Identification and Characterization of a Stem Cell-Like Population in Ovarian Cancer
Sharrow, Allison Catherine
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Eighty percent of patients with advanced ovarian cancer show an initial clinical response to therapy, but seventy-five percent of these patients eventually relapse. This transient clinical response would be consistent with the cancer stem cell hypothesis. A substantial body of recent evidence supports the cancer stem cell hypothesis in ovarian cancer. However, controversy exists regarding the phenotype of ovarian cancer stem cells. Additionally, their clinical relevance remains unclear. In order to test the hypothesis that ovarian cancer contains a population of stem-like cells, aldehyde dehydrogenase 1 high (ALDHhigh) cells from two ovarian cancer cell lines with distinct subtypes were examined for cancer stem cell properties. Compared to ALDHlow cells, ALDHhigh cells displayed nonadherent growth, an absence of contact inhibition, smaller size, quiescence, the ability to regenerate the phenotypic diversity of the cell line, in vivo tumorigenicity, multi-drug resistance, and gene expression differences consistent with a stem cell phenotype. Because ALDHhigh cells phenotypically resemble cancer stem cells, studying this population in two different subtypes may reveal biological properties of ovarian cancer stem cells. Differential gene expression suggested that the ALDHhigh population had increased tight junction signaling, downregulation of tumor suppressors, increased invasion, and decreased coagulation. No consistent differences were observed in previously reported ovarian cancer stem cell markers, hormone receptors, Her-2/neu, CA125 or developmental pathways. The only ABC transporter with consistent upregulation was MDR1. The ultimate goal of studying ovarian cancer stem cells is to develop therapies to eradicate these cells. Gene expression patterns in ALDHhigh cells identified four potential therapeutic targets: mTOR, Her-2/neu, CD47 and FGF18. This project provides further support for the existence of ovarian cancer stem cells as well as the use of high aldehyde dehydrogenase 1 activity for their isolation. Few studies have comprehensively examined ovarian cancer stem cells from multiple subtypes. This work demonstrated substantial variability between the two studied subtypes. However, those features that were consistent would likely represent universal features of ovarian cancer stem cells. Finally, the potential therapeutic targets identified in this study may allow patients with ovarian cancer to achieve durable remission.