Ascites-derived ALDH+CD44+ tumour cell subsets endow stemness, metastasis and metabolic switch via PDK4-mediated STAT3/AKT/NF-κB/IL-8 signalling in ovarian cancer

Abstract

Background Ovarian 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. Methods Ovarian 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. Results We 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. Conclusion Ascites-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.

The pleiotropic role of transcription factor STAT3 in oncogenesis and its targeting through natural products for cancer prevention and therapy

“…Later, cardiotrophin‐like cytokine factor 1, CNTF, cardiotrophin 1, and oncostatin M have been discovered as activators of the STAT3 pathway via LIFR to regulate the dedifferentiation of stem cells. STAT3 is one of the most critical transcription factors for maintaining the stemness of cancer cells because it regulates the transcription of genes involved in the maintenance of stem cell phenotype in human cancers including glioma, breast, ovarian, prostate, liver, colon, and lung 187–192 . To date, several groups have discovered a number of CSC markers including transmembrane glycoproteins CD24, CD34, CD38, CD44, CD90, CD133, ALDH 193 .…”

EIF5A2 enhances stemness of epithelial ovarian cancer cells via a E2F1/KLF4 axis

“…2 c). Previous study reported that ascites-derived tumor cells exhibit CSC properties and ALDH combined with CD44 were used as markers to characterize OCSC-like cells [ 23 ]. To delineate the ALDH+CD44+ cells in EOC, we measured the percentage of ALDH+CD44+ cells in MCAs samples from EOC ascites and 3 ovarian cancer cell lines (Figure S 2 , Table S 2 ).…”

Loss of Krüppel‐like factor 9 facilitates stemness in ovarian cancer ascites‐derived multicellular spheroids via Notch1/slug signaling

“…29 Furthermore, several studies have reported that floating ascites-derived MCSs are a rich source of cells with OCSC traits, including the enhanced capacity of self-renewal, drug resistance, invasion, and high level of stemness-related markers. 30,[31][32][33] Based on these theories, ascites can be viewed as an OCSC-enriched niche, and future research should unravel the molecular mechanisms that are specifically involved in the modulation of OCSC. For example, ascites-derived OC cells exhibit high levels of interleukin-6 (IL-6), STAT3 activation, and enrichment for Wnt ligands, which suggested that the IL-6/JAK/STAT3 axis and Wnt signaling pathway are important effectors of the "communication" between OCSC and the tumor micro-environment.…”

“…For example, ascites-derived OC cells exhibit high levels of interleukin-6 (IL-6), STAT3 activation, and enrichment for Wnt ligands, which suggested that the IL-6/JAK/STAT3 axis and Wnt signaling pathway are important effectors of the "communication" between OCSC and the tumor micro-environment. [34][35][36] In addition, YX Jiang et al 30 suggested that ascites-derived ALDH + CD44 + tumor cell subsets endowed stemness, metastasis, and metabolic switch via PDK4-mediated signaling in OC. EMT, regulated by a complex network of genes, is a typical process of embryonic development and tumor progression, and has been proposed as one of the most important biological processes inducing stem cell properties.…”

“…For example, ascites‐derived OC cells exhibit high levels of interleukin‐6 (IL‐6), STAT3 activation, and enrichment for Wnt ligands, which suggested that the IL‐6/JAK/STAT3 axis and Wnt signaling pathway are important effectors of the “communication” between OCSC and the tumor micro‐environment. 34 , 35 , 36 In addition, YX Jiang et al 30 suggested that ascites‐derived ALDH + CD44 + tumor cell subsets endowed stemness, metastasis, and metabolic switch via PDK4‐mediated signaling in OC.…”