Therapeutic implications of an enriched cancer stem-like cell population in a human osteosarcoma cell line

<p>Abstract</p> <p>Background</p> <p>Osteosarcoma is a bone-forming tumor of mesenchymal origin that presents a clinical pattern that is consistent with the cancer stem cell model. Cells with stem-like properties (CSCs) have been identified in several tumors and hypothesized as the responsible for the relative resistance to therapy and tumor relapses. In this study, we aimed to identify and characterize CSCs populations in a human osteosarcoma cell line and to explore their role in the responsiveness to conventional therapies.</p> <p>Methods</p> <p>CSCs were isolated from the human MNNG/HOS cell line using the sphere formation assay and characterized in terms of self-renewal, mesenchymal stem cell properties, expression of pluripotency markers and ABC transporters, metabolic activity and tumorigenicity. Cell's sensitivity to conventional chemotherapeutic agents and to irradiation was analyzed and related with cell cycle-induced alterations and apoptosis.</p> <p>Results</p> <p>The isolated CSCs were found to possess self-renewal and multipotential differentiation capabilities, express markers of pluripotent embryonic stem cells Oct4 and Nanog and the ABC transporters P-glycoprotein and BCRP, exhibit low metabolic activity and induce tumors in athymic mice. Compared with parental MNNG/HOS cells, CSCs were relatively more resistant to both chemotherapy and irradiation. None of the treatments have induced significant cell-cycle alterations and apoptosis in CSCs.</p> <p>Conclusions</p> <p>MNNG/HOS osteosarcoma cells contain a stem-like cell population relatively resistant to conventional chemotherapeutic agents and irradiation. This resistant phenotype appears to be related with some stem features, namely the high expression of the drug efflux transporters P-glycoprotein and BCRP and their quiescent nature, which may provide a biological basis for resistance to therapy and recurrence commonly observed in osteosarcoma.</p

Expression of glycolytic enzymes in ovarian cancers and evaluation of the glycolytic pathway as a strategy for ovarian cancer treatment

Table S2. Spearman correlation of the expression of four glycolytic enzymes in a cohort of 380 ovarian cancers. Spearman rho correlation values (top value) along with the respective adjusted P value (bottom value) of statistically significant correlations thresholded at FDR P < 0.01 are summarised. (DOCX 21 kb

Decoupling nutrient signaling from growth rate causes aerobic glycolysis and deregulation of cell size and gene expression

To survive and proliferate, cells need to coordinate their metabolism, gene expression, and cell division. To understand this coordination and the consequences of its failure, we uncoupled biomass synthesis from nutrient signaling by growing, in chemostats, yeast auxotrophs for histidine, lysine, or uracil in excess of natural nutrients (i.e., sources of carbon, nitrogen, sulfur, and phosphorus), such that their growth rates (GRs) were regulated by the availability of their auxotrophic requirements. The physiological and transcriptional responses to GR changes of these cultures differed markedly from the respective responses of prototrophs whose growth-rate is regulated by the availability of natural nutrients. The data for all auxotrophs at all GRs recapitulated the features of aerobic glycolysis, fermentation despite high oxygen levels in the growth media. In addition, we discovered wide bimodal distributions of cell sizes, indicating a decoupling between the cell division cycle (CDC) and biomass production. The aerobic glycolysis was reflected in a general signature of anaerobic growth, including substantial reduction in the expression levels of mitochondrial and tricarboxylic acid genes. We also found that the magnitude of the transcriptional growth-rate response (GRR) in the auxotrophs is only 40–50% of the magnitude in prototrophs. Furthermore, the auxotrophic cultures express autophagy genes at substantially lower levels, which likely contributes to their lower viability. Our observations suggest that a GR signal, which is a function of the abundance of essential natural nutrients, regulates fermentation/respiration, the GRR, and the CDC.National Institutes of Health (U.S.) (GM046406)National Institute of General Medical Sciences (U.S.) (Center for Quantitative Biology (GM071508