CD133 expression associated with poor prognosis in ovarian cancer

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Modern Pathology (Impact Factor: 6.36). 11/2011; 25(3):456-64. DOI: 10.1038/modpathol.2011.170
Source: PubMed

ABSTRACT As a putative marker for cancer stem cells in human malignant tumors, including ovarian cancer, CD133 expression may define a tumor-initiating subpopulation of cells and is associated with the clinical outcome of patients. However, at this time its clinical significance in ovarian cancer remains uncertain. The aim of this study was to clarify the clinical role of CD133 expression in human ovarian cancer. Immunohistochemical staining of CD133 expression was performed in 400 ovarian carcinoma samples using tissue microarray. The associations among CD133 expression and clinical factors (diagnosis, tumor grade, cancer stage, and clinical response to chemotherapy), overall survival and disease-free survival time were analyzed. CD133 expression was found in 31% of ovarian carcinoma samples. Fisher's exact test and one-way analysis of variance suggested that CD133 expression was associated with high-grade serous carcinoma (P=0.035), late-stage disease (P<0.001), ascites level (P=0.010), and non-response to chemotherapy (P=0.023). CD133 expression was also associated with shorter overall survival time (P=0.007) and shorter disease-free survival time (P<0.001) by log-rank test. Moreover, CD133 expression was an independent predictor of shorter disease-free survival time in an unconditional logistic regression analysis with multiple covariates (P=0.024). Our results thus show that CD133 expression is a predictor of poor clinical outcome for patients with ovarian cancer, supporting the proposed link between CD133 and cancer stem cells.

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    ABSTRACT: Seventy percent of ovarian cancer patients die due to consecutive episodes of recurrences resulting from the re-growth of ovarian tumor cells resistant to conventional chemotherapies. In an effort to identify chemoresistance mechanisms, we compared the expression of genes in tumor cells isolated from the ascites of advanced-stage serous ovarian cancer patients prior to (chemonaive, CN) and after chemotherapy treatments (chemoresistant/recurrent, CR). A novel, recently published method was used for the isolation of tumor cells from the ascites of CN and CR patients. Illumina HT-12 platform was used to assess the differential expression of genes (DEGs) between the isolated tumor cells from the ascites of CN and CR patients. The identification of DEGs was achieved by comparing the genetic signatures of CN versus CR samples by a mean expression ratio (fold change) of 2 and P < 0.05. Validation of selected genes was performed by quantitative Real Time Polymerase Chain Reaction (qRT-PCR). The dominant canonical pathways in the CR versus CN tumor cells were determined by Ingenuity Pathway Analysis. Gene expression analysis revealed differential expression of 414 genes, with 179 genes up regulated and 235 down regulated in the CR group. There were significant differences in gene expressions encoding for proteins involved with cancer stem cells, cell-cell adhesion, embryonic development, tumor suppression, immune surveillance, retinoic acid and energy metabolism in tumor cells isolated from CR compared to CN patients. Pathway analysis revealed that changes in cell cycle pathways, prominently those involved with mitosis and polo-like kinase (PLK1), G2/M DNA damage and proteins linked with cell cycle checkpoint regulation associated with chemoresistance. This preliminary molecular profiling, on a small number of patient samples, suggests an important discrimination of genes in the isolated tumor cells derived from the ascites of CN and CR patients. This type of study on a larger cohort of samples may have important clinical implications for the development of therapeutic strategies to overcome chemoresistance and associated recurrences in ovarian cancer patients.
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    ABSTRACT: Background: Cancer stem cells (CSCs) are believed to comprise a limited percentage of the malignant tumor cells; yet, they are considered the driving force behind cancer. The presence of such cells could explain why cancer often relapses despite a complete clinical remission with initial therapy; with time, a few residual treatment-resistant stem cells may repopulate the tumor. CD133 has been reported as a marker of CSCs in many malignant neoplasms, with few reports in ovarian carcinoma. Objectives: To demonstrate the CSCs in ovarian malignant surface epithelial tumors by immunohistochemical (IHC) expression of CD133 and to analyze the association of its expression with clinicopathological parameters. Materials and methods: The material of the study included paraffin blocks of tissue specimens from 54 surface epithelial ovarian carcinomas obtained from the archival file of the Early Cancer Detection Unit, Gynecology and Obstetrics Hospital, Ain-Shams University (Cairo, Egypt). Three normal ovaries and Fallopian tubes from radical specimens, and six cases of benign ovarian mucinous cystadenoma were also collected. IHC staining with monoclonal antibodies against CD133 was used for all specimens. The association of CD133 expression with clinicopathological data was analyzed. Results: The present study included 54 cases of malignant epithelial ovarian tumors. They included 15 cases of serous carcinoma (27.7%), 18 cases of mucinous carcinoma (33.3%), 12 cases of endometrioid carcinoma (22.2%), three cases of clear cell carcinoma (5.6%), three cases of mixed epithelial tumors (5.6%), and three cases of malignant Brenner tumor (5.6%). CD133 IHC expression was positive in 33 cases (61.1%) of primary surface epithelial ovarian carcinoma samples (60% of serous carcinoma, 50% of mucinous and endometrioid carcinoma, and all cases of clear cell carcinoma, malignant Brenner tumor, and mixed epithelial carcinoma), in one case (33.3%) of both normal ovarian and Fallopian tissue samples, and three cases (60%) of cystadenoma samples. We observed different distinct staining patterns among these groups. We found no association between CD133 expression and histopathological grade (χ2=1.403, P=0.236), surgical stage (χ2=1.48, P=0.223), bilaterality (χ2=0.3, P=0.57), ascites (χ2=2.24, P=0.13), omental metastases (χ2=0.7, P=0.24), and distant metastases (χ2=0.351, P=0.27). However, the expression of CD133 was associated with the absence of uterine and tubal metastases (χ2=3.89, P=0.024) and lymph node metastases (χ2=3.506, P=0.03). Conclusion: We conclude that a considerable percentage (61.1%) of all types of ovarian malignant surface epithelial tumors harbor CSCs; moreover, CD133 can be considered a useful and reliable marker for detecting human ovarian CSCs by immunohistochemistry in these tumors.
    01/2012; 32(2):192-197. DOI:10.1097/01.XEJ.0000421476.64126.8b
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    ABSTRACT: IntroductionElafin is an endogenous serine protease inhibitor. The majority of breast cancer cell lines lack elafin expression compared to human mammary epithelial cells. In this study, we hypothesized that elafin is downregulated during breast and ovarian tumorigenesis.Methods We examined elafin expression by immunohistochemistry (IHC) in specimens of normal breast tissue (n¿=¿24), ductal carcinoma in situ (DCIS) (n¿=¿54), and invasive breast tumor specimens (n¿=¿793). IHC analysis of elafin expression was also performed in normal fallopian tube tissue (n¿=¿20), ovarian cystadenomas (n¿=¿9), borderline ovarian tumors (n¿=¿21), and invasive ovarian carcinomas (n¿=¿216). To understand the significance of elafin in luminal breast cancer cell lines, wild type or M25G elafin (lacking the protease inhibitory function) were exogenously expressed in MCF-7 and T47D cells.ResultsElafin expression was downregulated in 24% of DCIS and 83% of invasive breast tumors when compared to elafin expression in the normal mammary epithelium. However, the presence of elafin positive cells in invasive breast tumors, even at low frequency, correlated with poor recurrence-free survival (RFS), reduced overall survival (OS), and clinicopathological markers of aggressive tumor behavior. Elafin positive cells were an especially strong and independent prognostic marker of reduced RFS in IHC-defined luminal A-like tumors. Elafin was also downregulated in 33% of ovarian cystadenomas, 43% of borderline ovarian tumors, and 86% of invasive ovarian carcinomas when compared to elafin expression in the normal fallopian tube. In ovarian tumors, elafin positive cells were correlated with reduced RFS, OS and disease specific survival (DSS) only in stage I/II patients and not in stage III/IV patients. Notably, exogenous expression of elafin or elafin M25G in the luminal breast cancer cell lines MCF-7 and T47D significantly decreased cell proliferation in a protease inhibitory domain independent manner.Conclusions Elafin predicts poor outcome in breast and ovarian cancer patients delineates a subset of endocrine receptor positive breast cancer patients susceptible to recurrence whom could benefit from more aggressive intervention. Our in vitro results suggest that elafin arrests cell luminal breast cancer cells, perhaps suggesting a role in tumor dormancy.
    Breast cancer research: BCR 12/2014; 16(6):3417. DOI:10.1186/s13058-014-0497-4 · 5.88 Impact Factor


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