The aim of this study was to establish the immunohistochemical localisation of 3 putative biomarkers of ovarian cancer and evaluate their utility as aids in the diagnosis of ovarian cancer in symptomatic women.
The data obtained identify cancer-associated changes in the immunohistochemical expression of all 3 antigens within the ovary. Immunoreactive hCAP-18 and ir lactoferrin was localised to ovarian epithelial cells and its expression was greater in cases compared to controls. The expression of ir CD163 was confined to stromal cells but was similarly increased in tissues obtained from women with ovarian cancer. The ir expression of all 3 biomarkers was significantly increased in grade 1 ovarian cancer tissues. These data are consistent with the hypothesis that these mediators may participate in cell transformation and development of metastatic potential.
Individually, the plasma concentrations of the biomarkers displayed only modest diagnostic efficiency (as indicated by AUC of less than 0.7). In combination as a 3-biomarker panel (multivariate index assay, MIA), however, AUC increased to 0.95 and, as such, may be of utility as an aid in the diagnosis of ovarian cancer in symptomatic women. While this phase 1 biomarker trial provides an estimate of diagnostic efficiency based on AUC, a larger phase 2 biomarker trial would be required to provide robust estimates of the sensitivity and specificity of the MIA.
Previously, hCAP-18 has been described in breast cancer , where hCAP-18 was constitutively expressed in normal mammary gland epithelium and significantly increased in high-grade tumours. While there was some variance of hCAP-18 expression within groups, the study concluded that there was a potential correlation between degree of malignancy of breast cancer and hCAP-18 expression. This association was further explored , finding that treatment with hCAP-18/LL-37 altered the growth phenotype of breast cancer cells and stimulated migration. Together with a lung cancer study  that also found over-expression of hCAP-18/LL-37 increased tumour growth, it is concluded that hCAP-18 contributes to cancer metastasis.
Differential expression of hCAP-18 has also been reported in ovarian cancer , where it was over-expressed in ovarian cancer tumours when compared to normal ovarian tissue. This finding correlates with the breast and lung cancer studies, where high-grade tumours express elevated levels of hCAP-18 when compared to controls. Our study, however, shows that normal ovarian tissue does not express hCAP-18 and the highest amount of staining was in grade 1 tumour, not grade 3. The concentration of hCAP-18 in blood was significantly increased in benign and borderline samples when compared to controls and graded tumours. This dissimilarity may be due to a number of factors; very limited sample numbers, or there could be a difference in the expression of soluble hCAP-18 in the blood and expression in tissues. There are, however, no studies that measure circulating hCAP-18 concentrations in the blood of cancer patients to verify this difference. Besides the recent studies of its role in cancer metastasis, hCAP-18 has been mostly been linked with wound healing and inflammatory disorders [10, 46, 47]. The results found in this study indicate the need for further studies using a larger cohort of blood samples.
CD163 has been identified, previously, in non-neoplastic monocytes/macrophages and neoplasms of monocyte/histiocyte derivation . CD163 is strongly expressed in “tumour-associated macrophages” and in a number of cancer types its expression is associated with survival [49, 50], reflecting the tumour supportive nature of tumour-associated macrophages . Monocytes express CD163 constitutively at low levels, and expression increases during macrophage differentiation  and infiltration . Increased sCD163 concentrations in plasma have been reported in pathological conditions, including sepsis and liver disease . There, however, is no clinical or biochemical evidence for inflammatory co-morbidity that explains the increase in sCD163 concentrations in these patients. It, therefore, is possible that the increased sCD163 is directly related to tumour-associated macrophages and other bone marrow-derived cells involved in e.g. tumour angiogenesis .
The present study involves analysis of three biomarkers in women with ovarian cancer, ranging from normal and benign to all grades of disease. While analysis of each group separates this study from others in the literature, the small sample sizes is a limitation and also the crux of the problem, as ovarian cancer is rarely caught in its early stages. Further, the biomarkers should be compared to CA-125, the gold standard in detecting advanced ovarian cancer; however, CA-125 was not measured in the control group (including benign and borderline samples) and analysis cannot be performed. While age did not affect the results in this study (data not shown), of note is whether patient history of inflammatory diseases and tumour subtype affected the expression of each biomarker. These cannot be addressed for this study (inability to access patient history after project conclusion and very small sample size), but future studies building tissue banks would benefit from obtaining these data sets for their samples.