Abstract
BackgroundOvarian cancer is characterised by frequent recurrence due to persistent presence of residual cancer stem cells (CSCs). Here, we identify and characterise tumour subsets from ascites-derived tumour cells with stemness, metastasis and metabolic switch properties and to delineate the involvement of pyruvate dehydrogenase kinase 4 (PDK4) in such process.MethodsOvarian cancer cells/cell lines derived from ascites were used for tumourspheres/ALDH+CD44+ subset isolation. The functional roles and downstream signalling of PDK4 were explored. Its association with clinical outcome of ovarian cancer was analysed.ResultsWe demonstrated enhanced CSC characteristics of tumour cells derived from ovarian cancer ascites, concomitant with ALDH and CD44 subset enrichment and high PDK4 expression, compared to primary tumours. We further showed tumourspheres/ALDH+CD44+ subsets from ascites-derived tumour cells/cell lines with CSC properties and enhanced glycolysis. Clinically, PDK4 expression was correlated with aggressive features. Notably, blockade of PDK4 in tumourspheres/ALDH+CD44+ subsets led to inhibition of CSC characteristics, glycolysis and activation of STAT3/AKT/NF-κB/IL-8 (signal transducer and activator of transcription 3/protein kinases B/nuclear factor-κB/interleukin-8) signalling. Conversely, overexpression of PDK4 in ALDH−CD44– subsets exerted the opposite effects.ConclusionAscites-derived ALDH+CD44+ tumour cell subsets endow stemness, metastatic and metabolic switch properties via PDK4-mediated STAT3/AKT/NF-κB/IL-8 signalling, suggesting PDK4 as a viable therapeutic molecular target for ovarian cancer management.
Highlights
Ovarian cancer is characterised by frequent recurrence due to persistent presence of residual cancer stem cells (CSCs)
Ovarian cancer spheroids derived from ascites and ovarian cancer cell lines are produced over successive generations, consistent with the known sphere-forming and self-renewal characteristics of stem cells.[4]
Our findings clearly suggested that ascites-derived tumour cells displayed CSC properties with increased pyruvate dehydrogenase kinase 4 (PDK4) expression
Summary
Ovarian cancer is characterised by frequent recurrence due to persistent presence of residual cancer stem cells (CSCs). Cancer stem-like cells (CSCs) represent a small subpopulation of tumour cells with stem-like properties that are responsible for tumour growth, metastasis, chemoresistance and recurrence,[1] leading to poor prognosis of ovarian cancer patients Effective targeting of this subset of cells may eventually aid in control of the disease. Accumulating studies have identified and characterised a self-renewing subpopulation of CSCs displaying stem-like properties in ovarian cancer,[2] the associated regulatory mechanisms remain unknown at present Owing to their location as intra-abdominal tumours, ovarian cancer cells exfoliated from the primary ovarian tumour floating in peritoneal fluid are prone to forming three-dimensional (3D) multicellular aggregates (spheroids), which serve as a vehicle for tumour cell dissemination within the peritoneal cavity.[3] Patients with advanced ovarian cancer are often diagnosed with peritoneal fluid accumulation ( known as ascites fluid). Ovarian cancer spheroids derived from ascites and ovarian cancer cell lines are produced over successive generations, consistent with the known sphere-forming and self-renewal characteristics of stem cells.[4]
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