Clinicopathologic significance of S 100 A 4 expression in osteosarcoma

– OBJECTIVE: Osteosarcoma is the most common primary malignancy, mainly arising from the metaphysis of the long bones of adolescents and young adults. Its poor prognosis is strongly associated with invasion and distant metastasis. The calcium-binding protein S100A4 promotes metastasis in several experimental animal models, including osteosarcoma (OS), and S100A4 protein expression is associated with patient outcome in a number of tumor types. In the present study, we investigated the expression of S100A4 and its clinicopathologic significance in OSs. PATIENTS AND METHODS: S100A4 were examined immunohistochemically in resected OSs from 120 patients with OS to clarify their clinicopathologic significance. Multivariate survival analyses were carried out on all investigated parameters. RESULTS: The immunohistochemical assays revealed that S1004A expression in osteosarcoma tissues was significantly higher than that in corresponding noncancerous bone tissues (p < 0.001). In addition, positive S100A4 expression more frequently occurred in osteosarcoma tissues with advanced clinical stage (p = 0.003), positive distant metastasis (p = 0.001) and poor response to chemotherapy (p = 0.04). In KaplanMeier analysis, only S100A4 positively stained cases showed a significantly decreased overall survival time and disease-free survival compared with negatively stained cases (both p < 0.001). On Cox multivariate analysis, positive S100A4 expression was an independent and significant prognostic factor to predict poor overall survival and disease-free survival (both p = 0.001). CONCLUSIONS: Expression of S100A4 protein in OS may be related to the prediction of metastasis potency, response to chemotherapy and poor prognosis for osteosarcoma patients, suggesting that S100A4 may serve as a prognostic marker for the optimization of clinical treatments. European Review for Medical and Pharmacological Sciences Clinicopathologic significance of S100A4 expression in osteosarcoma C.-M. CAO, F.-X. YANG1, P.-L. WANG2, Q.-X. YANG3, X.-R. SUN4 Medical Laboratory Diagnosis Center, Jinan Central Hospital, Jinan, Shangdong, China 1Ultrasonography, Weifang People’s Hospital Weifang, Shandong, China 2Center Laboratory, the Zhongshan Hospital of Zhongshan University, Guangzhou, Guangdong Province, China 3Surgery, Jinan Central Hospital, Jinan, Shangdong, China 4Clinical Laboratory, the Women and Children Hospital of Qingdao, Qingdao, Shandong, China Corresponding Author: Xuerong Sun, MD; e-mail: sxrrtyy@126.com 833

[1]  Ruolin Li,et al.  Clinicopathological and Prognostic Value of S100A4 Expression in Gastric Cancer: A Meta-Analysis , 2014, The International journal of biological markers.

[2]  F. T. ten Kate,et al.  Prognostic Biomarkers in Patients with Resected Cholangiocarcinoma: A Systematic Review and Meta-analysis , 2014, Annals of Surgical Oncology.

[3]  Shan Li,et al.  Clinicopathological and prognostic significance of S100A4 overexpression in colorectal cancer: a meta-analysis , 2013, Diagnostic Pathology.

[4]  Seung‐Mo Hong,et al.  S100A4 expression is a prognostic indicator in small intestine adenocarcinoma , 2013, Journal of Clinical Pathology.

[5]  Jun Liang,et al.  Clinicopathological significance of S100A4 expression in human hepatocellular carcinoma , 2013, The Journal of international medical research.

[6]  H. Zhao,et al.  S100A4 regulates motility and invasiveness of human esophageal squamous cell carcinoma through modulating the AKT/Slug signal pathway. , 2012, Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus.

[7]  Y. Glinka,et al.  Neuropilin-1 is expressed by breast cancer stem-like cells and is linked to NF-κB activation and tumor sphere formation. , 2012, Biochemical and biophysical research communications.

[8]  Xueqiong Zhu,et al.  Immunohistochemical expression of Annexin A2 and S100A proteins in patients with bulky stage IB-IIA cervical cancer treated with neoadjuvant chemotherapy. , 2012, Gynecologic oncology.

[9]  D. Komura,et al.  Stable knockdown of S100A4 suppresses cell migration and metastasis of osteosarcoma , 2011, Tumor Biology.

[10]  Guoyou Zhang,et al.  Knockdown of S100A4 decreases tumorigenesis and metastasis in osteosarcoma cells by repression of matrix metalloproteinase-9. , 2011, Asian Pacific journal of cancer prevention : APJCP.

[11]  Xu Ma,et al.  Small interfering RNA-directed knockdown of S100A4 decreases proliferation and invasiveness of osteosarcoma cells. , 2010, Cancer letters.

[12]  J. Adán,et al.  Overexpression of S100A4 in human cancer cell lines resistant to methotrexate , 2010, BMC Cancer.

[13]  G. Melloni,et al.  Prognostic Factors and Analysis of S100a4 Protein in Resected Pulmonary Metastases from Renal Cell Carcinoma , 2009, World Journal of Surgery.

[14]  J. Bovée,et al.  Osteosarcoma of the femur with skip, lymph node, and lung metastases. , 2008, Radiographics : a review publication of the Radiological Society of North America, Inc.

[15]  D. Helfman,et al.  The metastasis associated protein S100A4: role in tumour progression and metastasis , 2005, British Journal of Cancer.

[16]  E. Hovig,et al.  S100A4 regulates membrane induced activation of matrix metalloproteinase-2 in osteosarcoma cells , 2003, Clinical & Experimental Metastasis.

[17]  W. Park,et al.  Overexpression of S100A4 is closely related to the aggressiveness of gastric cancer , 2003, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[18]  L. Mazzucchelli Protein S100A4: too long overlooked by pathologists? , 2002, The American journal of pathology.

[19]  J. Winstanley,et al.  Prognostic significance of the metastasis-inducing protein S100A4 (p9Ka) in human breast cancer. , 2000, Cancer research.

[20]  O. T. Odegaard,et al.  S100A4 involvement in metastasis: deregulation of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in osteosarcoma cells transfected with an anti-S100A4 ribozyme. , 1999, Cancer research.

[21]  Yohko Nakamura,et al.  Expression of antisense RNA to S100A4 gene encoding an S100-related calcium-binding protein suppresses metastatic potential of high-metastatic Lewis lung carcinoma cells , 1997, Oncogene.

[22]  E. Hovig,et al.  Reversal of the in vivo metastatic phenotype of human tumor cells by an anti-CAPL (mts1) ribozyme. , 1996, Cancer research.

[23]  P. Rudland,et al.  Induction of the metastatic phenotype by transfection of a benign rat mammary epithelial cell line with the gene for p9Ka, a rat calcium-binding protein, but not with the oncogene EJ-ras-1. , 1993, Oncogene.