We investigated the metabolic profile of cancer stem cells (CSC) isolated from patients with epithelial ovarian cancer. CSC overexpressed genes associated with glucose uptake, oxidative phosphorylation (OXPHOS), and fatty acid β-oxidation, indicating higher ability to direct pyruvate towards the Krebs cycle. Consistent with a metabolic profile dominated by OXPHOS, the CSC showed higher mitochondrial reactive oxygen species (ROS) production and elevated membrane potential, and underwent apoptosis upon inhibition of the mitochondrial respiratory chain. The CSC also had a high rate of pentose phosphate pathway (PPP) activity, which is not typical of cells privileging OXPHOS over glycolysis, and may rather reflect the PPP role in recharging scavenging enzymes. Furthermore, CSC resisted in vitro and in vivo glucose deprivation, while maintaining their CSC phenotype and OXPHOS profile. These observations may explain the CSC resistance to anti-angiogenic therapies, and indicate this peculiar metabolic profile as a possible target of novel treatment strategies.
Cholangiocarcinoma (CCA) is characterized by an abundant stromal reaction. Cancer-associated fibroblasts (CAF) are pivotal players in tumor growth and invasiveness and represent a potential therapeutic target. To understand the mechanisms leading to CAF recruitment in CCA, we studied: 1) the expression of epithelial-mesenchymal transition (EMT) in surgical CCA specimens and CCA cells; 2) the lineage tracking of an EGFP-expressing human male CCA cell line (EGI-1) after xenotransplantation into severe-combined-immunodeficient mice; 3) the expression of platelet-derived growth factors (PDGFs) and their receptors in vivo and in vitro; 4) the secretion of PDGFs by CCA cells; 5) the role of PDGF-D in fibroblast recruitment in vitro; 6) the downstream effectors of PDGF-D signaling. CCA cells expressed several EMT biomarkers but not α-SMA. Xenotransplanted CCA masses were surrounded and infiltrated by α-SMA-expressing CAF, which were negative for EGFP and the human Y-probe, but positive for the murine Y-probe. CCA cells were strongly immunoreactive for PDGF-A and -D, whilst CAF expressed PDGFRβ. PDGF-D, a PDGFRβ agonist, was exclusively secreted by cultured CCA cells. Fibroblast migration was potently induced by PDGF-D and CCA conditioned medium, and was significantly inhibited by PDGFRβ blockade with Imatinib and by silencing PDGF-D expression in CCA cells. In fibroblasts, PDGF-D activated the Rac1 and Cdc42 Rho GTPases and JNK. Selective inhibition of Rho GTPases (particularly Rac1) and of JNK strongly reduced PDGF-D-induced fibroblast migration.
Conclusion
CCA cells express several mesenchymal markers, but do not transdifferentiate into CAF. Instead, CCA cells recruit CAF by secreting PDGF-D, which stimulates fibroblast migration via PDGFRβ and Rho GTPase and JNK activation. Targeting tumor/stroma interactions with inhibitors of PDGF-D pathway may offer a novel therapeutic approach.
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