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.

Epithelial ovarian cancer (EOC) is one of the most malignant gynecological tumors with a high mortality rate owing to tumor relapse after anticancer therapies. It is widely accepted that a rare tumor cell population, known as cancer stem cells (CSC), is responsible for tumor progression and relapse; intriguingly, these cells are able to survive nutrient starvation (such as in vitro culture in the absence of glucose) and chemotherapy treatment. Recent data also indicated that chemotherapy resistance is associated with autophagy activation. We thus decided to investigate both in vitro and in vivo the autophagic activity and the effects of the perturbation of this pathway in CSC isolated from EOC ascitic effusions. Ovarian CSC, identified according to their CD44/CD117 co-expression, presented a higher basal autophagy compared with the non-stem counterpart. Inhibition of this pathway, by in vitro chloroquine treatment or CRISPR/Cas9 ATG5 knockout, impaired canonical CSC properties, such as viability, the ability to form spheroidal structures in vitro, and in vivo tumorigenic potential. In addition, autophagy inhibition showed a synergistic effect with carboplatin administration on both in vitro CSC properties and in vivo tumorigenic activity. On the whole, these results indicate that the autophagy process has a key role in CSC maintenance; inhibition of this pathway in combination with other chemotherapeutic approaches could represent a novel effective strategy to overcome drug resistance and tumor recurrence. Cell Death and Disease (2017) 8, e2943; doi:10.1038/cddis.2017.327; published online 20 July 2017Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancies and the fifth leading cause of all cancer-related deaths among women in the Western world.1 Early diagnosis of ovarian carcinoma has proved difficult to achieve, largely owing to lack of an identified pre-malignant precursor lesion, and owing to the anatomical location of the ovaries.2 Indeed, the symptoms associated with this malignancy are shared with several other more common gynecologic, gastrointestinal and urinary pathologies. To date, no validated screening test exists as CA-125 dosage, pelvic and transvaginal sonography have very low sensitivity and specificity.3 As a consequence,~75% of patients present with signs of metastatic spread at the time of diagnosis, and~80% of women with advanced disease have a 5-year survival rate of only 30%. 4 In the last two decades, much effort has been spent in employing more effective surgery and combination treatment regimens, typically platinum-and taxane-based, resulting in complete response in 70% of patients.5 Despite these results, most patients relapse within 18 months with chemo-resistant disease.One emerging model for the development of drug-resistant carcinomas suggests that a pool of self-renewing malignant progenitor cells exists. These rare cancer-initiating cells, also named cancer stem cells (CSC), present several features that confer chemoresistance, such as the e...

Cancer treatment still represents a formidable challenge, despite substantial advancements in available therapies being made over the past decade. One major issue is poor therapeutic efficacy due to a lack of specificity and low bioavailability. The progress of nanotechnology and the development of a variety of nanoplatforms have had a significant impact in improving the therapeutic outcome of chemotherapeutics. Nanoparticles can overcome various biological barriers and localize at tumor site, while simultaneously protecting a therapeutic cargo and increasing its circulation time. Despite this, due to their synthetic origin, nanoparticles are often detected by the immune system and preferentially sequestered by filtering organs. Exosomes have recently been investigated as suitable substitutes for the shortcomings of nanoparticles due to their biological compatibility and particularly small size (i.e., 30-150 nm). In addition, exosomes have been found to play important roles in cell communication, acting as natural carriers of biological cargoes throughout the body. This review aims to highlight the use of exosomes as drug delivery vehicles for cancer and showcases the various attempts used to exploit exosomes with a focus on the delivery of chemotherapeutics and nucleic acids.