The cancer stem cell (CSC) theory proposes that a minor population in tumor cells with specific features, such as self-renewal and reproducible tumor phenotype could contribute to tumor relapse and chemotherapy resistance. Several studies have convincingly documented the existence of ovarian CSC, but questions related to the biologic behavior and specific biomarkers of ovarian CSC remain to be clarified. In the present study, we firstly established a tumor cell line with capability of regenerating tumors through serial transplantation of ovarian tumor tissue in non-obese/severe combined immunodeficient (SCID) mice. After separation of CD133+ cells with magnetic beads, we compared the phenotype and biologic behavior of CD133+ versus CD133-cells. It was found that the CD133+ cells were much more potent to produce colonies in semi-solid agar culture than CD133-cells. The proportion of the cells in G0/1 cell cycle is much higher in CD133+ cells than in CD133-cells. Furthermore, in vivo experiments demonstrated that the CD133+ cells were capable of repeatedly regenerate tumors in NOD/SCID mice, while the CD133-cells were not. Compared with CD133-cells, the CD133+ cells expressed much higher levels of the stem cell markers Oct4, Sox2, Nanog and Mcl-1. Clinically, among a total of 290 ovarian epithelial cancers, increased level of CD133 expression was positively correlated with a high cancer stage and had a worse 5-year survival rate. Taken together, the results suggest that the CD133+ cells from human ovarian cancer have the characteristics of CSC, which may contribute to ovarian cancer relapse and anti-apoptotic activity. The method of ovarian CSC enrichment we established provides a feasible and practical way of ovarian cancer research in a molecular level. In addition, CD133 may be used as a prognostic marker for ovarian epithelial cancer, which may have a role for future therapeutic effect.

Introdução: Anormalidades nos supressores tumorais p14, p16 e p53 são relatadas em diversos tipos de câncer em humanos. Na carcinogênese ovariana, p16 e p53 foram extensivamente estudados, mas p14 foi analisado somente em carcinomas. Objetivo: O estudo visa determinar a expressão imuno-histoquímica de p14, p16 e p53 em tumores ovarianos epiteliais benignos, borderline e malignos. Método: Estudo transversal utilizando imuno-histoquímica em amostras de tumores epiteliais ovarianos emblocados em parafina do Hospital de Clínicas de Porto Alegre. Resultados: p14 foi positivo em 93% dos tumores benignos, 94% dos borderline e 60% dos malignos. A perda de expressão foi estatisticamente associada com carcinomas. p16 foi positivo em 94,6% dos carcinomas, 75% dos tumores borderline e 45,7% dos benignos. p53 foi positivo em 29,7%, 16,7% e 2,9% dos tumores malignos, borderline e benignos, respectivamente. Os subtipos de carcinoma não mostraram diferenças de expressão. Conclusão: Nosso estudo foi o primeiro a descrever a expressão de p14 em tumores benignos e borderline. Ela permanece estável nos benignos e borderline, enquanto os carcinomas exibem uma perda de expressão significativa. Isso pode indicar que anormalidades de p14 acontecem tardiamente na carcinogênese. As taxas de expressão de p16 e p53 foram semelhantes a estudos anteriores. Estudos futuros devem investigar anormalidades genéticas nas sequencias codificadoras de p14 e incluir todos os tipos de tumor epitelial ovariano. / Background: Abnormalities in tumor suppressors p14, p16 and p53 are reported in several human cancers. In ovarian carcinogenesis, p16 and p53 have been extensively studied, but p14 was only analyzed in carcinomas. Aim: This study seeks to determine p14, p16 and p53 immunohistochemical expression in benign, borderline and malignant ovarian epithelial tumors and correlate them with survival and clinical variables. Methods: Cross-sectional study utilizing immunohistochemical staining of p14, p16 and p53 in paraffin-embedded tissue samples from ovarian epithelial tumors obtained from Hospital de Clinicas de Porto Alegre. Results: p14 was positive in 93% of benign, 94% of borderline and 60% of malignant tumors. Loss of expression was statistically associated with carcinomas. p16 was positive in 94.6% of carcinomas, 75% of borderline and 45.7% of benign tumors. p53 was positive in 29.7%, 16.7% and 2.9% of malignant, borderline and benign tumors, respectively. Carcinoma subtypes showed no difference in expression. Conclusions: To our knowledge, this is the first description of p14 expression in benign and borderline tumors. It remains stable in benign and borderline tumors, while carcinomas show a significant absence of staining. This may indicate p14 abnormalities occur later in carcinogenesis. p16 and p53 expression rates show similar results to previous reports. Future studies should investigate genetic abnormalities in p14 coding sequences and include all types of ovarian epithelial tumors.

Introdução: Anormalidades nos supressores tumorais p14, p16 e p53 são relatadas em diversos tipos de câncer em humanos. Na carcinogênese ovariana, p16 e p53 foram extensivamente estudados, mas p14 foi analisado somente em carcinomas. Objetivo: O estudo visa determinar a expressão imuno-histoquímica de p14, p16 e p53 em tumores ovarianos epiteliais benignos, borderline e malignos. Método: Estudo transversal utilizando imuno-histoquímica em amostras de tumores epiteliais ovarianos emblocados em parafina do Hospital de Clínicas de Porto Alegre. Resultados: p14 foi positivo em 93% dos tumores benignos, 94% dos borderline e 60% dos malignos. A perda de expressão foi estatisticamente associada com carcinomas. p16 foi positivo em 94,6% dos carcinomas, 75% dos tumores borderline e 45,7% dos benignos. p53 foi positivo em 29,7%, 16,7% e 2,9% dos tumores malignos, borderline e benignos, respectivamente. Os subtipos de carcinoma não mostraram diferenças de expressão. Conclusão: Nosso estudo foi o primeiro a descrever a expressão de p14 em tumores benignos e borderline. Ela permanece estável nos benignos e borderline, enquanto os carcinomas exibem uma perda de expressão significativa. Isso pode indicar que anormalidades de p14 acontecem tardiamente na carcinogênese. As taxas de expressão de p16 e p53 foram semelhantes a estudos anteriores. Estudos futuros devem investigar anormalidades genéticas nas sequencias codificadoras de p14 e incluir todos os tipos de tumor epitelial ovariano. / Background: Abnormalities in tumor suppressors p14, p16 and p53 are reported in several human cancers. In ovarian carcinogenesis, p16 and p53 have been extensively studied, but p14 was only analyzed in carcinomas. Aim: This study seeks to determine p14, p16 and p53 immunohistochemical expression in benign, borderline and malignant ovarian epithelial tumors and correlate them with survival and clinical variables. Methods: Cross-sectional study utilizing immunohistochemical staining of p14, p16 and p53 in paraffin-embedded tissue samples from ovarian epithelial tumors obtained from Hospital de Clinicas de Porto Alegre. Results: p14 was positive in 93% of benign, 94% of borderline and 60% of malignant tumors. Loss of expression was statistically associated with carcinomas. p16 was positive in 94.6% of carcinomas, 75% of borderline and 45.7% of benign tumors. p53 was positive in 29.7%, 16.7% and 2.9% of malignant, borderline and benign tumors, respectively. Carcinoma subtypes showed no difference in expression. Conclusions: To our knowledge, this is the first description of p14 expression in benign and borderline tumors. It remains stable in benign and borderline tumors, while carcinomas show a significant absence of staining. This may indicate p14 abnormalities occur later in carcinogenesis. p16 and p53 expression rates show similar results to previous reports. Future studies should investigate genetic abnormalities in p14 coding sequences and include all types of ovarian epithelial tumors.

Introdução: Anormalidades nos supressores tumorais p14, p16 e p53 são relatadas em diversos tipos de câncer em humanos. Na carcinogênese ovariana, p16 e p53 foram extensivamente estudados, mas p14 foi analisado somente em carcinomas. Objetivo: O estudo visa determinar a expressão imuno-histoquímica de p14, p16 e p53 em tumores ovarianos epiteliais benignos, borderline e malignos. Método: Estudo transversal utilizando imuno-histoquímica em amostras de tumores epiteliais ovarianos emblocados em parafina do Hospital de Clínicas de Porto Alegre. Resultados: p14 foi positivo em 93% dos tumores benignos, 94% dos borderline e 60% dos malignos. A perda de expressão foi estatisticamente associada com carcinomas. p16 foi positivo em 94,6% dos carcinomas, 75% dos tumores borderline e 45,7% dos benignos. p53 foi positivo em 29,7%, 16,7% e 2,9% dos tumores malignos, borderline e benignos, respectivamente. Os subtipos de carcinoma não mostraram diferenças de expressão. Conclusão: Nosso estudo foi o primeiro a descrever a expressão de p14 em tumores benignos e borderline. Ela permanece estável nos benignos e borderline, enquanto os carcinomas exibem uma perda de expressão significativa. Isso pode indicar que anormalidades de p14 acontecem tardiamente na carcinogênese. As taxas de expressão de p16 e p53 foram semelhantes a estudos anteriores. Estudos futuros devem investigar anormalidades genéticas nas sequencias codificadoras de p14 e incluir todos os tipos de tumor epitelial ovariano. / Background: Abnormalities in tumor suppressors p14, p16 and p53 are reported in several human cancers. In ovarian carcinogenesis, p16 and p53 have been extensively studied, but p14 was only analyzed in carcinomas. Aim: This study seeks to determine p14, p16 and p53 immunohistochemical expression in benign, borderline and malignant ovarian epithelial tumors and correlate them with survival and clinical variables. Methods: Cross-sectional study utilizing immunohistochemical staining of p14, p16 and p53 in paraffin-embedded tissue samples from ovarian epithelial tumors obtained from Hospital de Clinicas de Porto Alegre. Results: p14 was positive in 93% of benign, 94% of borderline and 60% of malignant tumors. Loss of expression was statistically associated with carcinomas. p16 was positive in 94.6% of carcinomas, 75% of borderline and 45.7% of benign tumors. p53 was positive in 29.7%, 16.7% and 2.9% of malignant, borderline and benign tumors, respectively. Carcinoma subtypes showed no difference in expression. Conclusions: To our knowledge, this is the first description of p14 expression in benign and borderline tumors. It remains stable in benign and borderline tumors, while carcinomas show a significant absence of staining. This may indicate p14 abnormalities occur later in carcinogenesis. p16 and p53 expression rates show similar results to previous reports. Future studies should investigate genetic abnormalities in p14 coding sequences and include all types of ovarian epithelial tumors.

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