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Clinical Cancer Research Vol. 8, 3205-3209, October 2002
© 2002 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Overexpression of the Peripheral Benzodiazepine Receptor Is a Relevant Prognostic Factor in Stage III Colorectal Cancer1

Kerstin Maaser2, Patricia Grabowski2, Andreas P. Sutter, Michael Höpfner, Hans-Dieter Foss, Harald Stein, Gerd Berger, Moshe Gavish, Martin Zeitz and Hans Scherübl3

Medical Clinic I [K. M., P. G., A. P. S., M. H., M. Z., H. S.], Institute of Pathology [H-D. F., H. S.], and Department of Surgery [G. B.], University Hospital Benjamin Franklin, Free University of Berlin, 12200 Berlin, Germany, and Department of Pharmacology, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, 31096 Haifa, Israel [M. G.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: The peripheral benzodiazepine receptor (PBR) has been implicated in the growth control of colorectal cancer, where PBR-specific ligand-binding is increased 3–4-fold. However, the prognostic relevance of PBR (over) expression has not yet been evaluated in colorectal cancer.

Experimental Design: A 5-year follow-up was performed in 116 consecutive patients undergoing surgery for colorectal cancer with regional or distant metastases [Union International Contre le Cancer (UICC) stage III, 59 patients; UICC stage IV, 57 patients]. The monoclonal anti-PBR antibody 8D7 was used for immunohistochemical examination of paraffin-embedded sections. PBR-specific staining was compared in cancer tissues and normal mucosa. Kaplan-Meier survival curves were calculated.

Results: Twenty-eight % of the colorectal cancers strongly overexpressed PBR. The mean survival of patients with stage III cancer was 56.2 ± 9.2 months with and 86.8 ± 6.6 months without high overexpression of PBR (P = 0.006). Univariate and multivariate analyses revealed that high PBR overexpression is an independent unfavorable prognostic factor in stage III colorectal cancer. In stage IV, however, the PBR status did not correlate with different survival times.

Conclusions: Strong PBR overexpression is a new independent prognostic marker in stage III colorectal cancer. Evaluating PBR overexpression may be useful for stratifying risk and developing risk-adapted strategies of adjuvant therapy.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Colorectal carcinoma is the second most common cause of cancer death in Western countries. The prognosis of colorectal carcinoma correlates closely with the pathological staging (1) . However, even the Tumor-Node-Metastasis classification (UICC4 I-IV) predicts prognosis only within a wide range. Thus, additional prognostic markers are needed to predict survival more precisely.

The PBR has been implicated in tumor growth (2) . Binding of PBR-specific ligands is increased in several tumor entities, including cancer of the colon (3) , brain (4) , breast (5) , ovary (6 , 7) , and liver (8) . PBR is an Mr 18,000 D protein located mainly in the outer mitochondrial membrane but also found in the plasma membrane and perinuclear region (2) . Almost all tissues express PBR, although to widely varying degrees. Levels of PBR expression are particularly high for organs involved in steroidogenesis but low for normal gut mucosa (9) . Although the functions of the PBR are not yet fully understood, there is good evidence for its involvement in steroid biosynthesis (10) . Moreover, it does play an important role in the proliferation of cancer cells (5 , 11, 12, 13, 14) . We showed recently that specific PBR ligands induced both apoptosis and cell cycle arrest in colorectal cancer (15) .

Despite its overexpression and its emerging importance in the regulation of colorectal cancer growth, the PBR has not yet been investigated for its possible prognostic value. The aim of this study was to determine whether the extent of PBR overexpression correlated with survival in stage III-IV colorectal cancer.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients.
Between 1989 and 1991, 116 consecutive patients with colorectal carcinoma UICC III-IV underwent primary tumor resection at the University Hospital Benjamin Franklin (Free University of Berlin, Germany). A complete follow-up of all patients was documented for at least 5 years or until death. There were 59 patients (35 women and 24 men) in UICC stage III and 57 (26 women and 31 men) in UICC stage IV. The mean age was 63.4 years (range, 26–87 years) for UICC III patients and 66.1 years (range, 42–87 years) for UICC IV patients. Only 3 of the 59 patients with colorectal cancer stage UICC III received adjuvant chemotherapy. Clinicopathological parameters have already been described elsewhere (16) .

Immunohistochemical Staining.
Microsections (2–3 µm) of paraffin-embedded primary tumors were deparaffinized and rehydrated in a decreasing alcohol series (16 , 17) . Immunohistochemistry was performed using a robotic system (Chemo-mate; DAKO, Heidelberg, Germany). Sections were incubated with the anti-PBR antibody 8D7 (0.5 µg/ml) for 30 min at room temperature. The antibody was kindly provided by P. Carayon (Sanofi-Synthelabo, Montpellier, France) (18) . After washing, samples were incubated with antimouse IgG (1:20 dilution) for 30 min at room temperature, and staining was detected by the "fast-red system" (DAKO). Samples were slightly counterstained in Mayer’s hematoxylin.

Semiquantitative Evaluation of PBR Staining.
Tissue staining was independently scored by two of the authors (K. M. and P. G.) with a variation of <10%. The staining intensity of tumor tissue was compared with that of the corresponding normal mucosa for each patient (0, no increase; 1, weak increase; 2, moderate increase; 3, strong increase). A score of 0–12 was calculated as the product of the increase in staining intensity and the frequency of stained cancer cells (0, 0%; 1, 1–25%; 2, 26–50%; 3, 51–75%; 4, 76–100%). The overexpression was rated as low (score <=6) or high (score >6).

Statistical Analysis.
The nonparametric Mann-Whitney U test was used to compare data between groups. Overall survivals were assessed by the Kaplan-Meier method, and the significance of differences was calculated by the log-rank test. Univariate and multivariate analyses were performed by the Cox regression model. Therefore, variables were used as dichotomized (categorical) variables: T-stage (T4 versus T1–3), N-stage (N2 versus N1), grading (G3 versus G1–2), tumor localization (rectum/rectosigmoid versus colon), age (>67 years versus <67 years), and PBR overexpression (PBRhigh versus PBRlow). Differences of P < 0.05 were considered to be significant. All statistical analyses were performed using SPSS software.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Survival of the Patients.
All patients were followed-up for at least 5 years or until death. The median follow-up period was 17 months with a range of 1–112 months. The 5-year survival was 54.2% for UICC stage III and 2% for UICC stage IV patients. Because survival differed between UICC stage III and IV patients (Mantel-Cox log-rank test, P < 0.0001), the following analyses were performed separately for each stage.

PBR Overexpression in Colorectal Carcinomas.
The immunohistochemical analysis showed that all colorectal tissues expressed PBR. PBR was detectable in the cytoplasm of both cancer cells and normal mucosa cells but not in the plasma membranes or nuclei (Fig. 1)Citation . PBR was homogeneously expressed in normal mucosa tissues (Fig. 1C, F, G, I)Citation , whereas the expression in tumor tissues was unevenly distributed (Fig. 1E)Citation . The expression levels of PBR in normal mucosa varied among different patients. Most normal epithelia displayed a low to intermediate PBR expression, and only four normal epithelia tissues showed high PBR expression. Therefore, the PBR staining score in tumor tissues was estimated in comparison with the corresponding normal mucosa of the same patient, and only tumor cells with a higher PBR expression than the corresponding mucosa cells were classified as PBR-overexpressing cells. In 88% of the colorectal carcinomas (stage III, 90%; stage IV, 86%), PBR was overexpressed in the tumor tissues. Only one tumor showed lower PBR expression than normal mucosa. In 11% of colorectal cancers (stage III, 10%; stage IV, 12%), PBR expression was the same as in normal mucosa. The staining score of PBR overexpression ranged from 0 to 12 with a mean of 4.3 ± 3.3. The Mann-Whitney t test revealed no significant PBR staining difference between stage III and stage IV cancers. The PBR staining score did neither correlate with the T-stage, N-stage, nor tumor localization (Fig. 2)Citation , nor with the histopathological grading, age, or sex in either stage III or stage IV patients.



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  		Fig. 1. Immunohistochemical detection of PBR. Immunohistochemical detection of PBR (red) in colorectal cancers (A, B, E, G ca, and H) and corresponding normal mucosa (C, F, G mu, and I). D, negative control staining. A–D, stage IV cancer of the sigmoid colon, score (PBR) = 12. E and F, stage III cancer of the rectum, score (PBR) = 9; 70% of the tumor cells strongly overexpressed PBR (black arrow), and 30% showed no PBR overexpression (white arrow). G, stage IV cancer of the rectum, score (PBR) = 8. H and I, stage III cancer of the cecum, score (PBR) = 0. Bars: A and C–I, 100 µM; B, 20 µM.

 


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  		Fig. 2. Analysis of PBR staining score in relation to clinicopathological parameters. The PBR staining score was analyzed in relation to tumor stage (A). A possible association of PBR expression with other clinicopathological parameters was separately analyzed for stage III (B–D, left panels) and stage IV patients (B–D, right panels). B, depth of infiltration. C, lymph node involvement. D, tumor localization. c, colon; r, rectum; rs, rectosigmoid tumor. In the box plot analysis, median, 25%, 75% percentile, and outliers are shown. None of these parameters displayed a significant difference (Mann-Whitney t test).

 
Strong PBR Overexpression Is an Independent Prognostic Factor.
Twenty-eight % of all tumors (stage III, 31%; stage IV, 25%) showed high overexpression of PBR (PBRhigh). Stage III patients had a mean survival of 86.8 ± 6.6 months (median survival, >112 months) for PBRlow but only 56.2 ± 9.2 months (median survival, 40 months) for PBRhigh tumors. Thus, the PBR status markedly influenced the overall survival of stage III colorectal cancer patients, which was significantly longer for PBRlow than for PBRhigh cancer patients (log-rank test, P = 0.006; Fig. 3Citation ). For stage IV patients, no significant differences in survival times were detected according to PBR status. Stage IV patients had a mean survival of 12.9 ± 2.0 months (median survival, 8 months).



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  		Fig. 3. Cumulative survival of stage III patients in relation to PBR overexpression. Cumulative survival (log-rank test, P = 0.006) differed significantly between stage III patients with PBRlow colorectal cancer (dotted line) and those with PBRhigh cancer (solid line).

 
Univariate Cox regression analysis for stage III patients showed that the overall survival was significantly influenced by the PBR status (P = 0.009), N-stage (P = 0.01), and tumor localization (P = 0.002) but not by other clinicopathological parameters such as the T-stage, grading, age, or sex. Multivariate Cox regression analysis identified PBRhigh overexpression as an independent marker for poor prognosis with a 2.28 times higher relative risk of cancer-related death (P = 0.048). In its predictive power, PBRhigh overexpression was comparable with the N-stage (P = 0.048; relative risk, 2.298), whereas tumor localization had a relative risk of 3.871 (P = 0.005).


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study provides first evidence that strong PBR overexpression is an independent prognostic marker of poor survival in stage III colorectal cancer. Increased binding capacities of PBR-specific ligands have been reported in both colorectal cancer (3) and a variety of other tumor entities (4, 5, 6, 7, 8) . However, direct evidence for PBR protein overexpression was obtained only in astrocytomas and breast cancers. PBR protein expression correlated with the tumor grade in the astrocytomas of 86 patients (19) and was also observed in a few breast cancers and cell lines, where it correlated with cancer malignancy (5 , 12) . In this study, we investigated PBR protein expression in 116 UICC stage III and IV colorectal cancers. Because a certain amount of PBR protein was also detected in normal mucosa, cancer-associated PBR protein expression was quantified in relation to normal mucosa. PBR protein was found to be overexpressed in 102 of the 116 colorectal cancer patients, confirming and supplementing previous results obtained by radioligand assays (3) . Cancer-specific PBR overexpression might form a basis for new diagnostic strategies using positron emission tomography. Radiolabeled PBR-specific ligands have been successfully used to image brain tumors (20) .

Our findings in stage III colorectal cancer are the first to demonstrate a significant correlation between PBR expression and survival within a stage-corrected group of tumor patients. Previous studies correlated PBR expression with the degree of malignancy of brain tumors and thus indirectly with survival. Expression differed between low or intermediate but not between higher grades of malignancy (19) . Our study likewise showed no difference in PBR overexpression between stage III and stage IV colorectal cancers.

Although its biological functions are not yet fully understood, PBR has been associated with apoptotic and mitotic processes. Antiapoptotic functions have been ascribed to the PBR protein itself. It was shown that transfection-induced PBR hyperexpression protected lymphocytes against UV-induced apoptosis (21) . The ability of breast cancer cells to grow in severe combined immunodeficient mice correlated with PBR expression (22) . Moreover, it was shown that PBR correlated positively with proliferation rate but inversely with spontaneous apoptosis in different glioma cell lines (data not shown). These PBR-mediated proliferative and/or apoptosis-protective effects might contribute to the poor prognosis of patients with PBR-overexpressing tumors. In a variety of tumor models, these functions of PBR can be reversed by PBR-specific exogenous ligands (5 , 11, 12, 13, 14, 15) .

The carcinogenesis of colorectal cancer is a well known multistep process requiring accumulating genetic alterations (23) . It progresses from normal epithelial tissues to adenomas, and finally to invasive carcinomas or even metastases. Future studies should investigate the mechanisms regulating PBR overexpression and their possible interactions with already known abnormalities of transcriptional control in colorectal cancer.

In conclusion, this study identified high PBR overexpression as a strong independent predictor of poor survival of stage III colorectal cancer patients. PBR overexpression appears useful for developing risk-adapted strategies of adjuvant therapy. Future clinical studies should evaluate whether PBR overexpression similarly identifies stage II patients that are at high risk for recurrent or metastatic disease.


   ACKNOWLEDGMENTS
 
We thank P. Carayon who generously provided us with the anti-PBR antibody 8D7. We thank C. Cieluch and E. Berg for technical assistance, and we thank W. Hopfenmüller for statistical advice.


   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 study was supported by grants from the Deutsche Forschungsgemeinschaft, the Deutsche Krebshilfe, and the Sonnenfeld Stiftung. Back

2 Both authors contributed equally to this work. Back

3 To whom requests for reprints should be addressed, at Medical Clinic I, University Hospital Benjamin Franklin, Free University of Berlin, Germany, Hindenburgdamm 30, 12200 Berlin, Germany. Phone: 49-30-84453534; Fax: 49-30-84454481; E-mail: hscher{at}zedat.fu-berlin.de Back

4 The abbreviations used are: PBR, peripheral benzodiazepine receptor; UICC, Union International Contre le Cancer. Back

Received 12/28/01; revised 6/11/02; accepted 6/19/02.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Compton C. C., Fenoglio-Preiser C. M., Pettigrew N., Fielding L. P. American Joint Committee on Cancer Prognostic Factors Consensus Conference: Colorectal Working Group. Cancer (Phila.), 88: 1739-1757, 2000.[CrossRef][Medline]
  2. Beurdeley-Thomas A., Miccoli L., Oudard S., Dutrillaux B., Poupon M. F. The peripheral benzodiazepine receptors: a review. J. Neurooncol., 46: 45-56, 2000.[CrossRef][Medline]
  3. Katz Y., Eitan A., Gavish M. Increase in peripheral benzodiazepine binding sites in colonic adenocarcinoma. Oncology, 47: 139-142, 1990.[CrossRef][Medline]
  4. Cornu P., Benavides J., Scatton B., Hauw J. J., Philippon J. Increase in omega 3 (peripheral-type benzodiazepine) binding site densities in different types of human brain tumours. A quantitative autoradiography study. Acta Neurochir., 119: 146-152, 1992.[CrossRef]
  5. Hardwick M., Fertikh D., Culty M., Li H., Vidic B., Papadopoulos V. Peripheral-type benzodiazepine receptor (PBR) in human breast cancer: correlation of breast cancer cell aggressive phenotype with PBR expression, nuclear localization, and PBR-mediated cell proliferation and nuclear transport of cholesterol. Cancer Res., 59: 831-842, 1999.[Abstract/Free Full Text]
  6. Katz Y., Ben-Baruch G., Kloog Y., Menczer J., Gavish M. Increased density of peripheral benzodiazepine-binding sites in ovarian carcinomas as compared with benign ovarian tumours and normal ovaries. Clin. Sci., 78: 155-158, 1990.[Medline]
  7. Batra S., Iosif C. S. Elevated concentrations of mitochondrial peripheral benzodiazepine receptors in ovarian tumors. Int. J. Oncol., 12: 1295-1298, 1998.[Medline]
  8. Venturini I., Alho H., Podkletnova I., Corsi L., Rybnikova E., Pellicci R., Baraldi M., Pelto-Huikko M., Helen P., Zeneroli M. L. Increased expression of peripheral benzodiazepine receptors and diazepam binding inhibitor in human tumors sited in the liver. Life Sci., 65: 2223-2231, 1999.[CrossRef][Medline]
  9. Gavish M., Bachman I., Shoukrun R., Katz Y., Veenman L., Weisinger G., Weizman A. Enigma of the peripheral benzodiazepine receptor. Pharmacol. Rev., 51: 629-650, 1999.[Abstract/Free Full Text]
  10. Papadopoulos V. Peripheral-type benzodiazepine/diazepam binding inhibitor receptor: biological role in steroidogenic cell function. Endocr. Rev., 14: 222-240, 1993.[Abstract/Free Full Text]
  11. Carmel I., Fares F. A., Leschiner S., Scherübl H., Weisinger G., Gavish M. Peripheral-type benzodiazepine receptors in the regulation of proliferation of MCF-7 human breast carcinoma cell line. Biochem. Pharmacol., 58: 273-278, 1999.[CrossRef][Medline]
  12. Beinlich A., Strohmeier R., Kaufmann M., Kuhl H. Relation of cell proliferation to expression of peripheral benzodiazepine receptors in human breast cancer cell lines. Biochem. Pharmacol., 60: 397-402, 2000.[CrossRef][Medline]
  13. Landau M., Weizman A., Zoref-Shani E., Beery E., Wasseman L., Landau O., Gavish M., Brenner S., Nordenberg J. Antiproliferative and differentiating effects of benzodiazepine receptor ligands on B16 melanoma cells. Biochem. Pharmacol., 56: 1029-1034, 1998.[CrossRef][Medline]
  14. Ikezaki K., Black K. L. Stimulation of cell growth and DNA synthesis by peripheral benzodiazepine. Cancer Lett., 49: 115-120, 1990.[CrossRef][Medline]
  15. Maaser K., Höpfner M., Jansen A., Weisinger G., Gavish M., Kozikowski A. P., Weizman A., Carayon P., Riecken E. O., Zeitz M., Scherübl H. Specific ligands of the peripheral benzodiazepine receptor induce apoptosis and cell cycle arrest in human colorectal cancer cells. Br. J. Cancer, 85: 1771-1780, 2001.[CrossRef][Medline]
  16. Grabowski P., Schindler I., Anagnostopoulos I., Foss H. D., Riecken E. O., Mansmann U., Stein H., Berger G., Buhr H. J., Scherübl H. Neuroendocrine differentiation is a relevant prognostic factor in stage III-IV colorectal cancer. Eur. J. Gastroenterol. Hepatol., 13: 405-411, 2001.[CrossRef][Medline]
  17. Grabowski P., Mann B., Mansmann U., Lovin N., Foss H. D., Berger G., Scherübl H., Riecken E. O., Buhr H. J., Hanski C. Expression of SIALYL-Le(x) antigen defined by MAb AM-3 is an independent prognostic marker in colorectal carcinoma patients. Int. J. Cancer, 88: 281-286, 2000.[CrossRef][Medline]
  18. Dussossoy D., Carayon P., Feraut D., Belugou S., Combes T., Canat X., Vidal H., Casellas P. Development of a monoclonal antibody to immunocytochemical analysis of the cellular localization of the peripheral benzodiazepine receptor. Cytometry, 24: 39-48, 1996.[CrossRef][Medline]
  19. Miettinen H., Kononen J., Haapasalo H., Helen P., Sallinen P., Harjuntausta T., Helin H., Alho H. Expression of peripheral-type benzodiazepine receptor and diazepam binding inhibitor in human astrocytomas: relationship to cell proliferation. Cancer Res., 55: 2691-2695, 1995.[Abstract/Free Full Text]
  20. Junck L., Olson J. M., Ciliax B. J., Koeppe R. A., Watkins G. L., Jewett D. M., McKeever P. E., Wieland D. M., Kilbourn M. R., Starosta-Rubinstein S. PET imaging of human gliomas with ligands for the peripheral benzodiazepine binding site. Ann. Neurol., 26: 752-758, 1989.[CrossRef][Medline]
  21. Stoebner P. E., Carayon P., Casellas P., Portier M., Lavabre-Bertrand T., Cuq P., Cano J. P., Meynadier J., Meunier L. Transient protection by peripheral benzodiazepine receptors during the early events of ultraviolet light-induced apoptosis. Cell Death Differ., 8: 747-753, 2001.[CrossRef][Medline]
  22. Hardwick M., Rone J., Han Z., Haddad B., Papadopoulos V. Peripheral-type benzodiazepine receptor levels correlate with the ability of human breast cancer MDA-MB-231 cell line to grow in SCID mice. Int. J Cancer, 94: 322-327, 2001.[CrossRef][Medline]
  23. Hamilton, S. R., Vogelstein, B., Kudo, S., Riboli, E., Nakamura, S., Hainaut, P., Rubio, C. A., Sobin, L. H., Fogt, F., Winawer, S. J., Godgar, D. E., and Jass, J. R. Carcinoma of the colon and rectum. In: S. R. Hamilton and L. A. Aaltonen (eds.), Pathology and Genetics of Tumours of the Digestive System, pp. 105–139. Lyon, France: IARC, 2000.



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Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
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