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Clinical Cancer Research Vol. 8, 3734-3740, December 2002
© 2002 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Expression of TRAIL and TRAIL Receptors in Colon Carcinoma: TRAIL-R1 Is an Independent Prognostic Parameter1

Jörn Sträter, Ulf Hinz, Henning Walczak, Gunhild Mechtersheimer, Karin Koretz, Christian Herfarth, Peter Möller2 and Thomas Lehnert

Department of Pathology, University of Ulm, 89081 Ulm [J. S., K. K., P. M.]; Section of Surgical Oncology, Department of Surgery [U. H., C. H., T. L.] and Department of Pathology [G. M.], University of Heidelberg, 69120 Heidelberg; and Deutsches Krebsforschungszentrum, 69120 Heidelberg [H. W.], Germany


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in cancer cells and may be involved in protection from metastases. TRAIL receptor (TRAIL-R) 1 and TRAIL-R2, but not TRAIL-R3 and TRAIL-R4, mediate apoptosis. We examined the expression of TRAIL and its receptors in normal and neoplastic colon epithelium, and studied its correlation with prognosis in colon cancer.

Experimental Design: Immunohistochemistry was performed on normal colon mucosa (n = 10), colon adenomas (n = 20), and R0-resected Unio Internationale Contra Cancrum stage II/III colon carcinomas (n = 129). Disease-free survival was examined by Kaplan-Meier estimates and the log-rank test. Prognostic factors were determined by multivariate Cox-analysis.

Results: In normal colon mucosa, TRAIL and TRAIL-R2 were expressed mostly in the surface epithelium, whereas TRAIL-R1 and TRAIL-R4 were detected all along the crypt axis. In adenomas, this expression pattern was mostly retained, although some adenomas also neoexpressed TRAIL-R3. In carcinomas, the expression of TRAIL and TRAIL receptors was much more variable. TRAIL, TRAIL-R2, TRAIL-R3, and TRAIL-R4 expression did not correlate statistically with disease-free survival (multivariate analysis: P = 0.54, P = 0.67, P = 0.45, and P = 0.69, respectively), but TRAIL-R1 expression was significantly associated with disease-free survival in colon cancer (multivariate analysis: P = 0.003).

Conclusions: TRAIL-R1 is an independent prognostic factor in R0-resected Unio Internationale Contra Cancrum stage II/III colon cancer.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
TRAIL,3 also known as APO-2 ligand, is an apoptosis-inducing member of the TNF family (1 , 2) . To date, four homologous TRAIL receptors have been described, two of which (TRAIL-R1 and TRAIL-R2) carry cytoplasmic death domains and mediate apoptosis (3, 4, 5, 6, 7, 8, 9, 10, 11) . Two other receptors (TRAIL-R3 and TRAIL-R4) either lack or have a truncated death domain and do not transmit an apoptotic signal (5, 6, 7 , 9 , 12, 13, 14) . TRAIL may have therapeutic potential, because malignant cells are more sensitive to TRAIL-induced apoptosis than their benign counterparts (1 , 2 , 15) . In mouse models, administration of TRAIL suppressed the growth of TRAIL-sensitive carcinoma cell lines without relevant systemic toxicity (16 , 17) . Tumor cells can be sensitized additionally toward TRAIL by cytotoxic drugs such as 5-fluorouracil, doxorubicin, or CPT-11 (17, 18, 19, 20) . Experimental data indicate that TRAIL may be involved in the prevention of tumor metastasis by NK cells (21) . Therefore, integrity of the TRAIL system may be important for the host defense against malignancy. The aims of the present study were: (a) to determine the TRAIL/TRAIL receptor expression pattern in normal and neoplastic colon epithelium; and (b) to correlate immunohistochemical expression patterns with disease-free survival after potentially curative resection of UICC stage II and III colon cancer.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients.
Tissue samples of normal colon mucosa (n = 10) and colon adenoma (n = 20) with low-grade dysplasia (8 tubular, 9 tubulovillous, and 3 villous) were snap frozen in liquid nitrogen.

The prognostic factor study included 129 patients with curatively resected (R0) primary sporadic colon adenocarcinomas treated between 1990 and 1996 at the Department of Surgery, University of Heidelberg, for which snap-frozen tissue was available. Patients with rectal cancer were excluded. Clinical and pathological data were documented prospectively, and entered into a specific tumor registry at the time of surgery and at each follow-up (Table 1)Citation . The registry was maintained, and statistical analysis of the data were performed by a biostatistician (U. H.). All of the patients were followed according to a standard protocol, which included colonoscopy, abdominal ultrasound, chest radiography, and tumor marker studies in the outpatient clinic or by the family physician. Median follow-up time of patients alive at last follow-up was 91 months (IQR: 67–104 months). Twenty-one UICC-stage III patients and 3 UICC-stage II patients received adjuvant chemotherapy outside of clinical studies according to patient or physician preference.


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  		Table 1 Clinical and pathological characteristics of carcinoma cases

 
Immunohistochemistry.
For protein detection by immunohistochemistry, 4-µm frozen sections of frozen tissue containing representative tumor tissue of at least 1 cm2 were fixed in acetone for 10 min. Sections were incubated for 60 min with the following monoclonal antibodies: mouse antihuman TRAIL (IgG1 isotype, clone M182), mouse antihuman TRAIL-R1 (clone M272, IgG1 isotype), mouse antihuman TRAIL-R2 (clone M412, IgG1 isotype), mouse antihuman TRAIL-R3 (clone M430, IgG1 isotype), and mouse antihuman TRAIL-R4 (clone M440, IgG2a isotype) at appropriate concentrations in PBS (all antibodies were kindly supplied by Immunex, Seattle, WA). Whereas immunohistochemistry for TRAIL receptors was done on all 129 of the carcinoma cases, immunohistochemical studies of TRAIL expression were limited to 120 carcinomas for technical reasons. The sensitivity and specificity of antibodies used in this study were assessed recently (22) . Binding sites of primary antibodies were visualized using the Dako EnVision kit (Dako, Copenhagen, Denmark) according to the manufacturer’s instructions. Finally, sections were faintly counterstained with Harris’ hematoxylin and mounted with glycerol gelatin. Negative controls were performed by omission of the primary antibody.

Slides of cancer specimens were analyzed by two pathologists (J. S. and P. M.) who had no prior knowledge of the clinical data. On the basis of the estimated percentage of positive cells and staining intensity (negative, faintly positive, and strongly positive), staining results were divided into five categories (Fig. 1)Citation : negative ("neg," no positive cells at all), focal low expression ("f-lo," faint positivity in <40% of cells), low expression ("lo," faint positivity in >=40% of cells), focal high expression ("f-hi," all cases with both a strongly positive and negative subpopulation), and high expression ("hi," 100%-positive cells with a strongly positive subpopulation).



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  		Fig. 1. Staining categories defined for immunohistochemical expression of TRAIL and TRAIL receptors in colon carcinomas paradigmatically shown for TRAIL-R1 expression. In f-hi, the negative subpopulation is highlighted by arrows.

 
Statistics.
SAS software (Release 8.01; SAS Institute, Inc. Cary, NC) was used for statistical analyses. The distribution of age at operation and follow-up time of patients alive were presented as the median with an IQR. The Mann-Whitney t test was used to compare the age distribution between subgroups of patients. Comparisons between UICC-stage, and expression of TRAIL and TRAIL-R1–4, respectively, were performed by the two-tailed Fisher’s exact test or the {chi}2 test, as appropriate. Disease-free survival from the date of colon resection was calculated by the Kaplan-Meier estimate (23) . Patients alive without local or distant recurrence at the last follow-up were censored, as were 2 patients who died of other causes after 101 and 118 months, and 1 patient who was lost to follow-up after 3 months. One patient died postoperatively and was excluded from disease-free survival analysis to avoid bias. Expression of TRAIL and TRAIL-R1–4 were dichotomized for disease-free survival analysis. The log-rank test was performed to compare disease-free survival time distributions. Univariate and multivariate HR estimates and corresponding 95% CIs were computed using the Cox proportional hazards regression analysis (24) . As the overall test, the likelihood ratio test of the final model was presented. Ps < 0.05 were considered statistically significant.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Expression of TRAIL and TRAIL Receptors in Normal and Neoplastic Colon Epithelium.
The normal colon mucosa expressed TRAIL, as well as TRAIL receptors 1, 2, and 4 (Fig. 2A)Citation as published recently (22) . TRAIL and TRAIL-R2 were predominantly found in the upper parts of the crypt and the luminal surface epithelium, whereas TRAIL-R1 was expressed in all of the epithelial cells from the crypt base to the surface epithelium. TRAIL-R4 was detected only at low levels in colonocytes, which was in contrast to its strong expression in lamina propria cells.



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  		Fig. 2. a, schematic representation of TRAIL and TRAIL-receptor expression in the normal colon mucosa (left) and colon adenomas (right). Dotted outlines signify inconsistent antigen expression. b, immunohistochemical expression of TRAIL and TRAIL receptors in adenomas (top panel) and carcinomas (bottom panel). In the bottom panel, TRAIL-R1 expression is shown in carcinoma cells (below) and adjacent normal epithelium (above). Note strong TRAIL-R2 expression at the invasion front (below) of the carcinoma.

 
In adenomas of low-grade dysplasia (Fig. 2, A and B)Citation , this expression pattern was mostly preserved, but TRAIL was seen only focally in scattered cells of the most superficial parts of the adenomas. This was in contrast to the more band-like pattern of TRAIL expression in the surface epithelium of the normal colon. TRAIL-R2 expression was frequently stronger than in normal mucosa and extended to the base of the neoplastic tubuli in most cases. In contrast to normal colon mucosa, a strictly nuclear expression of TRAIL-R3 was demonstrable at low levels in 9 of the 20 adenomas examined. Finally, TRAIL-R4 expression was generally more pronounced in adenomas compared with the rather weak expression of this receptor in the normal mucosa.

One hundred and twenty colon cancers were examined for TRAIL expression (Table 2Citation ; Fig. 2BCitation ). Eighty-one tumors (67%) were completely negative, 9 tumors (8%) showed focally low, 2 (2%) low, and 28 (23%) focally high TRAIL expression. In positive carcinomas, the patchy pattern of TRAIL expression as seen in adenomas was retained, although TRAIL expression in carcinomas was not restricted to the luminal surface of the tumor. It was also noted that TRAIL was only rarely detected in tumor-infiltrating lymphocytes (not shown).


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  		Table 2 Expression patterns of TRAIL and TRAIL-R1-4 in colon carcinomas

 
TRAIL receptors investigated in 129 carcinomas showed a broad spectrum of expression patterns with variation both between individual tumors and frequently also within different micro-areas of the same tumor (Table 2Citation ; Fig. 2BCitation ). TRAIL-R1 was expressed in all of the tumors to various degrees. The majority of tumors (58%) expressed high levels of TRAIL-R1, and no tumor was completely negative for TRAIL-R1. In TRAIL-R1hi tumors, TRAIL-R1 expression levels frequently exceeded those of the normal mucosa adjacent to the tumor in the same section (data not shown). TRAIL-R2 was found at high levels in 40% of tumors and only 1 of the 129 carcinomas was completely negative for TRAIL-R2. In TRAIL-R2hi cases, tumor cells at the invasion front were frequently the most prominent TRAIL-R2 expressers.

Most tumors were either TRAIL-R3 negative (43%) or had only focally low TRAIL-R3 expression (21%), which was hardly above background levels. As in adenomas, TRAIL-R3 expression was mostly restricted to the nucleus, and only 3 tumors exhibited a significant cytoplasmic positivity.

TRAIL-R4 was expressed at high levels throughout (19%) or at least focally (17%) indicating significant TRAIL-R4 overexpression in these tumors compared with normal mucosa.

Influence of TRAIL and TRAIL Receptor Expression, and Clinicopathological Parameters on Disease-free Survival.
The 5-year overall survival rate of 128 patients was 72%, with 44 deaths observed in the follow-up period. The 5-year disease-free survival rate was 68%, with 47 events observed during follow-up. Forty-one patients (32%) developed distant metastases. Local tumor recurrence was diagnosed in 6 patients (5%). Univariate and multivariate Cox proportional hazards regression analyses were performed with clinicopathological factors including median age, gender, UICC-stage, T-category, adjuvant treatment, and expression of TRAIL and TRAIL-R1–4 (Table 3)Citation .


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  		Table 3 Results from univariate and multivariate analyses of disease-free survival

 
In univariate analysis, age (P = 0.005), T-category (P = 0.011), and TRAIL-R1 expression (P = 0.003) were associated with a statistically significant effect on disease-free survival (Fig. 3A)Citation . Moreover, a significant association of TRAIL-R1 expression with disease-free survival was observed for both UICC-stage II (P = 0.019; Fig. 3BCitation ) and UICC-stage III (P = 0.031; Fig. 3CCitation ). The role of TRAIL-R1 as a prognostic indicator was substantiated additionally when patients were not only dichotomized but also divided into three groups with respect to TRAIL-R1 expression: this analysis demonstrated that patients with TRAIL-R1f-lo, lo-tumors were at a significantly higher risk of recurrence or of dying from colon carcinoma than those bearing TRAIL-R1f-hi-tumors and TRAIL-R1hi-tumors (5-year survival rates: 47%, 60.1%, 79.1%, respectively; P = 0.0033; Fig. 3DCitation ).



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  		Fig. 3. Kaplan-Meier estimates of disease-free survival after R0-resection of a colon carcinoma with regard to TRAIL receptor 1 expression. Dichotomized analysis (TRAIL-R1hi versus TRAIL-R1f-hi, lo, f-lo) of all 128 patients (a), 68 UICC-stage II patients (b), and 60 UICC-stage III patients (c). In d, disease-free survival is analyzed for three groups according to TRAIL-R1 expression (TRAIL-R1hi versus TRAIL-R1f-hi versus TRAIL-R1lo, f-lo).

 
UICC-stage, gender, treatment, and expression of TRAIL and TRAIL-R2–4 were not significantly correlated with disease-free survival in univariate analysis.

Age, UICC-stage, tumor-category, adjuvant treatment, and TRAIL-R1 expression were included in the final model of multivariate analysis (likelihood ratio test: {chi}2 = 30.9; degrees of freedom, 5; P < 0.001). Age (P = 0.006), UICC-stage (P = 0.033), and T stage (P = 0.017) were significantly associated with disease-free survival, whereas the influence of adjuvant treatment on disease-free survival just failed to reach statistical significance (P = 0.14). After adjusting for confounding factors, the statistically significant effect of TRAIL-R1f-lo, lo, f-hi tumors compared with TRAIL-R1hi tumors in predicting recurrence or death from colon carcinoma was confirmed (P = 0.003). Statistically, expression of TRAIL or TRAIL receptors other than TRAIL-R1 was not associated with disease-free survival on multivariate analysis.

Multivariate analysis identified a significantly increased risk [HR, 2.03 (1.06–3.88)] for UICC-stage III patients, although no significant effect of UICC stage on disease-free survival had been demonstrable on univariate analysis (P = 0.35). This difference was because of a distinct distribution of the confounding factor "age" in both UICC-stage groups. Patients in UICC stage II were considerably older (median age, 66 years; IQR, 60–71) than UICC-stage III patients (median age, 62 years; IQR, 55–69). This age difference reached almost significant levels (P = 0.052).


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The present study describes differential expression of TRAIL and TRAIL receptors in normal colon mucosa, low-grade colon adenoma, and colon carcinoma. Moreover, TRAIL-R1 was identified as an independent prognostic factor for disease-free survival in 128 patients with colon cancer. These observations extend the understanding of molecular changes during the adenoma carcinoma sequence and may eventually bear on the treatment of colon cancer.

TRAIL can selectively induce apoptosis in tumor cells (1 , 2 , 15) . In colon cancer cell lines, TRAIL induces apoptosis both in vitro and in xenograft tumor models (17 , 20) , whereas normal human colon epithelium is resistant to TRAIL-induced cell death (22) . To examine changes of the TRAIL system during colon cancer development, expression patterns in normal mucosa, low-grade adenomas, and carcinomas were compared.

The normal colon epithelium expresses TRAIL-R1 and TRAIL-R4 throughout the crypt axis, whereas TRAIL and TRAIL-R2 are predominantly present in epithelial surface cells, and TRAIL-R3 is not expressed in normal colon mucosa (22) . This pattern is largely maintained in low-grade adenomas, but nearly 50% of the adenomas and carcinomas neoexpressed TRAIL-R3, which was confined to the nucleus in most tumors. This is in agreement with observations in melanoma cells, in that TRAIL-R3 is relocated from the nucleus to the cytoplasm and cell membranes only on binding of TRAIL to surface TRAIL-R1 and TRAIL-R2 (25) . Expression of TRAIL-R3 and TRAIL-R4 increased from normal mucosa over adenomas to carcinomas, but their expression is not associated with a poor prognosis in colon cancer. This is consistent with reports that expression of the so-called decoy receptors correlates poorly with resistance of tumor cells to TRAIL in vitro (26 , 27) . Inhibition of TRAIL-induced apoptosis by these receptors has mainly been described in in vitro transfection experiments (5, 6, 7 , 25) . Their role under more physiological conditions remains to be determined.

Expression patterns of the two apoptosis-mediating receptors, TRAIL-R1 and TRAIL-R2, were quite complex in carcinomas. The expression of both receptors ranged from negative, at least in some micro-areas, to high levels, even exceeding those of adjacent normal mucosa. Interestingly, TRAIL-R2 was often most strongly expressed in tumor cells at the invasion front of TRAIL-R2hi carcinomas. This expression pattern very much resembles that described for ß-catenin in colorectal carcinomas (28) . Nuclear ß-catenin forms complexes with the DNA-binding proteins of the T cell factor-family and, thus, functions as a transcriptional activator, which may regulate a variety of genes involved in tumor progression and invasion, e.g., matrix metalloproteinase-7 and laminin-{gamma}2 (28 , 29) . The TRAIL-R2 promoter also contains a potential ß-catenin/TCF-binding motif4 so that TRAIL-R2 may turn out to be up-regulated by nuclear ß-catenin at the invasion front of colorectal cancers. At present, we can only speculate about the role TRAIL-R2 may have in this specific localization. In this respect, it is important that TRAIL-R2 not only mediates apoptosis but also, via an alternative signaling pathway, activates the transcriptional factor nuclear factor {kappa}B (4 , 9) , which, in turn, may even contribute to apoptosis resistance (30) . Thus, in a different cellular/molecular context, ligation of TRAIL-R2 may be able to promote tumor aggressiveness. This dual role of TRAIL-R2 may also explain why we do not find a significant correlation between TRAIL-R2 expression and disease-free survival.

In contrast to TRAIL-R2, TRAIL-R1 expression was associated with a favorable prognosis of colon cancer and was identified as an independent prognostic marker by multivariate analysis. The prognostic analysis focused on colon cancer rather than rectal cancer in order specifically to examine tumor- and patient-related prognostic factors. The inclusion of rectal cancer would have introduced severe bias, because surgeon-related factors are important prognosticators in rectal cancer (31 , 32) .

Recent experimental data may provide a clue as to how TRAIL-R1 expression may influence the outcome of cancer patients: NK cells from mice express TRAIL and confer cytotoxic activity against TRAIL-sensitive tumor cells in vitro, whereas neutralizing antibodies to TRAIL or NK cell depletion increased the incidence of experimental liver metastases after injection of tumor cells in a mouse model (21) . Thus, loss of the apoptosis-mediating TRAIL-R1 may go along with resistance to TRAIL-induced apoptosis and survival of metastasized tumor cells, which would otherwise be killed by TRAIL-expressing NK cells.

In our cohort, survival in UICC stages II and III was not significantly different on univariate analysis. This is because of the higher age of patients with UICC II colon cancer. As expected, multivariate analysis confirmed a significantly increased risk for UICC-stage III [HR, 2.03 (1.06–3.88); P = 0.033]. When patients in UICC stage II and III are analyzed separately, TRAIL-R1 expression remains an independent predictive marker in each UICC stage. Considering the prognostic inhomogeneity of colon carcinoma UICC stage II and III (33 , 34) TRAIL-R1 expression may be used to select patients for adjuvant treatment. Of course, additional prospective trials are required to prove the value of TRAIL-R1 in this respect.

Moreover, the observations of the present study may eventually have implications for the treatment of colon cancer in another respect: human recombinant TRAIL could be used as a potential anticancer agent in large bowel cancer. The expression of TRAIL receptors TRAIL-R1 and TRAIL-R2 could then render tumor cells susceptible to TRAIL-induced apoptosis, and improve treatment response and prognosis. Of importance in this context, is that, in contrast to other TNF-family members such as CD95L (FasL/APO-1L) or TNF itself, the application of TRAIL was not associated with significant toxicity in animal models (16 , 17) . This latter feature would make TRAIL a particularly attractive anticancer agent.

However, in our study, patients with low TRAIL-R1 expression have a poor prognosis. This may be related to resistance of tumor cells to TRAIL, and treatment with recombinant TRAIL alone may be ineffective. In these patients, the combined application of TRAIL together with cytotoxic drugs may overcome TRAIL resistance, because 5-fluorouracil and CPT-11 can sensitize tumor cells toward TRAIL-induced apoptosis (17, 18, 19, 20) . Alternatively, it is conceivable that adjuvant chemotherapy augments tumor cell apoptosis induced by intrinsic TRAIL derived from NK cells (21) . In this event, TRAIL-R1 expression may be useful for response prediction to adjuvant chemotherapy. Such a marker would be welcome, as it would allow adjuvant treatment to be specifically directed at those patients who would benefit most.


   ACKNOWLEDGMENTS
 
We thank Kathrin Pruy and Simone Westenfelder for expert technical assistance, and Caroline Higginson and Werner Kugler for assistance in the preparation of the manuscript and photographic documentation.


   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 Supported by grants from the Deutsche Krebshilfe (Str 10-1644-St1). Back

2 To whom requests for reprints should be addressed, at Department of Pathology, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany. Phone: 49-731-500-23320; Fax: 49-731-500-23884; E-mail: peter.moeller{at}medizin.uni-ulm.de Back

3 The abbreviations used are: TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; CI, confidence interval; HR, hazard ratio; IQR, interquartile range; TNF, tumor necrosis factor; UICC, Unio Internationale Contra Cancrum; NK, natural killer. Back

4 J. Sträter and P. Möller, unpublished observations. Back

Received 3/18/02; revised 6/25/02; accepted 8/27/02.


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Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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