Shed membrane fragment-associated markers for endometrial and ovarian cancers

OBJECTIVE: The objective of this study was to assess circulating tumor-derived membrane fragments (MFs) and specific proteins associated with them as diagnostic and prognostic markers for ovarian and endometrial cancers. METHODS: The level of shed tumor-derived plasma MFs was analyzed chromatographically on high exclusion limit agarose-based gels, using sera from non-cancer-bearing female controls (n = 50), women with ovarian disease (benign, n = 43, and stages III and IV ovarian cancer, n = 62), and women with early (n = 10) and late (n = 12) stage endometrial cancers. The presence of specific proteins on MFs associated with development and progression of cancer was examined by Western immunoblot, while the association of proteolytic enzymes with MFs was analyzed by zymography. RESULTS: Shed MFs were demonstrated in the circulation of women with both ovarian (4.12 plus minus 1.46 mg/ml) and endometrial cancers (2.53 +/- 0.34 mg/ml in women with stage I and 4.51 +/- 1.33 mg/ml with late stage); however, they were not demonstrated in control sera or in sera from women with benign disease. In endometrial cancer, the level of MFs correlated with the tumor's progression. Specific proteins, including MMP-2, MMP-9, and Fas ligand (FasL), were present on MFs from both endometrial and ovarian cancer sera. However, FasL (3.2-fold) and MMP-2 and -9 (5.9x and 7.5x, respectively) levels were significantly elevated on MFs from late stage cancer. CONCLUSION: This study demonstrates the unique elevation of circulating MFs in ovarian and endometrial cancer patients. The levels of specific MF-associated proteins differentiate between early and late stage endometrial cancers and benign versus malignant ovarian disease.