Ovarian Cancer Stem Cell Heterogeneity

Hatina, Jiřı́; Boesch, Maximilian; Sopper, Sieghart; Kripnerová, Michaela; Wolf, Dominik; Reimer, Daniel; Marth, Christian; Zeimet, Alain G.

doi:10.1007/978-3-030-14366-4_12

Cited by 34 publications

(50 citation statements)

References 80 publications

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“…ALDH activity may be the result of ALDH1A1 or ALDH1A2 or a combination of both isoforms, as we have previously demonstrated [25]. These data again highlight the heterogeneity of ovarian TIC populations across cell lines and supplement previous findings demonstrating differential expression of TIC markers in OVCAR5, SKOV3, and A2780 cell lines [18,[47][48][49]. Quantification of SOX2, OCT4, and NANOG in FACS sorted marker positive populations relative to marker negative populations revealed that CD44+ cells did not have increased SOX2, OCT4, and NANOG, except in the ACI23 line, which had significantly elevated levels of OCT4 and NANOG (Fig.…”

Section: Resultssupporting

confidence: 88%

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Characterization of SOX2, OCT4 and NANOG in ovarian cancer tumor-initiating cells

Robinson

Gilbert

Waters

et al. 2020

Preprint

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Identification of tumor initiating cells (TICs) has traditionally relied on expression of surface markers such as CD133, CD44, and CD117 and enzymes such as aldehyde dehydrogenase (ALDH). Unfortunately, these markers are often cell type specific and not reproducible across patient samples. A more reliable indication of TICs may include elevated expression of stem cell transcription factors such as SOX2, OCT4, and NANOG that function to support long-term self-renewal, multipotency, and quiescence. RNA-sequencing studies presented here highlight a potential role for SOX2 in cell cycle progression in cells grown as 3-D spheroids, which are more tumorigenic and contain higher numbers of TICs than their 2-D monolayer cultured counterparts. SOX2, OCT4, and NANOG have not been comprehensively evaluated in ovarian cancer cell lines, although their expression is often associated with tumorigenic cells. We hypothesize that SOX2, OCT4, and NANOG will be enriched in ovarian TICs and will correlate with chemotherapy resistance, tumor initiation, and expression of traditional TIC markers. To investigate this hypothesis, we evaluated SOX2, OCT4, and NANOG in a panel of eight ovarian cancer cell lines grown as a monolayer in standard 2-D culture or as spheroids in TIC-enriching 3-D culture. Our data show that the high-grade serous ovarian cancer (HGSOC) lines CAOV3, CAOV4, OVCAR4, and OVCAR8 had longer doubling-times, greater resistance to chemotherapies, and significantly increased expression of SOX2, OCT4, and NANOG in TIC-enriching 3-D culture conditions. We also found that in vitro chemotherapy treatment enriches for cells with significantly higher expression of SOX2. We further show that the traditional TIC marker, CD117 identifies ovarian cancer cells with enhanced SOX2, OCT4, and NANOG expression. Tumor-initiation studies and analysis of The Cancer Genome Atlas (TCGA) suggest a stronger role for SOX2 in ovarian cancer relapse compared with OCT4 or NANOG. Overall, our study clarifies the expression of SOX2, OCT4, and NANOG in TICs from a variety of ovarian cancer cell lines. Our findings suggest that SOX2 expression is a stronger indicator of ovarian TICs with enhanced tumor-initiation capacity and potential for relapse. Improved identification of ovarian TICs will advance our understanding of TIC biology and facilitate the design of better therapies to eliminate TICs and overcome chemotherapy resistance and disease relapse.

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Section: Resultssupporting

confidence: 88%

“…Given the heterogeneity of ovarian cancer cell lines [18,[39][40][41], we first evaluated growth properties of a panel of commonly reported lines cultured in 2-D and 3-D conditions. Standard 2-D culture conditions revealed differential growth over a 7-day period among the cell lines ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Characterization of SOX2, OCT4 and NANOG in ovarian cancer tumor-initiating cells

Robinson

Gilbert

Waters

et al. 2020

Preprint

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“…A previous study identified CD24, CD44, CD117, CD133, and ROR1 as ovarian cancer stem cells [17]. ALDEFLUOR™ and side population assays were also used for isolated ovarian cancer stem cells [17]. We found some CSC markers such as CD133, ROR1, and CD44 were expressed in half to almost all the populations in FTECs.…”

Section: Discussionmentioning

confidence: 65%

“…Markers of HGSOC stem cells may also be relevant to stem cells of FTEC. A previous study identified CD24, CD44, CD117, CD133, and ROR1 as ovarian cancer stem cells [17]. ALDEFLUOR™ and side population assays were also used for isolated ovarian cancer stem cells [17].…”

Section: Discussionmentioning

confidence: 99%

“…The FTEC were identified by fallopian tube epithelial stem cell marker LGR5 [GeneTex, Irvine, CA, USA], and embryonic stem cell markers SSEA3 [eBioscience] and SSEA4 [Abcam]. The cancer stem cell markers including CD24 (eBioscience), CD44 (eBioscience), CD117 (eBioscience), ROR1 (BD) [16], and CD133 (eBioscience) [17] were also characterized in FTEC and control HGSOC cell lines. HGSOC cell lines (KURAMOCHI and OVSAHO) were used as positive controls [18].…”

Section: Flow Cytometry Of Ftecmentioning

confidence: 99%

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Human fallopian tube epithelial cells exhibit stemness features, self-renewal capacity, and Wnt-related organoid formation

2020

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Background: Fallopian tube epithelial cells (FTEC) were thought to be the origin of high-grade serous ovarian carcinoma (HGSOC). Knowledge of the stemness or initiating characteristics of FTEC is insufficient. Previously, we have characterized the stemness cell marker of FTEC, this study aims to further characterize the clonogenicity and spheroid features of FTEC. Methods: We successfully derived FTECs from the epithelial layer of the human fallopian tubes. We examined the morphology, proliferation rate, doubling time, and clonal growth of them. At passage 3, the sphere formations on gelatin-coated culture, suspension culture, and matrigel culture were observed, and the expression of LGR5, SSEA3, SSEA4, and other stemness markers was examined. Furthermore, tissue-reconstituted organoids from coculture of FTEC, fallopian stromal cells (FTMSC) and endothelial cells (HUVEC) were examined.Results: FTEC exhibited cuboidal cell morphology and maintained at a constant proliferation rate for up to nine passages (P9). FTEC could proliferate from a single cell with a clonogenic efficiency of 4%. Flow cytometry revealed expressions of normal stem cell markers (SSEA3, SSEA4, and LGR5) and cancer stem cell markers (CD24, CD44, CD117, ROR1, and CD133). FTEC formed spheres and colonies when cultured on low attach dish. In the presence of Matrigel, the stemness and colony formation activity were much enhanced. In co-culturing with FTMSC and HUVEC, FTEC could form organoids that could be blocked by Wnt inhibitor DKK1. Expressions of LGR5 and FOXJ1 expression were also decreased by adding DKK1. Conclusion: We demonstrated abundantly presence of stem cells in human FTECs which are efficient in forming colonies, spheres and organoids, relying on Wnt signaling. We also reported for the first time the generation of organoid from reconstitutied cell lineages in the tissue. This may provide a new model for studying the regneration and malignant transformation of the tubal epithelium.

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