Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness

Szotek, Paul P.; Pieretti-Vanmarcke, Rafael; Masiakos, Peter T.; Dinulescu, Daniela M.; Connolly, Denise C.; Foster, Rosemary; Dombkowski, David; Preffer, Frederic I.; MacLaughlin, David T.; Donahoe, Patricia K.

doi:10.1073/pnas.0603672103

Cited by 686 publications

(617 citation statements)

References 40 publications

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“…As EMT is a required step in the generation and persistence of cancer stem cells (Mani et al, 2008), we attribute these findings to TG2's function of inducing and maintaining a mesenchymal phenotype. Along with others, we previously demonstrated that TG2 expression levels correlate with chemoresistance (Mehta et al, 2004;Cao et al, 2008), a characteristic of stem cells (Szotek et al, 2006), further supporting the link between TG2 and the OCIC phenotype. In summary, the current results provide strong evidence for the involvement of TGF-b in OC invasion and tumor progression through regulation of TG2.…”

Section: Tissue Transglutaminase L Cao Et Alsupporting

confidence: 78%

Tissue transglutaminase links TGF-β, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer

et al. 2011

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Tissue transglutaminase (TG2), an enzyme involved in cell proliferation, differentiation and apoptosis is overexpressed in ovarian carcinomas, where it modulates epithelial-to-mesenchymal transition (EMT) and promotes metastasis. Its regulation in ovarian cancer (OC) remains unexplored. Here, we show that transforming growth factor (TGF)-b, a cytokine involved in tumor dissemination is abundantly secreted in the OC microenvironment and induces TG2 expression and enzymatic activity. This is mediated at transcriptional level by SMADs and by TGFb-activated kinase 1-mediated activation of the nuclear factor-jB complex. TGF-b-stimulated OC cells aggregate as spheroids, which enable peritoneal dissemination. We show that TGF-b-induced TG2 regulates EMT, formation of spheroids and OC metastasis. TG2 knock-down in OC cells decreases the number of cells harboring a cancer stem cell phenotype (CD44 þ /CD117 þ ). Furthermore, CD44 þ /CD117 þ cells isolated from human ovarian tumors express high levels of TG2. In summary, TGFb-induced TG2 enhances ovarian tumor metastasis by inducing EMT and a cancer stem cell phenotype.

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Section: Tissue Transglutaminase L Cao Et Alsupporting

confidence: 78%

Tissue transglutaminase links TGF-β, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer

et al. 2011

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“…Several groups have shown that epithelial ovarian cancer initiates from the clonal expansion of a single progenitor cell (Jacobs et al, 1992;Mok et al, 1992). More recently, Szotek et al (2006) have demonstrated that a subpopulation of cells isolated from ovarian cancer cell lines and ascitic fluid of ovarian cancer patients phenotypically resembles cancer stem cells. In addition, Ferrandina et al (2007) used flow cytometry to find that CD133 þ cells were more frequently detected in primary ovarian cancers than in their metastatic omental lesions or in normal ovaries.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells

et al. 2008

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The cancer stem cell hypothesis posits that malignant growth arises from a rare population of progenitor cells within a tumor that provide it with unlimited regenerative capacity. Such cells also possess increased resistance to chemotherapeutic agents. Resurgence of chemoresistant disease after primary therapy typifies epithelial ovarian cancer and may be attributable to residual cancer stem cells, or cancer-initiating cells, that survive initial treatment. As the cell surface marker CD133 identifies cancerinitiating cells in a number of other malignancies, we sought to determine the potential role of CD133 þ cells in epithelial ovarian cancer. We detected CD133 on ovarian cancer cell lines, in primary cancers and on purified epithelial cells from ascitic fluid of ovarian cancer patients. We found CD133 þ ovarian cancer cells generate both CD133 þ and CD133À daughter cells, whereas CD133À cells divide symmetrically. CD133 þ cells exhibit enhanced resistance to platinum-based therapy, drugs commonly used as first-line agents for the treatment of ovarian cancer. Sorted CD133 þ ovarian cancer cells also form more aggressive tumor xenografts at a lower inoculum than their CD133À progeny. Epigenetic changes may be integral to the behavior of cancer progenitor cells and their progeny. In this regard, we found that CD133 transcription is controlled by both histone modifications and promoter methylation. Sorted CD133À ovarian cancer cells treated with DNA methyltransferase and histone deacetylase inhibitors show a synergistic increase in cell surface CD133 expression. Moreover, DNA methylation at the ovarian tissue active P2 promoter is inversely correlated with CD133 transcription. We also found that promoter methylation increases in CD133À progeny of CD133 þ cells, with CD133 þ cells retaining a less methylated or unmethylated state. Taken together, our results show that CD133 expression in ovarian cancer is directly regulated by epigenetic modifications and support the idea that CD133demarcates an ovarian cancer-initiating cell population. The activity of these cells may be epigenetically detected and such cells might serve as pertinent chemotherapeutic targets for reducing disease recurrence.

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“…Treatment with MIS is able to inhibit cell proliferation in both SP and non-SP cells, whereas classic chemotherapies inhibit mainly non-SP cells. Thus MIS is able to actively suppress growth of the chemoresistant SP subpopulation [165].…”

Section: Ovarian Cancer: Pluripotency and Putative Cscsmentioning

confidence: 99%

“…Gene expression profiles indicate that cells in the SP-gated fraction express high levels of stem-cell markers and low levels of differentiation markers [66]. Recently, an SP has been identified in two distinct mouse ovarian cancer cell lines as well as in human ovarian cell lines and primary ascites tumor cells [165]. These SP cells show growth characteristics similar to CSCs [71] and are capable of self-renewal and asymmetric division in culture.…”

Section: Ovarian Cancer: Pluripotency and Putative Cscsmentioning

confidence: 99%

“…These SP cells show growth characteristics similar to CSCs [71] and are capable of self-renewal and asymmetric division in culture. In vivo, ovarian SP cells have the potential to initiate tumor growth more quickly and at lower cell numbers than non-SP ovarian cancer cells [165]. Moreover, cell clones with sustained clonogenic potential in vitro and tumorgenicity in vivo, even after serial transplantation in mice, have been identified in ovarian cancer [16].…”

Section: Ovarian Cancer: Pluripotency and Putative Cscsmentioning

confidence: 99%

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Cancer stem cells as targets for cancer therapy: selected cancers as examples

Hombach‐Klonisch

Paranjothy

Wiecheć

et al. 2008

Arch. Immunol. Ther. Exp.

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It is becoming increasingly evident that cancer constitutes a group of diseases involving altered stem-cell maturation/differentiation and the disturbance of regenerative processes. The observed malignant transformation is merely a symptom of normal differentiation processes gone astray rather than the primary event. This review focuses on the role of cancer stem cells (CSCs) in three common but also relatively under-investigated cancers: head and neck, ovarian, and testicular cancer. For didactic purpose, the physiology of stem cells is first introduced using hematopoietic and mesenchymal stem cells as examples. This is followed by a discussion of the (possible) role of CSCs in head and neck, ovarian, and testicular cancer. Aside from basic information about the pathophysiology of these cancers, current research results focused on the discovery of molecular markers specific to these cancers are also discussed. The last part of the review is largely dedicated to signaling pathways active within various normal and CSC types (e.g. Nanog, Nestin, Notch1, Notch2, Oct3 and 4, Wnt). Different elements of these pathways are also discussed in the context

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Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness

Cited by 686 publications

References 40 publications

Tissue transglutaminase links TGF-β, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer

Tissue transglutaminase links TGF-β, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer

Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells

Cancer stem cells as targets for cancer therapy: selected cancers as examples

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