Original ArticleAnnexin A2 and S100A10 are independent predictors of serous ovarian cancer outcome
Introduction
Ovarian cancer is the most lethal gynecological cancer. Up to 70% of ovarian cancer patients are diagnosed at advanced stage (stage III and IV) with a 5-year survival rate of only 27%.1 More than 70% of epithelial ovarian cancers represent the serous histologic subtype.2 The standard treatment for ovarian cancer consists of radical debulking surgery and platinum containing chemotherapy. However, treatment outcome remains poor because of high recurrence rates and the development of chemoresistant disease.2 Prognostic markers are important for predicting outcome, to guide in the management of ovarian cancer patients and aid in the development of better therapeutic targets.3
Annexin A2, a calcium phospholipid binding protein, plays an important role in tumorigenesis.4 We have previously shown increased stromal annexin A2 protein expression in serous ovarian cancer tissues compared with the stroma of normal ovaries, serous cystadenomas, and noninvasive borderline ovarian tumors.5 Moreover, depletion of annexin A2 inhibited motility and invasion of ovarian cancer cells and adhesion to the peritoneal cells in vitro. Neutralizing annexin A2 antibodies effectively inhibited ovarian cancer cell invasion in the chick chorioallantoic membrane model and ovarian tumor growth and metastasis in the intraperitoneal xenograft mouse model.5 Annexin A2 has been shown to be a promising prognostic biomarker in various malignancies,6 and high annexin A2 immunostaining was associated with poor prognosis in non-small cell lung cancer,7, 8, 9 colorectal carcinoma,10, 11 cholangiocarcinoma,12 gastric carcinoma,13, 14 and glioma.15
S100A10, an annexin A2 binding protein, forms an annexin A2 heterotetramer on the cell surface of various tumor cells.16, 17 S100A10, also known as p11 protein, is a member of S100 protein family that has 2 EF-hand calcium binding motifs.18 S100A10 is a cytosolic protein and on binding to annexin A2, the annexin A2 heterotetramer complex translocates to the plasma membrane.19 It has been shown to play an important role in oncogenesis,17 and S100A10 protein expression has been characterized by immunohistochemistry in cancers of the bowel,20 thyroid,21 and kidney.22 There have been limited studies that have assessed the prognostic value of annexin A2 and S100A10 in serous ovarian cancer,23, 24 the most common and lethal ovarian cancer subtype. In this study, we investigated whether messenger RNA (mRNA) and protein expressions of both annexin A2 and S100A10 have prognostic utility in a uniform cohort of stage III serous ovarian cancer.
Section snippets
Tissue microarray cohort
Tissue microarrays (TMAs) were assembled from archived formalin-fixed paraffin embedded tissues obtained from 123 stage III serous ovarian cancer patients diagnosed between 1988 and 2010. Approval was obtained from the Royal Adelaide Hospital Human Ethics Committee (RAH protocol number 140101 and 060903) and study conforms to the ethical guidelines for human research. Each tissue block was represented by duplicate or triplicate 1.0 mm diameter tissue cores (cancer areas identified by
Strong correlation of annexin A2 and S100A10 expressions in primary ovarian tumors
Annexin A2 immunostaining was observed in the membrane and cytoplasm of serous ovarian cancer cells as well as the cancer-associated stroma. High membrane and cytoplasmic annexin A2 was observed in 77% (84/109) and 82.6% (90/109) of tumor tissues, respectively. High stromal annexin A2 expression was present in 58.7% (64/109) of the tumor tissues examined. Representative images of the annexin A2 immunostaining patterns are shown in Fig 1, A–D. Very similar staining patterns to annexin A2 were
Discussion
This is the first study to investigate the prognostic significance of both annexin A2 and its binding partner, S100A10, in serous ovarian cancer. We show that in FIGO stage III serous ovarian cancer (1) high ANXA2 mRNA expression or high stromal annexin A2 immunostaining predicts reduced PFS and OS, (2) high S100A10 mRNA or high cytoplasmic S100A10 staining expression predicts reduced OS, (3) ANXA2 and S100A10 are increased in the mesenchymal serous ovarian cancer subtype, and (4) both high
Conclusions
We demonstrated that annexin A2 and S100A10 mRNA and protein expressions are associated with poor prognosis in advanced serous ovarian cancer. The strength and uniqueness of our study is that we have examined the expressions of annexin A2 and S100A10 mRNA and protein levels in a uniform cohort of stage III serous ovarian cancer. Our findings highlight that both high expressions of stromal annexin A2 and cytoplasmic S100A10 in serous ovarian cancer are significantly associated with reduced PFS
Acknowledgments
Conflicts of Interest: All authors have read the journal’s policy on disclosure of potential conflicts of interest and have none to declare.
This research has been funded by the Ovarian Cancer Research Foundation (OCRF), Australia and the Cancer Council SA's Beat Cancer Project on behalf of its donors and the State Government of South Australia through the Department of Health.
The authors thank Mrs Wendy Bonner for her help with tissue sectioning.
All authors have read the journal's authorship
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