10.1245/s10434-006-9281-8
Annals of Surgical Oncology 14:1703-1711 (2007)
© 2007 Society of Surgical Oncology
L1 Expression as a Marker for Poor Prognosis, Tumor Progression, and Short Survival in Patients with Colorectal Cancer
Yoon-Jung Boo, MD1,
Joong-Min Park, MD1,
Jin Kim, MD1,
Yang-Seok Chae, MD2,
Byung-Wook Min, MD1,
Jun-Won Um, MD1 and
Hong-Young Moon, MD1
1 Department of Surgery, Korea University College of Medicine, Seoul, Korea
2 Department of Pathology, Korea University College of Medicine, Seoul, Korea
Correspondence: Address correspondence and reprint requests to: Hong-Young Moon, MD; E-mail: hymoon{at}korea.ac.kr
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ABSTRACT
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Background: L1, a new target gene for Wnt/ß-catenin–TCF signaling, has been identified in the invasive front of colorectal cancer cells in vitro study. The L1 molecule is localized on the cell surface in tumor tissues, accompanied with loss of ß-catenin and E-cadherin. However, such association between L1 expression and prognosis of colorectal cancer has not yet been investigated in clinical study. We investigated the expression of L1, E-cadherin, and ß-catenin in tumor cells to determine correlations between the clinicopathologic characteristics and the expression of these molecules and to evaluate the efficacy of the use of these molecules as prognostic markers for patient survival.
Methods: We investigated 138 patients who received diagnoses of colorectal cancer and who underwent surgery between January 1995 and December 2000 at the Korea University Hospital. Tissues were obtained from paraffin-embedded blocks of the tumors and studied by tissue microarray analysis. Immunohistochemical staining for L1, ß-catenin, and E-cadherin was performed for each specimen.
Results: L1 expression was found to be correlated with advanced cancer stage (P = .001), distant metastasis (P < .001), and tumor recurrence (P = .006). Survival analysis showed that reduced expression of ß-catenin and E-cadherin, and expression of L1 were statistically significantly related to poor survival. Multivariate analysis revealed that L1 expression was an independent prognostic factor for patient survival.
Conclusions: L1 expression is associated with tumor progression and poor survival in patients with colorectal cancer and may be clinically useful as a marker for poor prognosis.
Key Words: L1 • ß-Catenin • E-cadherin • Colorectal cancer
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INTRODUCTION
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Colorectal cancer is one of the most common malignancies worldwide; the incidence has increased substantially in Asia during the past few decades.1 Treatment advances such as standardized technique of total mesorectal excision, preoperative radiotherapy, and adjuvant chemotherapy have reduced the earlier high local recurrence rates and have improved survival in patients with colorectal cancer. The prognosis of colorectal cancer is based on stage, lymph node metastasis, and distant metastasis.2,3 However, some patients eventually die from recurrence and dissemination of cancer soon after surgery despite progress in its management, whereas other patients with disease of a similar stage do not. This difference may be the result of the different malignant potential of cancers with variable biologic properties. Therefore, identification of novel biological markers related to tumor aggressiveness is needed to recognize high-risk patients who would benefit from adjuvant therapy and to identify new molecular targets for the development of novel treatments.
The L1 adhesion molecule is a 200- to 220-kDa type I membrane glycoprotein of the immunoglobulin superfamily that plays an important role in the development of the nervous system by regulation of cell interactions, including neuronal migration.4 L1 is normally expressed in neural cells, endothelial cells, certain epithelial cells, fibroblasts, and cells of lymphoid and myelomonocytic origin.5 The expression of L1 has been shown to have prognostic importance in patients with ovarian and uterine carcinoma and to be associated with metastatic melanoma and clear cell carcinoma.6–9 L1 expression is also correlated with tumor progression and metastasis of several other types of cancer, including gliomas,10 recurrent neuroblastoma,11 and renal cell carcinoma.8
Colorectal cancer is one of the tumors best characterized at the molecular level. Aberrant activation of ß-catenin–TCF signaling, induced by mutation of the adenomatous polyposis coli (APC), axin, or ß-catenin genes, plays a key role in the carcinogenesis of colorectal cancer at the initiation stage as well as during invasion and metastasis.12 L1 has been identified as a new target gene of ß-catenin–TCF signaling in colorectal cancer cells in in vitro study; L1 was localized at the invasive front of the tumor tissue that expresses loss of ß-catenin and E-cadherin on the cell surface and increased cell motility, growth, transformation, and tumorigenesis.13 However, these in vitro findings have not yet been investigated by clinical study in patients with colorectal cancer.
The objective of this study was therefore to investigate L1, E-cadherin, and ß-catenin expression in patients with colorectal cancer and its relationship to tumor progression, and to evaluate the role of these molecules as a biological marker for prediction of poor patient survival.
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MATERIALS AND METHODS
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Patients and Specimens
We retrospectively reviewed 138 patients with colorectal cancers who underwent curative surgical resection between January 1995 and December 2000 at the Korea University Medical Center, Seoul. The patients had no history of familial aggregation of colorectal carcinoma. No patients had received chemotherapy or radiotherapy before surgery. Postoperative adjuvant chemotherapy was performed for all stage III and IV disease with 5-fluorouracil (600 mg/d/m2, 5 days) and folinic acid for 6 months from day 14 after surgery. All patients were followed under the same protocol for at least 5 years after surgery. All tissue and clinical data were obtained after patients provided informed consent. The clinicopathologic characteristics of patients with colorectal cancers are listed in Table 1
. Tumor sites were classified according to the International Classification of Disease for colon cancers (71 cases, 51.4%) and rectal cancers (67 cases, 48.6%). Eleven patients had distant metastasis at the time of surgery: eight patients had liver metastasis, and three patients had ovarian metastasis. All the patients underwent concurrent or consecutive surgical resection for metastatic lesions. Tumor stage was classified according to the tumor, node, metastasis system: 28 (20.3%) were stage I, 48 (34.8%) were stage II, 51 (37.0%) were stage III, and 11 (8.0%) were stage IV. After curative resection, 43 patients (31.2 %) experienced recurrence of disease.
Preparation for Tissue Microarray and Immunohistochemistry
Hematoxylin and eosin–stained slides were obtained from each patient’s paraffin-embedded tumor block. Viable representative areas of tumor specimen were marked by a pathologist (Y.-S.C.). Core needle biopsy samples were retrieved from the original tumor blocks with a Quik-Ray needle by visual alignment with the corresponding hematoxylin and eosin–stained section on the slide. The retrieved donor block was positioned on a recipient paraffin array block. After block construction was completed, 5-µ m sections of the resulting tumor tissue micro-array block were cut with microtome.
Immunohistochemical staining was performed on the tissue microarray sections. After paraffin was removed and the samples were hydrated, sections were pretreated with ethylenediaminetetraacetic acid solution, pH 8.0, in a microwave oven set at full power (700 W) for two cycles of 5 minutes. Endogenous peroxidase was inhibited with 3% hydrogen peroxide in methanol, and nonspecific binding was blocked with normal goat serum. Slides were incubated overnight with the primary antibodies in a humidified chamber at 4° C. The primary antibodies to the ectodomain of L1 (monoclonal antibody UJ127.11, Abcam, Cambridge, UK), and monoclonal antibodies against ß-catenin (clone ß-catenin 1, Dako, CA, USA) and against E-cadherin (clone NCH-38, Dako, CA, USA) were used. Specimens were reacted with peroxidase-labeled streptavidin for 1 hour at room temperature. Sections were thoroughly washed in phosphate-buffered saline between individual procedures. Reaction products were visualized with diaminobenzidine, and slides were then counterstained with hematoxylin or 1% methyl green, dehydrated, and evaluated by light microscope.
Scoring and Statistical Analysis
Immunohistochemical slide evaluation was independently conducted by two investigators who had no knowledge of the clinicopathologic data. Positive control sections were also processed from normal colonic epithelium. Peripheral nerves served as an internal positive control for L1 immunostaining. The percentage of tumor cells with positive expression of membranous E-cadherin and ß-catenin was scored. When more than 80% of the tumor cells were positively stained for membranous E-cadherin or ß-catenin, the tumor was classified as having preserved E-cadherin or ß-catenin expression (Fig. 1). L1 expression was not identified in the normal colonic epithelium. Specimens were considered immunopositive for L1 when more than 5% of the tumor cells had clear evidence of L1 immunostaining (Fig. 2).
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FIG. 1. Immunohistochemical staining of ß-catenin and E-cadherin. (A) ß-Catenin expression in normal epithelium. (B) Negative expression of ß-catenin in tumor cells. (C) Reduced expression of ß-catenin (less than 80% of membranous staining). (D, E) Preserved expression of ß-catenin (more than 80% of membranous staining). (F) E-cadherin expression in normal epithelium. (G) Negative expression of E-cadherin in tumor cells. (H) Reduced expression of E-cadherin (<80% of membranous staining). (I, J) Preserved expression of E-cadherin (>80% of membranous staining).
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FIG. 2. Immunohistochemical staining of L1. (A) Strong L1 expression of tumor cells. (B) L1 expression of invasive front of the tumor. (C) Focal expression of L1. (D) Negative expression of L1.
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The correlation between the expression of each marker and clinicopathologic variables were analyzed by 
2 test and Fisher’s exact test. Survival data were analyzed according to the method of Kaplan-Meier survival curves and tested for significance between the groups with the log rank test. A P value of less than .05 was considered significant. All calculations were performed by SPSS software, version 13.0 for Windows (SPSS, Chicago, IL).
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RESULTS
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Correlation Between the Expressions of ß-catenin and E-cadherin and the Clinicopathologic Characteristics of Colorectal Cancers
A reduced expression of ß-catenin was identified in 47 (34.1%) of 138 patients with colorectal cancer. The reduced expression of ß-catenin was significantly associated with lymph node metastasis (P = .020) and advanced stage (P = .047). However, there was no statistically significant correlation between the reduced expression of ß-catenin and invasion depth, differentiation, distant metastasis, or recurrence (Table 2).
E-cadherin expression was reduced in 56 (40.1%) of 138 cases. The reduced expression of E-cadherin correlated with lymph node metastasis (P = .002), differentiation (P = .015), advanced stage (P < .001), and tumor recurrence (P = .008). No statistically significant association was observed between reduced expression of E-cadherin and invasion depth or distant metastasis (Table 3).
Correlation Between L1 Expression and Clinicopathologic Characteristics
Positive expression of L1 was found in 15 (10.9%) of 138 of the cases. L1 expression was correlated with distant metastasis. Eight of 11 patients with distant metastasis had positive L1 expression (P < .001). Positive expression of L1 was also associated with advanced stage (P = .001) and tumor recurrence (P = .006). However, L1 expression was not related to invasion depth, lymph node metastasis, or differentiation (Table 4).
Correlation Between ß-catenin, E-cadherin, and L1 Expression
Thirty-six (75%) of 47 patients with reduced expression of ß-catenin also showed a reduced expression of E-cadherin. There was a strong correlation with the expression of ß-catenin and E-cadherin (P < .001) (Table 5). In addition, L1 expression was statistically significantly associated with reduced expression of ß-catenin (P = .040) and E-cadherin (P = .010) (Table 6).
Survival Analysis
The median duration of follow-up was 70.9 ± 36.6 months (range, 3–129 months), and the 5-year survival rate of the 138 patients was 66.3%. The 5-year survival by ß-catenin expression is illustrated in Fig. 3. The difference in overall survival between reduced expression of ß-catenin (5-year survival rate, 62.7%) and preserved expression of ß-catenin (5-year survival rate, 76.8%) was statistically significant (P = .028, log rank test) (Fig. 3). The group with reduced expression of E-cadherin had a 5-year survival rate of 60.7%, which was lower than the group with preserved expression of E-cadherin (5-year survival rate, 79.1%, P = .021) (Fig. 4). The 5-year survival rate of the L1-positive group was 26.7%, which was significantly lower than that of the L1-negative group (77.1%, P < .001) (Fig. 5).
To determine the independent prognostic factors for our cases, we performed a univariate analysis of the clinicopathologic variables. Seven factors were found to be associated with patient survival: invasion depth, lymph node metastasis, advanced stage, distant metastasis, ß-catenin expression, E-cadherin expression, and L1 expression (Table 7). The multivariate analysis for these seven factors by stepwise logistic regression method revealed that invasion depth (hazard ratio, 3.911, P = .011) and L1 expression (hazard ratio, 2.641, P = .030) were independent prognostic factors for patient survival (Table 8).
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DISCUSSION
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The important factors for cancer progression are invasion and metastasis, and the cadherin-mediated cell-cell adhesion system is obviously imperative for cancer invasion and metastasis. Loss of expression of E-cadherin and ß-catenin has been found to be associated with dedifferentiation, invasion, and metastasis, and it also has been found to have a potential for prognostic factor in colorectal carcinoma.14 The cytoplasmic domain of E-cadherin is the site of interaction with catenin molecules that mediates its bindings to the actin cytoskeleton, and this binding is essential for the formation of strong cell-cell adhesion.15 ß-Catenin, which mediates the connection of E-cadherin and actin cytoskeleton, reduces its membranous expression by reduced binding of E-cadherin or reduction of ß-catenin itself.16 Under physiologic conditions, unbounded cytosolic free ß-catenin is bound by the APC-Axin-GSK complex and degraded by the proteasome. However, free ß-catenin accumulates in the cytosol and translocates to the nucleus by inactivation of the APC gene, Axin mutations, or mutations of the ß-catenin gene. After translocation to the nucleus and binding to TCF, ß-catenin promotes transcriptional activation of specific target oncogenes.12 This aberrant ß-catenin–TCF signaling plays a key role in colorectal cancer; L1 is identified as a new target gene of this signaling by an in vitro study of colorectal cancer cells.13
In the present study, we investigated the clinicopathologic significance of ß-catenin, E-cadherin, and L1 expression in colorectal cancer cells. Reduced membranous ß-catenin expression was found to be associated with lymph node metastasis and advanced tumor stage. Reduced E-cadherin expression was also correlated with lymph node metastasis, tumor differentiation, advanced tumor stage and recurrence. Furthermore, we found that reduced expression of these adhesion molecules was correlated not only with poor clinicopathologic characteristics but also with a short patient survival. Takayama et al.17 reported that colorectal carcinoma with reduced expression of E-cadherin, 
-catenin, or ß-catenin frequently showed lymph node metastasis. The role of expression of the E-cadherin/catenin system in the progression of tumors has become an important focus of investigation over the past few years because of its apparent promise as a prognostic indicator; loss or reduction of expression has been correlated with aggressiveness, dedifferentiation, and metastasis in many cancers.15 For colorectal cancer, however, there have been many different controversial reports. An immunohistochemical analysis of rectal cancer showed that lack of cytoplasmic staining of ß-catenin, reduced membranous staining of ß-catenin, and reduced membranous staining for E-cadherin increased the risk of tumors.18
In contrast, Gofuku et al.19 reported that E-cadherin expression was not associated with the depth of invasion or metastasis, but was associated with differentiation. To explain these different results, some investigators have suggested that the differences are because the frequency of dedifferentiated cancer and E-cadherin reduction is lower in colorectal cancers than in cancers of other organs.19 In our study, the proportion of reduced expression of ß-catenin and E-cadherin was 34.1% and 40.1%, respectively, which was consistent with other reports. However, we found that their levels of expression were related to tumor progression and patient survival. Because there have been only a few reports that evaluated these molecules on the basis of long-term clinical follow-up, these results are meaningful even though they were not found to be independent prognostic factors by multivariate analysis. Because poorly differentiated cancers accounted for only six cases (4.3%) and most of the tumors in our study were moderate (84 cases, 60.9%) and well-differentiated cancers (42 cases, 30.4%), these results suggest that the biological changes of the cancer cells based on the polarized epithelial organization of these adhesion molecules are more important predictive factors for cancer progression than morphological differentiation.
We found a strong correlation between the reduced membranous expression of ß-catenin and E-cadherin, which were also correlated with L1 expression, which is consistent with the findings of previous studies.13,20 Gavert et al.13 demonstrated that in colon cancer cells, the ß-catenin–TCF transcriptional complex activates the L1 gene, which can confer increased cell motility, transformation, and tumorigenesis. Because L1 expression is absent in normal human colonic epithelium, neoexpression of the L1 in colon cancer cells seems to provide several properties characteristics of cancer cells, including enhancement of motility, cell transformation, and proliferation abilities. L1 is primarily a cell-surface molecule, but it can be shed from the cell surface of normal or tumor cells and deposited in the extracellular matrix, where it helps tumor cells to migrate by autocrine or paracrine loops.21 Moreover, the ectodomain of L1 promotes heightened and sustained activation of the extracellular signal-regulated kinase pathway and concomitant induction of extracellular signal-regulated kinase-regulated gene products intimately associated with cell motility and invasion.5 These gene products have shown to contribute directly to L1-mediated migration and matrix invasion. On the basis of these mechanisms, L1 may allow tumor cells to induce a motile phenotype that facilitates metastasis.
L1 expression has been found to be a valuable marker for poor prognosis in variety of human malignancies, including melanoma, uterine cancer, and ovarian cancer.6,9,22 In our study, L1 expression was found to be correlated with advanced tumor stage, distant metastasis, and recurrence of colon cancers. L1 was also found to be associated with poor patient survival, and it was also found to be an independent poor prognostic factor in the multivariate analysis. However, our study is limited because total cases and the L1-positive arm of the survival curve were too small to reach definite conclusions. Further study with a larger series is needed to clarify these results. In a recent study, the efficient inhibition of intraperitoneal tumor growth and dissemination of ovarian cancer cells in nude mice with an anti-monoclonal antibody against L1 was reported; anti-L1 antibody effectively inhibited the proliferation of L1-expressing tumor cell lines (including renal carcinoma, neuroblastoma, and colon carcinoma) in an in vitro study.23 These promising results suggest that L1 may provide a potential target for novel molecular treatments of aggressive colorectal cancers.
In summary, L1 expression and reduced expressions of ß-catenin and E-cadherin were related to tumor progression and poor clinicopathologic outcomes. L1 expression was related to tumor stage, distant metastasis, recurrence of colon cancers, and poor patient survival. In a multivariate analysis, L1 was found to be an independent predictive factor associated with a poor prognosis. These findings suggest that L1 may be a useful marker for aggressive cancers with poor prognosis.
Received for publication August 18, 2006.
Accepted for publication November 4, 2006.
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ABSTRACT
INTRODUCTION
