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

Abstract

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.

The enhanced delivery of salinomycin to CD133+ ovarian cancer stem cells through CD133 antibody conjugation with poly(lactic-co-glycolic acid)-poly(ethylene glycol) nanoparticles

“…Ovarian cancer is the most lethal gynecologic malignancy, with a majority of cases being diagnosed following metastasis of the disease (1). Due to the acquisition of chemoresistance by residual ovarian cancer cells, recurrence is frequent.…”

Ovarian cancer stem cells express ROR1, which can be targeted for anti–cancer-stem-cell therapy

“…Studies have identified phenotypic and functional characteristics of CSCs that may distinguish such cells from other neoplastic cells (7,8). Compared with other ovarian cancer cells, ovarian CSCs have relatively high aldehyde dehydrogenase (ALDH1) enzymatic activity (9)(10)(11), which may serve to detoxify intracellular aldehydes or various cytotoxic drugs (12,13).…”

“…Ovarian CSCs also can extrude small molecules, such as various chemotherapeutic drugs or fluorescent dyes, allowing for their identification as a less fluorescent "side population" in flowcytometric analysis of tumor cells stained with the DNA-binding dye Hoechst 33342 (14)(15)(16). Furthermore, ovarian CSCs may express various surface antigens, such as CD44, CD117, or CD133 (7,8,(17)(18)(19). Functionally, human ovarian CSCs apparently can form nonadherent cellular spheres, called "spheroids," which in turn are enriched for ovarian cancer cells that have high ALDH1 activity, are relatively resistant to chemotherapeutic drugs, and have enhanced potential for seeding metastatic sites or engrafting immune-deficient mice (5,17,18,(20)(21)(22).…”

Review: Mechanotransduction in ovarian cancer: Shearing into the unknown

“…Clinical research has shown that side populations of ovarian cancer cells found within the ascites can display the characteristics of both EMT and stem cell-like behavior. [119][120][121] EMT is an important part of ovarian cancer progression, in which free floating spheroids attach to the mesothelium, disseminate and metastasize to surrounding tissues. 122,123 Expression of CD44 and CA125, high levels of IL-6, CXR4, and CXCL12 and the amplification of PIK3CA, Akt and bone morphogenetic protein (BMP) pathways have been associated with ovarian cancer EMT.…”