Abstract
The initial aim of this study was to identify novel serum diagnostic markers for the human ovarian granulosa cell tumor (GCT), a tumor that represents up to 5% of all ovarian cancers. To circumvent the paucity of human tissues available for analyses, we used the Ctnnb1 tm1Mmt/+;Pten tm1Hwu/tmiHwu;Amhr2 tm3(cre)Bhr/+ transgenic mouse model, which features the constitutive activation of CTNNB1 signaling combined with the loss of Pten in granulosa cells and develops GCTs that mimic aggressive forms of the human disease. Proteomic profiling by mass spectrometry showed that vinculin, enolase 1, several heat shock proteins, and valosin containing protein (VCP) were more abundantly secreted by cultured mouse GCT cells compared to primary cultured GC. Among these proteins, only VCP was present in significantly increased levels in the preoperative serum of GCT cancer patients compared to normal subjects. To determine the specificity of VCP, serum levels were also measured in ovarian carcinoma, non-Hodgkin's lymphoma and breast, colon, pancreatic, lung, and prostate cancer patients. Increased serum VCP levels were observed in the majority of cancer cases, with the exception of patients with lung or prostate cancer. Moreover, serum VCP levels were increased in some GCT, ovarian carcinoma, breast cancer, and colon cancer patients who did not otherwise display increased levels of widely used serum tumor markers for their cancer type (e.g. inhibin A, inhibin B, CA125, CEA, or CA15.3). These results demonstrate the potential use of VCP as highly sensitive serum marker for GCT as well as several other human cancers.
Highlights
Serum markers are of considerable value for the clinical screening, diagnosis, and follow-up of cancers
Proteins from the media were separated by SDS-PAGE and fourteen protein bands observed in granulosa cell tumor (GCT) but not in GC medium were subjected to mass spectrometry analysis (Figure 1)
To determine the specificity of valosin containing protein (VCP) as a tumor marker for GCT, serum VCP levels were assessed in patients with ovarian carcinomas, as well as in small cohorts of patients with major non-ovarian cancers of known histology and grade (Table 3)
Summary
Serum markers are of considerable value for the clinical screening, diagnosis, and follow-up of cancers. Most currently used serum markers are hormones, glycoproteins, or other proteins overexpressed by cancer cells. These markers are usually not specific to a unique cancer type and sometimes lack sensitivity [1]. An alternative two-step approach involves the initial identification of proteins that are differentially expressed and/or secreted between normal and tumor cells, followed by the identification of these proteins in the serum of cancer patients. This approach ideally requires the isolation of primary tumor cells and corresponding normal cells. The use of relevant animal models of tumor development can provide essential starting materials for proteomic or genomic analysis, and lead to the identification of tumorspecific candidate proteins or genes whose expression can be be investigated in human samples, as demonstrated in ovarian cancer [3,4,5]
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