Abstract
Ovarian Cancer is the fifth most common cancer in females and remains the most lethal gynecological malignancy as most patients are diagnosed at late stages of the disease. Despite initial responses to therapy, recurrence of chemo-resistant disease is common. The presence of residual cancer stem cells (CSCs) with the unique ability to adapt to several metabolic and signaling pathways represents a major challenge in developing novel targeted therapies. The objective of this study is to investigate the transcripts of putative ovarian cancer stem cell (OCSC) markers in correlation with transcripts of receptors, transporters, and enzymes of the energy generating metabolic pathways involved in high grade serous ovarian cancer (HGSOC). We conducted correlative analysis in data downloaded from The Cancer Genome Atlas (TCGA), studies of experimental OCSCs and their parental lines from Gene Expression Omnibus (GEO), and Cancer Cell Line Encyclopedia (CCLE). We found positive correlations between the transcripts of OCSC markers, specifically CD44, and glycolytic markers. TCGA datasets revealed that NOTCH1, CD133, CD44, CD24, and ALDH1A1, positively and significantly correlated with tricarboxylic acid cycle (TCA) enzymes. OVCAR3-OCSCs (cancer stem cells derived from a well-established epithelial ovarian cancer cell line) exhibited enrichment of the electron transport chain (ETC) mainly in complexes I, III, IV, and V, further supporting reliance on the oxidative phosphorylation (OXPHOS) phenotype. OVCAR3-OCSCs also exhibited significant increase in CD36, ACACA, SCD, and CPT1A, with CD44, CD133, and ALDH1A1 exhibiting positive correlations with lipid metabolic enzymes. TCGA data show positive correlations between OCSC markers and glutamine metabolism enzymes, whereas in OCSC experimental models of GSE64999, GSE28799, and CCLE, the number of positive and negative correlations observed was significantly lower and was different between model systems. Appropriate integration and validation of data model systems with those in patients’ specimens is needed not only to bridge our knowledge gap of metabolic programing of OCSCs, but also in designing novel strategies to target the metabolic plasticity of dormant, resistant, and CSCs.
Highlights
Ovarian cancer (OvCa) is the fifth most common cancer in females and remains the most lethal gynecologic malignancy in the present day [1]
Correlation analysis of The Cancer Genome Atlas (TCGA) data using GEPIA web tool revealed that CD44 transcripts significantly correlated with other putative ovarian cancer stem cell (OCSC) markers SOX2, Notch homolog 1 (NOTCH1), OCT4/POU5F1, ALDH1A1, but not with CD24, CD117/KIT, CD133/PROM1, or NANOG
We sought to investigate the predictive significance of the gene expression of OCSCs in correlation with transcripts of metabolic pathways that are upregulated in high grade serous ovarian cancer (HGSOC), that could inform about the metabolic plasticity of tumors, predict the behavior of recurrent or chemo-resistant disease, and may guide on therapeutics targeting the enriched pathways in combination with standard of care therapy
Summary
Ovarian cancer (OvCa) is the fifth most common cancer in females and remains the most lethal gynecologic malignancy in the present day [1]. Active CSCs can metabolize glucose via the pentose phosphate pathway (PPP), producing an abundance of reduced NADPH and macromolecules that serve as the energetic building blocks needed for increased proliferation. Several factors affect this metabolic switch [17]. OCSCs reprogram their metabolic and signaling machinery to maximize their survival and re-populate the tumor bulk [3] This intrinsic ability of OCSCs to switch between different energy sources is viewed as “metabolic plasticity” and continues to pose as a challenge in cancer treatment [4].
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