Elsevier

Lung Cancer

Volume 47, Issue 1, January 2005, Pages 59-67
Lung Cancer

Sialyl Lewis antigens: association with MUC5AC protein and correlation with post-operative recurrence of non-small cell lung cancer

https://doi.org/10.1016/j.lungcan.2004.05.018Get rights and content

Summary

Sialyl Lewis antigens (sLex/a) are cancer-associated carbohydrate determinants, serve as ligands of the selectin family and are associated with hematogenous metastasis of cancer. So far, the clinicopathologic values of sialyl Lewis x (sLex) and sialyl Lewis a (sLea) in lung cancer have remained controversial. Using immunohistochemistry, the expressions of sLex and sLea antigens, and an airway mucin (MUC5AC) protein, which was supposed to be the major carrying protein of sialyl Lewis moieties, were studied in surgically resected tumor tissues of 61 patients with stages I or II NSCLC. Thirty-two (52.5%) of the 61 studied subjects were found to be positive for expression of sLea, 40 (65.6%) were positive for expression of sLex, and 16 (26.2%) were positive for MUC5AC protein. Both the expression of sLex and MUC5AC were associated with adenocarcinoma subtype. Patients bearing tumors with MUC5AC and/or sLex expression had a higher probability of post-operative distant metastasis. Survival analysis demonstrated that patients bearing tumors with expression of sLex antigen or MUC5AC had shorter overall survival. The multivariate logistic regression showed that age >65 years old (OR = 0.207, 95% CI = 0.075–0.569, P = 0.002), nodal status (OR = 6.575, 95% CI = 2.459–17.583, P < 0.001), and MUC5AC (OR = 5.545, 95% CI = 1.998–15.386, P = 0.001) were independent factors affecting survival. We concluded that the expression of sLex was related to MUC5AC protein, while patients with tumors co-expressing both MUC5AC and sLex antigen had the worst survival.

Introduction

Lung cancer is one of the most common causes of cancer death worldwide [1]. Despite advances in diagnostic techniques for early detection of the disease and the progression in surgical procedures, the prognosis of patients with lung cancer is still unsatisfactory. Disease recurrence is common even after curative resection for the early stages of lung cancer [2]. In stage I lung cancer, approximately 50% of patients develop recurrent disease and eventually die of metastatic disease [3], [4]. Identification of specific indicators in the primary tumor for invasiveness or metastatic potential at the time of surgery would allow for a better prognostic stratification of patients, and thus, more effective treatment.

To date, the prognostic gold standard of NSCLC is the staging of patients according to the tumor-node-metastasis classification [2]. However, patients’ prognosis within a single stage is not the same, particularly within the earlier stages of the disease [5]. Because the clinicopathologic stratification is based on morphologic characterization, additional factors implicated in the biologic function that affect tumor progression and metastasis should be sought to identify subgroups among patients within the same stage who are most at risk for tumor recurrence and death [6].

Sialyl Lewis x (sLex) and sialyl Lewis a (sLea) are cancer-associated carbohydrate antigens involved in the process of metastasis [7]. Both compounds serve as ligands for P-, l-, and E-selectins expressed on the surface of platelets, leukocytes, and vascular endothelial cells. They mediate the adhesion of malignant cells to the vascular endothelium [8], [9]. The roles of these antigens in tumor metastasis are suggested by several observations, including the ability of the antibodies to block tumor cell adhesion on the endothelial cells in vitro, the correlation of the antigen expression with increased metastatic potential of cancer cells, and the inhibitory effects of the antibodies in angiogenesis [10], [11], [12], [13]. The augmented expression of sLex and sLea antigens is frequently observed in some cancerous tissues, including lung cancer [14], [15], [16], [17]. However, despite the fact that correlations were established between sLex/a expression and the poor outcome of patients with breast and colon cancer [14], [16], controversy remains whether the evaluation of the expression of sLex/a is useful as an independent prognostic indicator in lung cancer [18], [19], [20], [21].

Previously, it had been demonstrated that lung cancers over-expressing sialomucins (highly sialylated mucins) tend to have higher chance of recurrence and metastasis [22]. Patients bearing tumors with sialomucin expression tended to have post-operative relapses and poor prognoses despite curative resection. Although it had also been demonstrated then that the over-expression of sialomucin correlated with at least one mucin core peptide (MUC5AC apomucin) [23], many are still unaware of the specific process that led to the sialylation on the MUC5AC protein, and how sialomucin influenced the behavior of cancer cells. It is possible that the over-expression of a specific apomucin, such as MUC5AC, in cancer cells may guide its own pattern of glycosylation and generate specific sialylated carbohydrate antigens, like sLex or sLea, which mediate the metastatic or invasive behavior of cancer cells.

In this study, immunohistochemical stains were used to evaluate the expression status of sialyl Lewis antigens and MUC5AC proteins in the early stages (stage I and II) of NSCLC. The study is aimed at elaborating the relationship between the MUC5AC apomucin and the sialylation process in NSCLC.

Section snippets

Patients and tumor tissues

Between July 1995 and December 1996, surgical specimens of normal and cancerous lung tissues were obtained from 61 patients with stage I and stage II NSCLC at the National Taiwan University Hospital (NTUH) after informed consents were obtained. This investigation was performed with the approval of the Institutional Review Board of the NTUH. All underwent a complete resection of the tumor. The resections were judged if all of the known tumor tissue was removed completely, resection margins were

Clinical and pathological features

There were 33 adenocarcinomas, 23 squamous cell carcinomas, three large cell carcinomas, and two adenosquamous carcinoma. The gender distribution was 41 men and 20 women. The mean age was 61.8 ± 11.4 years old, with the range from 24.7 to 77 years old. Cigarette smoking was more prevalent in male patients (27 patients, 65.9%) than in female patients (5 patients, 25.0%), P = 0.003. The distribution of pathological stage was: 40 stage I disease (9 stage IA and 31 stage IB) and 21 stage II (3

Discussion

The Lewis blood group antigens are biosynthetically and structurally related carbohydrate structures used as markers of cell differentiation and embryonic development [25]. Neoplastic transformation is often associated with characteristic changes in the expression of this blood group of oligosaccharides, and their amounts usually increase during the acquisition of malignant phenotypes and tumor progression [26]. Both sialyl Lewis antigens play a primary role in the adhesion of cancer cells to

Acknowledgements

This work was supported by grant NSC-89-2314-B-002-488-M54 and NSC 89-2314-B-002-123-M54 from the National Science Council, Executive Yuan, Taiwan, Republic of China.

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