The prognostic impact of cancer stem-like cell biomarker aldehyde dehydrogenase-1 (ALDH1) in ovarian cancer: A meta-analysis

Ruscito, Ilary; Darb‐Esfahani, Silvia; Kulbe, Hagen; Bellati, Filippo; Zizzari, Ilaria Grazia; Koshkaki, Hassan Rahimi; Napoletano, Chiara; Caserta, Donatella; Rughetti, Aurelia; Kessler, Mirjana; Sehouli, Jalid; Nuti, Marianna; Braicu, Elena Ioana

doi:10.1016/j.ygyno.2018.05.006

Cited by 24 publications

(17 citation statements)

References 42 publications

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“…There is evidence that stemness features in treatment-naive tumours indicate a poor response to chemotherapy and aggressive behaviour. The most consistent results have been achieved using IHC for ALDH1A1, where abundant ALDH1A1 immunoreactivity has been associated with poor PFS and OS (reviewed in [37]). Correlation has also been achieved with other putative stemness markers, including CD44 and PROM1, although these results have been more ambiguous.…”

Section: Discussionmentioning

confidence: 83%

ALDH1A1‐related stemness in high‐grade serous ovarian cancer is a negative prognostic indicator but potentially targetable by EGFR/mTOR‐PI3K/aurora kinase inhibitors

Kaipio

Chen

Roering

et al. 2019

The Journal of Pathology

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Poor chemotherapy response remains a major treatment challenge for high-grade serous ovarian cancer. Cancer stem cells are the major contributors to relapse and treatment failure as they can survive conventional therapy. Our objectives were to characterise stemness features in primary patient derived cell lines, correlate stemness markers with clinical outcome, and test the response of our cells to both conventional and exploratory drugs. Tissue and ascites samples, treatment-naïve and/or after neoadjuvant chemotherapy, were prospectively collected. Primary cancer cells, cultured under conditions favouring either adherent or spheroid growth, were tested for stemness markers; the same markers were analysed in tissue and correlated with chemotherapy response and survival. Drug sensitivity and resistance testing was performed with 306 oncology compounds. Spheroid growth-condition HGSC cells showed increased stemness marker expression (including ALDH1A1) as compared to adherent growth-condition cells, and increased resistance to platinum and taxane. A set of eight stemness markers separated treatment-naïve tumours into two clusters and identified a distinct subgroup of HGSC with enriched stemness features. Expression of ALDH1A1, but not most other stemness markers, was increased after neoadjuvant chemotherapy and its expression in treatment-naïve tumours correlated with chemoresistance and reduced survival. In DSRT, five compounds, including two PI3K-mTOR inhibitors, demonstrated significant activity in both cell culture conditions. Thirteen compounds, including EGFR, PI3K-mTOR and aurora kinase inhibitors, were more toxic to spheroid cells than adherent cells.

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Section: Discussionmentioning

confidence: 83%

ALDH1A1‐related stemness in high‐grade serous ovarian cancer is a negative prognostic indicator but potentially targetable by EGFR/mTOR‐PI3K/aurora kinase inhibitors

Kaipio

Chen

Roering

et al. 2019

The Journal of Pathology

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“…Aldh1 is a known cancer stem cell marker and is correlated with prognosis 49. Aldh1 is also responsible for enhanced invasiveness and the endothelial-mesenchymal transition process 50.…”

Section: Discussionmentioning

confidence: 99%

Estradiol and Progesterone Induced Differentiation and Increased Stemness Gene Expression of Human Fallopian Tube Epithelial Cells

2019

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Fallopian tube epithelial cells (FTECs) are thought to be the origin of epithelial ovarian cancer. However, the effect of the hormones on FTECs is unknown, and therefore, this study explored this effect. We successfully derived FTECs from the fallopian tube epithelial layer and treated them with estradiol and progesterone. Reverse transcription polymerase chain reaction was used to evaluate the gene expression of the FTECs' hormone receptors. Confocal and electron microscopy were used to evaluate the morphology of the FTECs after they were treated with hormones. Finally, quantitative PCR was used to evaluate the gene expression of the hormone-treated FTECs. The results showed that the FTECs exhibited cuboidal cell morphology and could be maintained at a constant proliferation rate. Furthermore, flow cytometry revealed that the FTECs expressed stem cell markers, such as SSEA3, SSEA4, and Lgr5. Moreover, the FTECs could express both estrogen and progesterone receptors. In a culture treated with 400 nM estrogen, the FTECs differentiated toward ciliated cells, whereas in a culture treated with estradiol or progesterone, the FTECs increased their expression of certain stem cell markers (SSEA3, SSEA4, and Aldh1) and stemness genes [Wnt (AXIN2, LGR5, LGR6, and OLFM4) and Notch (Hes1) signaling]. In conclusion, hormones may alter the gene expressions of FTECs, and these cells may provide new insights into how FTECs regenerate in response to hormones.

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“…Studies have shown a direct correlation between CSC abundance and the onset of relapse, suggesting CSCs promote chemotherapy resistance [24][25][26] . For example, expression of different biomarkers for CSCs, CD44, ALDH, CD133 and MyD88, was observed to be associated with chemotherapy resistance and poor patient outcome in EOC [27][28][29] . Recently, the transcription factor NFATC4 (nuclear factor of activated T cells cytoplasmic 4) was identified as a regulator of quiescence in ovarian cancer, enriched in ovarian CSCs and associated with chemotherapy resistance and poor prognosis [30] .…”

Section: Introductionmentioning

confidence: 99%

“…Recently, the transcription factor NFATC4 (nuclear factor of activated T cells cytoplasmic 4) was identified as a regulator of quiescence in ovarian cancer, enriched in ovarian CSCs and associated with chemotherapy resistance and poor prognosis [30] . Using a model of ovarian malignant ascites in a heterospheroid assay of CSCs and carcinoma-associated mesenchymal stem/stromal cells, Raghavan et al [28] demonstrated that PDGF (platelet-derived growth factor) signaling in these heterospheroids significantly increased stemness, metastatic potential and platinum resistance of CSCs. TWIST1 was suggested to be a regulator of EOC stemness through controlling stem cell differentiation via regulation of miR-199a and miR-214 [31][32][33] .…”

Section: Introductionmentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR pathway in epithelial ovarian cancer, therapeutic treatment options for platinum-resistant ovarian cancer

Rinne¹,

Christie²,

Ardasheva³

et al. 2021

CDR

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The survival rates for women with ovarian cancer have shown scant improvement in recent years, with a 5-year survival rate of less than 40% for women diagnosed with advanced ovarian cancer. High-grade serous ovarian cancer (HGSOC) is the most lethal subtype where the majority of women develop recurrent disease and chemotherapy resistance, despite over 70%-80% of patients initially responding to platinum-based chemotherapy. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway regulates many vital processes such as cell growth, survival and metabolism. However, this pathway is frequently dysregulated in cancers including different subtypes of ovarian cancer, through amplification or somatic mutations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), amplification of AKT isoforms, or deletion or inactivation of PTEN. Further evidence indicates a role for the PI3K/AKT/mTOR pathway in the development of chemotherapy resistance in ovarian cancer. Thus, targeting key nodes of the PI3K/AKT/mTOR pathway is a potential therapeutic prospect. In this review, we outline dysregulation of PI3K signaling in ovarian cancer, with a particular emphasis on HGSOC and platinum-resistant disease. We review preclinical evidence for inhibitors of the main components of the PI3K pathway and highlight past, current and upcoming trials in ovarian cancers for different inhibitors of the pathway. Whilst no inhibitors of the PI3K/AKT/mTOR pathway have thus far advanced to the clinic for the treatment of ovarian cancer, several

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The prognostic impact of cancer stem-like cell biomarker aldehyde dehydrogenase-1 (ALDH1) in ovarian cancer: A meta-analysis

Cited by 24 publications

References 42 publications

ALDH1A1‐related stemness in high‐grade serous ovarian cancer is a negative prognostic indicator but potentially targetable by EGFR/mTOR‐PI3K/aurora kinase inhibitors

ALDH1A1‐related stemness in high‐grade serous ovarian cancer is a negative prognostic indicator but potentially targetable by EGFR/mTOR‐PI3K/aurora kinase inhibitors

Estradiol and Progesterone Induced Differentiation and Increased Stemness Gene Expression of Human Fallopian Tube Epithelial Cells

Targeting the PI3K/AKT/mTOR pathway in epithelial ovarian cancer, therapeutic treatment options for platinum-resistant ovarian cancer

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