Elsevier

European Journal of Cancer

Volume 46, Issue 16, November 2010, Pages 2919-2925
European Journal of Cancer

Nuclear S100A4 is a novel prognostic marker in colorectal cancer

https://doi.org/10.1016/j.ejca.2010.07.013Get rights and content

Abstract

Current staging classifications in colorectal cancer are not able to accurately predict patient outcome, and the need for novel prognostic markers is evident. S100A4 is a Ca2+-binding protein which promotes metastasis in several tumour types, and the aim of the present study was to investigate the prognostic impact of S100A4 expression in colorectal cancer. Two hundred and forty two patients with curatively resected adenocarcinoma of the colon or rectum were prospectively included in the study at the time of surgery. S100A4 expression was analysed by immunohistochemistry, and associations with clinicopathological variables and patient outcome were investigated. Nuclear expression of S100A4 was observed in 29% and cytoplasmic expression was observed in 64% of the tumours. In univariate analysis, nuclear S100A4 was a negative predictor of metastasis-free (P = 0.006) and overall survival (P = 0.01), whereas cytoplasmic S100A4 was not associated with patient outcome. In multivariate analysis, nuclear localisation was inversely associated with metastasis-free (P = 0.03) and overall survival (P = 0.02). Interestingly, the prognostic impact was largely confined to TNM stage II, and stage II patients with tumours expressing nuclear S100A4 had a similar prognosis as stage III patients. In conclusion, nuclear expression of S100A4 is a novel prognostic marker in colorectal cancer, and the prognostic value in TNM stage II suggests that nuclear S100A4 could be used in the stratification of stage II patients for adjuvant treatment.

Introduction

Distant metastasis is the main cause of death in patients with colorectal cancer. At present, clinical staging and histopathological criteria are the only parameters in clinical use to stratify patients according to the risk of developing metastatic disease after curatively intended surgery. However, current staging classifications are not able to accurately predict patient outcome,1 illustrating the considerable biological heterogeneity of tumours within the separate disease stages. Molecular markers could possibly account for this diversity, and several prognostic factors have been identified.2 Still, none of these have so far been proven robust enough to be incorporated into routine practice.3

Today, clinical and pathological staging is also the basis for selection of patients for adjuvant treatment. Patients with stage III disease generally profit from adjuvant chemotherapy due to an increased risk of subsequent metastatic disease, whereas adjuvant treatment in stage I and II has shown no clear survival benefit.4 A number of patients in these early disease stages still develop metastases in distant organs. Thus, there is a need for novel prognostic biomarkers to identify subgroups of patients that could benefit from adjuvant treatment, but also to identify subsets with low probability of treatment benefit that should be spared the toxic effects of chemotherapy.

One potential prognostic factor is S100A4, a small, calcium-binding protein belonging to the S100 protein family.5 S100A4 promotes metastasis in experimental animal models from a number of tumour types, and is involved in several steps of the metastatic cascade, including cell motility, invasion and angiogenesis.6, 7, 8, 9 The protein is localised in the nucleus, cytoplasm and the extracellular space, and the expression of S100A4 has been shown to predict patient outcome in several tumour types.6, 10, 11 However, the prognostic impact of nuclear S100A4 has so far not been assessed. In a prospectively collected panel of tumour specimens from colorectal cancer patients we have previously demonstrated that nuclear expression of S100A4 correlated with tumour stage.12 In the present study, the association between S100A4 protein expression and patient outcome in this patient cohort was investigated.

Section snippets

Patient cohort

Between September 1998 and July 2000, 316 patients from five hospitals in the Oslo region were included in the study at the time of primary surgery for assumed or verified colorectal cancer.13 The study was approved by the Regional Ethics Committee (#S-98080) and informed consent was obtained from the patients. Seventy-four patients were excluded from the present study for the following reasons: not invasive cancer (25), histology other than adenocarcinoma (5), distant metastases at the time of

Patient characteristics and outcome

Clinical and histological parameters of the study cohort are summarised in Table 1. Mean patient age at the time of surgery was 73 years (range 35–98 years). Thirty patients in TNM stage III (39%) and two patients in stage II (2%) received adjuvant chemotherapy. Postoperative radiotherapy was administered in two cases. All patients included in this study had undergone R0 resections and did not have metastatic disease at the time of diagnosis. Outcome parameters are presented in Table 2.

Discussion

In this prospective study, we demonstrate for the first time that the presence of nuclear S100A4 in tumour cells is of prognostic significance in colorectal cancer. Nuclear expression was a significant and robust predictor of metastasis-free and overall survival, and was also associated with patient outcome in multivariate analysis, indicating that the observed results may translate into clinically important differences. The validity of our findings is strengthened by the prospective study

Conflict of interest statement

None declared.

Acknowledgements

We acknowledge the contributions of members of the Study Group for Bone Marrow Micrometastases in Colorectal Cancer: Øystein Fodstad, The Norwegian Radium Hospital (Study Group Leader); Hans Olaf Johannessen, Ullevål University Hospital (local study coordinator); Ida Bukholm, Akershus University Hospital (local study coordinator); Rocio Rosales, Asker and Bærum Hospital (local study coordinator); Lisbeth Hårklau, Aker University Hospital (local study coordinator); and Hedin Jacobsen,

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    This work was supported by the Norwegian Cancer Society, the Research Council of Norway, the Norwegian Foundation for Health and Rehabilitation, the National Program for Functional Genomics in the Research Council of Norway, the Legacy for Cancer Research and Jeanette and Søren Bothner’s Legacy.

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