Mesothelial cells facilitate cancer stem‑like properties in spheroids of ovarian cancer cells

Shishido, Akemi; Mori, Satoshi; Yokoyama, Yuhki; Hamada, Y.; Minami, Kazumasa; Qian, Yamin; Wang, Jiaqi; Hirose, Haruka; Wu, Xin; Kawaguchi, Naomasa; Nagumo, Sachiko; Matsuura, Nariaki; Yamamoto, Hideya

doi:10.3892/or.2018.6605

Cited by 24 publications

(34 citation statements)

References 34 publications

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“…Interestingly, adhesion of OC cells to the peritoneal mesothelium has been shown to occur through the OCSC markers CD44 and integrin-β1, which are recognized by the HA receptor in the membrane of mesothelial cells [83,84]. Indeed, mesothelial cells are able to increase the stem-like properties of OC spheres, suggesting a positive feedback loop in which adhesion and stemness promote each other [85].…”

Section: Metastasis Of Ovarian Cancermentioning

confidence: 99%

Targeting Cancer Stem Cells to Overcome Therapy Resistance in Ovarian Cancer

Muñoz-Galván

Carnero

2020

Cells

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Ovarian cancer is the most lethal gynecological malignancy due to its late detection and high recurrence rate. Resistance to conventional platinum-based therapies and metastasis are attributed to a population of cells within tumors called cancer stem cells, which possess stem-like features and are able to recapitulate new tumors. Recent studies have deepened the understanding of the biology of ovarian cancer stem cells and their special properties and have identified multiple markers and signaling pathways responsible for their self-renewal abilities. Targeting cancer stem cells represents the most promising strategy for overcoming therapy resistance and reducing mortality in ovarian cancer, but further efforts must be made to improve our understanding of the mechanisms involved in therapy resistance. In this review, we summarize our current knowledge about ovarian cancer stem cells, their involvement in metastasis and their interactions with the tumor microenvironment; we also discuss the therapeutic approaches that are being developed to target them to prevent tumor relapse.

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Section: Metastasis Of Ovarian Cancermentioning

confidence: 99%

Targeting Cancer Stem Cells to Overcome Therapy Resistance in Ovarian Cancer

Muñoz-Galván

Carnero

2020

Cells

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“…Spheroids are multicellular tumor cell aggregates that mimic those found in patient ascites and exhibit enhanced drug resistance and high tumorigenicity [15,38,42,43]. Spheroid formation is an in vitro surrogate used to identify cell lines with potentially high tumor-initiation capacity [44][45][46]. All cell lines had relatively equal ability to form spheroids in 3-D conditions (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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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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“…It is unclear, however, how DPP4 inactivation might influence invasion in the poorly oxygenated peritoneal environment and ascites fluid present in metastatic ovarian cancers [11]. DPP4 expression has been associated with tumour initiating cell populations in several tumour types [50,51], and ovarian cancer spheroids (free-floating organoids with a hypoxic core) found in ascites fluid contain putative ovarian cancer stem cells [52]. The alterations in DPP4 abundance and activity observed under hypoxic conditions may therefore be related to a transition state between transcriptionally plastic cell phenotypes, required to preserve or maintain cancer cell populations during hypoxic stress.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Regulates DPP4 Expression, Proteolytic Inactivation, and Shedding from Ovarian Cancer Cells

Moffitt

Bilandzic

Wilson

et al. 2020

IJMS

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The treatment of ovarian cancer has not significantly changed in decades and it remains one of the most lethal malignancies in women. The serine protease dipeptidyl peptidase 4 (DPP4) plays key roles in metabolism and immunity, and its expression has been associated with either pro- or anti-tumour effects in multiple tumour types. In this study, we provide the first evidence that DPP4 expression and enzyme activity are uncoupled under hypoxic conditions in ovarian cancer cells. Whilst we identified strong up-regulation of DPP4 mRNA expression under hypoxic growth, the specific activity of secreted DPP4 was paradoxically decreased. Further investigation revealed matrix metalloproteinases (MMP)-dependent inactivation and proteolytic shedding of DPP4 from the cell surface, mediated by at least MMP10 and MMP13. This is the first report of uncoupled DPP4 expression and activity in ovarian cancer cells, and suggests a previously unrecognized, cell- and tissue-type-dependent mechanism for the regulation of DPP4 in solid tumours. Further studies are necessary to identify the functional consequences of DPP4 processing and its potential prognostic or therapeutic value.

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Mesothelial cells facilitate cancer stem‑like properties in spheroids of ovarian cancer cells

Cited by 24 publications

References 34 publications

Targeting Cancer Stem Cells to Overcome Therapy Resistance in Ovarian Cancer

Targeting Cancer Stem Cells to Overcome Therapy Resistance in Ovarian Cancer

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

Hypoxia Regulates DPP4 Expression, Proteolytic Inactivation, and Shedding from Ovarian Cancer Cells

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