Analysis.
Statistical analyses were performed using JMP software (SAS Institute, Inc., Cary, NC). The {chi}2 test and Fisher’s exact probability test were used to analyze the correlation between VCP expression on immunohistochemistry and clinicopathological features. Kaplan-Meyer methods with the log-rank test were used to calculate overall survival rates and differences in survival curves (8) . Cox’s proportional hazards regression model with stepwise analysis was used to analyze the independent prognostic factors (9) . Ps of <0.05 were considered as statistically significant.


   RESULTS
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 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Expression of VCP in Colorectal Carcinoma.
Immunohistochemical assays were performed on 129 patients with adenocarcinoma of colon and rectum and their matched nontumor tissues in the same section. In both normal colorectal mucosa and colorectal carcinoma, VCP expression was observed predominantly in the cytoplasm (Fig. 1, B, D, F, and G)Citation . In contrast, no staining was observed when the primary antibody was substituted with nonimmunized mouse IgG. Forty tumors (31.0%) exhibited evenly distributed high VCP expression in every area of the tumor (Fig. 1, E and F)Citation , whereas 48 (37.2%) had high expression at the infiltrating marginal areas but low expression in the remaining main tumor. In total, 88 tumors (68.2%) were classified into the high VCP expression group. The remaining 41 tumors (31.8%), with constant low VCP immunoreactivity (Fig. 1, C and D)Citation , were classified as the low expression group. All 8 cases of colorectal adenoma showed low VCP expression (Fig. 1, A and B)Citation , and all 10 cases of metastatic foci in the liver showed high VCP expression (Fig. 1G)Citation .



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  		Fig. 1. A and B, normal mucosa (top) and adenoma (bottom) of the colon. Both normal mucosa and adenoma show faint valosin-containing protein (VCP) staining in the cytoplasm (A, H&E; B, VCP immunohistochemistry; scale bar: 200 µm). C and D, well-differentiated colorectal adenocarcinoma with low VCP expression. Tumor cells exhibited weak VCP staining in the cytoplasm (C, H&E; D, VCP immunohistochemistry). E and F, moderately differentiated colorectal adenocarcinoma with high VCP expression. Tumor cells show strong VCP staining (E, H&E; F, VCP immunohistochemistry). G, metastatic foci of colorectal adenocarcinoma in the liver. Tumor cells show strong VCP staining.

 
Relationship between VCP Staining Status in Colorectal Carcinoma and Clinicopathological Features.
Table 1Citation shows the relationship between various clinicopathological features and VCP expression. Mean size of the tumor was 4.7 cm. There were no significant differences between low and high VCP expression groups with regard to age, gender, location of primary tumor, tumor size, histological type, microscopic lymphatic invasion, and lymph node invasion. However, significant differences were observed in depth of invasion (T1–2 versus T3–4 of pTNM classification, P < 0.05), presence or absence of venous invasion (P < 0.05), and tumor stage (I and II versus III and IV of pTNM classification, P < 0.05) between the two groups.


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  		Table 1 Relationship between valosin-containing protein (VCP) expression and clinicopathological factors of 129 patients with colorectal carcinoma

 
The association between sites and frequency of recurrent tumors and VCP expression in the primary tumors in 107 patients who received curative resection is summarized in Table 2Citation . Patients undergoing noncurative operations were eliminated from additional analyses because unresectable metastatic tumors might have contributed to poor survival and would not facilitate precise analysis of recurrence. The high expression group had a significantly higher recurrence rate than that of the low expression group (P < 0.01). The difference was far more marked when limited to distant metastasis (20 of 70 in the high expression group versus 1 of 37 in the low expression group; P < 0.01). All 11 cases presenting with liver metastasis after surgery belonged to the high expression group (P < 0.01).


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  		Table 2 Recurrence pattern of colorectal carcinoma according to valosin-containing protein (VCP) expression

 
Survival Analysis.
The prognostic significance of VCP expression was analyzed for disease-free and overall survival in 107 patients undergoing curative resection. Patients with low VCP expression had better 5-year survival rates than did the high expression group (disease free: 93.9 versus 66.8%, P < 0.01; overall: 93.8 versus 77.3%, P < 0.05; Fig. 2Citation and Table 3Citation ). Clinicopathological features such as histological differentiation, depth of invasion, and presence of lymph node metastasis were significant factors for both disease-free and overall survival (Table 3)Citation . Venous invasion was significant for disease-free survival but not for overall survival, and tumor size was significant for overall survival but not for disease-free survival. Multivariate analysis was performed with factors proven to be significant in the univariate analysis. This revealed that VCP expression level, lymph node metastasis, and histological differentiation were independent prognostic factors for disease-free survival and that VCP expression level, lymph node metastasis, and depth of invasion were independent prognostic factors for overall survival (Table 4)Citation .



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  		Fig. 2. Disease-free (A) and overall (B) survival of patients with low and high valosin-containing protein (VCP)-expressing colorectal adenocarcinomas. A significant difference was observed between the two groups (A, P < 0.01; B, P < 0.05).

 

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  		Table 3 Univariate analysis of clinicopathological factors for disease-free and overall survival of 107 patients with colorectal carcinoma

 

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  		Table 4 Multivariate analysis of clinicopathological factors for disease-free and overall survival of patients with colorectal carcinoma

 
Prognostic Significance of VCP Expression According to pTNM Classification.
The prognostic significance of VCP expression was additionally analyzed in patients with colorectal carcinoma according to the pTNM classification (5) . There was no significant difference in the disease-free survival between the low and high VCP expression groups in patients with stage I disease in which recurrence is infrequent with good prognosis (Fig. 3A)Citation . However, there were significant differences in disease-free survival in stages II and III patients. In detail, among 37 patients with low VCP expression, only 2 patients with stage I disease had local recurrence, and none had recurrence in stages II and III (Fig. 3, B and C)Citation .



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  		Fig. 3. Disease-free survival of patients with low and high valosin-containing protein (VCP)-expressing colorectal adenocarcinomas in each pathological Tumor-Node-Metastasis stage. A significant difference was observed between the two groups for stage II (B, P < 0.05) and stage III (C, P < 0.01). N.S., not significant.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Several biological factors such as somatic gene mutations in p53 (10 , 11) and K-ras (10 , 11) and modulated expression of carbohydrate antigens (12) have been proposed as candidates for prognostic indicators in colorectal carcinomas; however, the precise mechanism underlying metastasis of colorectal carcinomas has not yet been clarified. We undertook the present study in an attempt to determine whether VCP expression status might be a valid prognosticator for these tumors.

In the present study, VCP expression level was examined by immunohistochemical analysis. Clear correlation in VCP expression between mRNA and protein level has been reported by us (13) in cases with hepatocellular carcinomas and Muller et al. (14) in murine nontumoral tissue using reverse transcription-PCR and immunohistochemistry and in situ hybridization and immunohistochemistry, respectively, indicating the reliability of immunohistochemistry for evaluation of VCP expression.

All 8 cases of colorectal adenoma had low VCP expression levels, and all 10 hepatic metastatic foci had high expression levels. Of the colorectal adenocarcinomas, 41 of 129 expressed low VCP levels, and the remaining 88 expressed high levels of VCP. The accumulation of sequential mutations in genes such as adenomatous polyposis coli, K-ras, and p53 has been known to be the main process of colorectal tumorigenesis (15) . However, genes involved in the acquisition of metastatic potential have not yet been clarified. Our demonstration of high VCP expression in all hepatic metastatic foci, about two-thirds of primary colorectal carcinomas, and no benign adenomas indicates that modulated expression of VCP is a late event in tumorigenesis and might be crucial in the acquisition of metastatic potential.

The mechanism underlying increased VCP expression in colorectal adenocarcinomas compared with their nontumoral counterparts is not clear at present. The nucleotide sequence of the 5'-flanking region of VCP contains consensus-binding sites for several transcriptional activators, suggesting complex regulation of VCP expression (14) . VCP is a target gene of Pim-1, a proto-oncogene serine/threonine-protein kinase (16) Therefore, expression of VCP could be regulated by several oncogenes or antioncogenes, whereas influences of key genes in colorectal carcinogenesis such as p53 and K-ras have not been elucidated. Enhanced VCP expression was demonstrated in a metastatic variant of a murine melanoma cell line (17) . These findings suggest that VCP expression is under precise control but that it increases in cancer cells in association with acquisition of metastatic potential. Additional investigations are required to elucidate the mechanism of modulation of VCP expression in malignant tumors.

Among the clinicopathological factors examined, a significant correlation was observed between VCP expression and depth of invasion, presence or absence of venous invasion, and distant metastasis. These findings could be consistent with those of our previous in vitro study in which VCP overexpression is correlated with the increased metastatic potential of tumor cells in an experimental metastasis model (6) . Because successful tumor formation in the circulation and distant organs require activation of antiapoptotic pathways, including NF-{kappa}B signaling (18) , VCP may has an antiapoptotic effect via up-regulation of NF-{kappa}B signaling by influencing the degradation process of cytoplasmic phosphorylated inhibitor {kappa}B{alpha}, an inhibitor of NF-{kappa}B, as shown in our previous in vitro study (6) . Although our preliminary results with immunohistochemical detection of NF-{kappa}B expression failed to show the significant difference in staining intensity between colorectal carcinoma with high and low VCP expression, colon cancer cells with high metastatic potential could have the increased antiapoptotic potential in association with up-regulated NF-{kappa}B and down-regulated inhibitor {kappa}B{alpha} expression (19) . Additional studies should be needed to clarify the mechanism behind the present findings.

In this study, univariate and multivariate analyses revealed the VCP expression level to be an independent prognosticator for recurrence of colorectal carcinoma and patient survival. In addition, the VCP level proved to be a prognosticator for recurrence of the disease in lymph node-positive patients (stage III) as well as node-negative patients (stage II): 5-year disease-free survival rate in patients with low and high VCP expression was 100 and 72.8% at stage II and 100 and 48.4% at stage III, respectively. Although lymph node metastasis is an indicator of poor prognosis of patients with colorectal carcinomas, heterogeneity of the prognosis among patients with positive lymph nodes has been a problem (20) . The present study has clearly demonstrated the usefulness of VCP expression in predicting distant metastasis in node-positive patients.

In conclusion, VCP expression as determined by immunohistochemistry could be used as a new prognosticator for colorectal carcinomas. Stratification of colorectal carcinoma patients based on the stage of disease and VCP expression levels should be a useful tool for predicting tumor recurrence and patient prognosis. This system might represent a novel way to explore effective treatment modalities for colorectal carcinoma.


   FOOTNOTES
 
Grant support: Grants-in-aid for the Second Term Comprehensive 10-Year Strategy for Cancer Control and Cancer Research from the Ministry of Health and Welfare, Japan, and Grants-in-aid for Scientific Research on Priority Areas, and Basic Research from the Ministry of Education, Science, Sports, and Culture, Japan.

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: Shoji Nakamori, Department of Surgery and Clinical Oncology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita Osaka 565-0871, Japan. Phone: 81-6-6879-3251; Fax: 81-6-6879-3259; E-mail: nakamori{at}surg2.med.osaka-u.ac.jp

Received 12/20/02; revised 9/30/03; accepted 10/10/03.


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 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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