The Clinical Impact of Cancer Stem Cells

Lathia, Justin D.; Liu, Huiping; Matei, Daniela

doi:10.1634/theoncologist.2019-0517

Cited by 66 publications

(50 citation statements)

References 54 publications

(74 reference statements)

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“…In addition to characterizing SOX2, OCT4, and NANOG in ovarian TICs, our work confirms the heterogeneity of ovarian cancer cells and TIC properties [14,[26][27][28]. Recent genomic analyses of ovarian cancer cell lines have demonstrated that some cell lines often used in research do not represent the genetic profile or ovarian tumor type with which they are often associated [29][30][31].…”

Section: Discussionsupporting

confidence: 69%

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: Discussionsupporting

confidence: 69%

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

Robinson

Gilbert

Waters

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…TICs share properties of tissue stem cells such as quiescence, asymmetric division, and long-term self-renewal [ 2 , 3 , 4 , 5 , 6 ]. Consequently, chemotherapeutic drugs are inefficient at eliminating TICs, and these cells likely drive recurrence [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies showed that SOX2 [ 13 ] or ALDH [ 14 ], CD133, and CD117 [ 10 ] gene expression levels varied across cell lines and patient samples. The genetic heterogeneity of ovarian cancer, as well as the disease stage and/or tissue origin for subsets of ovarian TICs, contribute to the expression of different markers [ 7 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

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

Robinson

Gilbert

Waters

et al. 2021

Cancers

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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.

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“…Over the past number of decades, cancer stem cells (CSCs) have attracted widespread attention due to their capabilities of self-renewal and differentiation during cellular stress or drug resistance (13,14). CSCs have been reported in several types of human cancer, including LUAD (15,16). Cluster of differentiation 133 (CD133) has been previously demonstrated to be a key marker of lung CSCs, which have the ability to grow indefinitely into tumor spheres in serum-free medium supplemented with epidermal growth factor (EGF) and basal fibroblast growth factor (bFGF) (17).…”

Section: Introductionmentioning

confidence: 99%

miR‑140‑3p enhances cisplatin sensitivity and attenuates stem cell‑like properties through repressing Wnt/β‑catenin signaling in lung adenocarcinoma cells

Wang

Pan

et al. 2020

Exp Ther Med

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Lung adenocarcinoma (LUAD) is the most predominant subtype of non-small cell lung cancer (NSCLC) that is experiencing the fastest growth rate in incidence. Chemoresistance and the presence of cancer stem cells are considered to be the main obstacles preventing the successful treatment of patients with NSCLC, the molecular mechanism of which remains poorly understood. The present study aimed to investigate the effects of microRNA (miR)-140-3p on cisplatin sensitivity and stem cell-like properties of LUAD cells. Analysis of publicly available data demonstrated that miR-140-3p expression was downregulated in LUAD, and positively associated with the overall survival rate of patients. In addition, transfection with the miR-140-3p mimic reduced LUAD cell viability and induced apoptosis following treatment with cisplatin whilst decreasing stem cell-like properties. miR-140-3p overexpression was also found to attenuate cisplatin resistance and reduce stem cell-like properties in LUAD cells by suppressing Wnt/β-catenin signaling, all of which were reversed by the overexpression of β-catenin. Taken together, results of the present study suggest miR-140-3p to be an effective therapeutic strategy for patients with LUAD.

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The Clinical Impact of Cancer Stem Cells

Cited by 66 publications

References 54 publications

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

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

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

miR‑140‑3p enhances cisplatin sensitivity and attenuates stem cell‑like properties through repressing Wnt/β‑catenin signaling in lung adenocarcinoma cells

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