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Characterization of SOX2, OCT4 and NANOG in Ovarian Cancer Tumor-Initiating Cells

1
Biology Department, San Diego State University, San Diego, CA 92106, USA
2
Moores Cancer Center, University of California San Diego, La Jolla, CA 92037, USA
*
Author to whom correspondence should be addressed.
Cancers 2021, 13(2), 262; https://doi.org/10.3390/cancers13020262
Received: 18 November 2020 / Revised: 29 December 2020 / Accepted: 8 January 2021 / Published: 12 January 2021
SOX2, OCT4, and NANOG are enriched in ovarian cancer spheroids and correlate with tumor-initiating cell markers, CD117 and ALDH/CD133. SOX2, relative to OCT4 or NANOG, is a stronger indictor of chemoresistance, tumor-initiation, and recurrent disease. Including SOX2 in evaluation of ovarian cancer TICs may improve reliability of TIC markers and our understanding of mechanisms of relapse.
The identification of tumor-initiating cells (TICs) has traditionally relied on surface markers including CD133, CD44, CD117, and the aldehyde dehydrogenase (ALDH) enzyme, which have diverse expression across samples. A more reliable indication of TICs may include the expression of embryonic transcription factors that support long-term self-renewal, multipotency, and quiescence. We hypothesize that SOX2, OCT4, and NANOG will be enriched in ovarian TICs and may indicate TICs with high relapse potential. We evaluated a panel of eight ovarian cancer cell lines grown in standard 2-D culture or in spheroid-enriching 3-D culture, and correlated expression with growth characteristics, TIC marker expression, and chemotherapy resistance. RNA-sequencing showed that cell cycle regulation pathways involving SOX2 were elevated in 3-D conditions. HGSOC lines had longer doubling-times, greater chemoresistance, and significantly increased expression of SOX2, OCT4, and NANOG in 3-D conditions. CD117+ or ALDH+/CD133+ cells had increased SOX2, OCT4, and NANOG expression. Limiting dilution in in vivo experiments implicated SOX2, but not OCT4 or NANOG, with early tumor-initiation. An analysis of patient data suggested a stronger role for SOX2, relative to OCT4 or NANOG, for tumor relapse potential. Overall, our findings suggest that SOX2 may be a more consistent indicator of ovarian TICs that contribute to tumor repopulation following chemotherapy. Future studies evaluating SOX2 in TIC biology will increase our understanding of the mechanisms that drive ovarian cancer relapse. View Full-Text
Keywords: ovarian cancer; tumor-initiating cells; chemotherapy resistance; SOX2; OCT4; NANOG; spheroids ovarian cancer; tumor-initiating cells; chemotherapy resistance; SOX2; OCT4; NANOG; spheroids
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MDPI and ACS Style

Robinson, M.; Gilbert, S.F.; Waters, J.A.; Lujano-Olazaba, O.; Lara, J.; Alexander, L.J.; Green, S.E.; Burkeen, G.A.; Patrus, O.; Sarwar, Z.; Holmberg, R.; Wang, C.; House, C.D. Characterization of SOX2, OCT4 and NANOG in Ovarian Cancer Tumor-Initiating Cells. Cancers 2021, 13, 262. https://doi.org/10.3390/cancers13020262

AMA Style

Robinson M, Gilbert SF, Waters JA, Lujano-Olazaba O, Lara J, Alexander LJ, Green SE, Burkeen GA, Patrus O, Sarwar Z, Holmberg R, Wang C, House CD. Characterization of SOX2, OCT4 and NANOG in Ovarian Cancer Tumor-Initiating Cells. Cancers. 2021; 13(2):262. https://doi.org/10.3390/cancers13020262

Chicago/Turabian Style

Robinson, Mikella; Gilbert, Samuel F.; Waters, Jennifer A.; Lujano-Olazaba, Omar; Lara, Jacqueline; Alexander, Logan J.; Green, Samuel E.; Burkeen, Gregory A.; Patrus, Omid; Sarwar, Zinia; Holmberg, Ryne; Wang, Christine; House, Carrie D. 2021. "Characterization of SOX2, OCT4 and NANOG in Ovarian Cancer Tumor-Initiating Cells" Cancers 13, no. 2: 262. https://doi.org/10.3390/cancers13020262

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