Epigenetic Targeting of Ovarian Cancer Stem Cells

• Published in: Cancer research (Chicago, Ill.) Vol. 74; no. 17; pp. 4922 - 4936
• Main Authors: YINU WANG, CARDENAS, Horacio, FANG FANG, CONDELLO, Salvatore, TAVERNA, Pietro, SEGAR, Matthew, YUNLONG LIU, NEPHEW, Kenneth P, MATEI, Daniela
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-09-2014
• Subjects: Aldehyde Dehydrogenase - genetics; Animals; Antineoplastic agents; Azacitidine - analogs & derivatives; Azacitidine - pharmacology; Biological and medical sciences; Carboplatin - pharmacology; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cell Line, Tumor; DNA Methylation - drug effects; DNA Methylation - genetics; Epigenesis, Genetic - drug effects; Epigenesis, Genetic - genetics; Epigenomics - methods; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Humans; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplastic Stem Cells - drug effects; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Pharmacology. Drug treatments; Tumors; Ovarian diseases; Target; Targeting; Ovary cancer; Stem cell; Epigenetics; Malignant tumor; Tumor cell; Cancer; Female genital diseases
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-14-1022

Emerging results indicate that cancer stem-like cells contribute to chemoresistance and poor clinical outcomes in many cancers, including ovarian cancer. As epigenetic regulators play a major role in the control of normal stem cell differentiation, epigenetics may offer a useful arena to develop strategies to target cancer stem-like cells. Epigenetic aberrations, especially DNA methylation, silence tumor-suppressor and differentiation-associated genes that regulate the survival of ovarian cancer stem-like cells (OCSC). In this study, we tested the hypothesis that DNA-hypomethylating agents may be able to reset OCSC toward a differentiated phenotype by evaluating the effects of the new DNA methytransferase inhibitor SGI-110 on OCSC phenotype, as defined by expression of the cancer stem-like marker aldehyde dehydrogenase (ALDH). We demonstrated that ALDH(+) ovarian cancer cells possess multiple stem cell characteristics, were highly chemoresistant, and were enriched in xenografts residual after platinum therapy. Low-dose SGI-110 reduced the stem-like properties of ALDH(+) cells, including their tumor-initiating capacity, resensitized these OCSCs to platinum, and induced reexpression of differentiation-associated genes. Maintenance treatment with SGI-110 after carboplatin inhibited OCSC growth, causing global tumor hypomethylation and decreased tumor progression. Our work offers preclinical evidence that epigenome-targeting strategies have the potential to delay tumor progression by reprogramming residual cancer stem-like cells. Furthermore, the results suggest that SGI-110 might be administered in combination with platinum to prevent the development of recurrent and chemoresistant ovarian cancer.