In this comprehensive study, expression of S100A1 was found to be increased at the mRNA and protein levels in ovarian cancer tissues and cell lines as detected by several techniques, whereas expression in normal ovarian tissues and cell lines was low.
We also examined S100A1 expression on TMAs and correlated the results with tumor stage, grade, and survival. In the small subset of endometrioid subtype of ovarian cancers that expressed S100A1, relapse-free survival was significantly shorter. Half of the patients with S100A1+ endometrioid tumors had recurrent ovarian cancer within 11 years of diagnosis, whereas fewer than 20% of patients with S100A1− endometrioid tumors had recurrent ovarian cancer at the end of the study (18 years). These findings were recapitulated in S100A1+ endometrial endometrioid cancers as well, strengthening the results. Overall, the survival rates for endometrioid ovarian cancer are superior to those of other ovarian cancer subtypes.25
Our findings in this study suggest that S100A1 expression could represent a way to predict which patients will have earlier relapse.
Previous studies have found a correlation between the presence of intraepithelial CD8+ T cells and improved survival in ovarian cancer.26,27
By using the same ovarian TMAs that we used in this study, Clarke et al28
stained for T cells using antibodies against CD3 (a pan–T-cell marker), CD4, and CD8 (T-cell subset-specific markers). They found that although the presence of CD3+ intraepithelial T cells improved disease-specific survival in the serous subtype, only the presence of CD8+ intraepithelial T cells correlated with improved disease-specific survival in the entire cohort, including serous, endometrioid, and clear cell subtypes.28
When the T-cell marker results were analyzed in conjunction with our S100A1 endometrioid ovarian cancer data, an inverse correlation between CD3+ T cells and S100A1 expression was found to be significant (P
= .004). Thus, S100A1+ tumors tended to lack CD3+ T cells, which may partially explain the shorter relapse-free survival of the patients. When expression of S100A1 and the presence of CD8+ T cells were analyzed, however, there was no significant correlation (P
Recent studies using the same TMAs have found type 1 histone deacetylases (HDACs) to be markers of poor prognosis in endometrioid ovarian cancer.16
Specifically, expression of HDAC1 in multivariable survival analysis inversely correlated with relapse-free survival.16
A similar trend toward worse prognosis with HDAC1 expression in endometrioid endometrial cancers was also found.16
When analyzed with our immunohistochemical data for S100A1 staining, no significant correlation between the S100A1 and HDAC1 expression was found. Thus, the 2 markers identify different subsets of endometrioid ovarian cancer patients with decreased relapse-free survival. In prospective clinical trials, one could envision that tissues from patients with the endometrioid subset of ovarian cancer would be tested by immunohistochemical staining for HDAC1 and S100A1. The patients whose tissues stained positively for either marker would be monitored more closely for recurrence or could be candidates for additional therapy owing to the likelihood of a decreased relapse-free survival time.
High-grade serous tumors had increased S100A1 staining (66.0%) compared with low-grade serous tumors (25%). Although not fully understood, it is proposed that low- and high-grade serous tumors have different routes to pathogenesis. Malpica et al18
found that although 60% of low-grade serous tumors were associated with a serous neoplasm of low malignant potential, only 2% of high-grade serous tumors had a similar association. Although they have similar histologic features, low- and high-grade tumors likely arise from different molecular mechanisms, which could explain the difference in staining that we found in the TMAs.
The S100 family of proteins consists of more than 20 calcium-binding proteins. Binding of calcium induces a conformational change, allowing interaction with target proteins.29
Increased expression of S100 family members, including S100A1, has been reported in several tumors. Several groups have identified increased S100A1 expression in renal cell carcinoma, and although the functional significance is not well understood, expression may be useful in differential diagnosis among renal cell carcinoma subtypes.23,30–32
In other tissues, S100A1 is involved in muscle contraction,33–35
and cell structure.38
The role of S100A1 in ovarian cancer is unknown, but potentiation of antiapoptotic pathways represents one possible mechanism. Exogenous S100A1 can activate the receptor for advanced glycation end products, resulting in activation of the NF-κB signaling pathway, increasing the antiapoptotic protein bcl-2 and survival.39
S100A1 can also activate the Erk1/2 signaling cascade, resulting in increased resistance to apoptosis.
To date, there have been no reports of S100A1 being secreted in cancer. However, bulky tumors harbor areas of central necrosis with relative hypoxemia.40,41
Necrotic cells could release S100A1, providing it to nearby cells, preventing apoptosis, and imparting a survival advantage. Likewise, ovarian cancer cells are able to survive the relative hypoxia of ascitic fluid, which may provide a similar stress stimulus.42
Whether S100A1 will be an exploitable therapeutic target is unclear. Our seemingly discordant observations that S100A1-expressing serous ovarian cancer tumors were of higher grade but similar prognosis, whereas among endometrioid histologies, S100A1 expression did not correlate with grade or stage but appeared to impart a significantly worsened prognosis, may be the coincidental result of subgroup analysis or overmatching. However, the results from the endometrial TMAs recapitulate the results from the endometrioid ovarian carcinomas, making this highly unlikely. Alternatively, the observed survival difference may represent a true decrease in the normally superior survival of endometrioid carcinomas in the group overexpressing S100A1 (to the level expected for serous or clear cell tumors), whereas the subset not expressing S100A1 retains a relatively favorable prognosis.25
This is the first report demonstrating that S100A1 is specifically and frequently overexpressed in ovarian cancer. Although expression did not uniformly correlate with known prognostic indicators such as stage, it was associated with worsened cytologic features in serous tumors and worse clinical outcomes for patients with endometrioid ovarian cancer. Given our findings of worsened overall prognosis in a subset of patients, the role of S100A1 in ovarian cancer biology and tumor surveillance merits further study.