ABSTRACT
Cancer stem cells (CSCs) are believed to be maintained within a microenvironmental niche. Here we used polymer microarrays for the rapid and efficient identification of glioma CSC (GSC) niche mimicries and identified a urethane-based synthetic polymer, upon which two groups of niche components, namely extracellular matrices (ECMs) and iron are revealed. In cultures, side population (SP) cells, defined as GSCs in the rat C6 glioma cell line, are more efficiently sustained in the presence of their differentiated progenies expressing higher levels of ECMs and transferrin, while in xenografts, ECMs are supplied by the vascular endothelial cells (VECs), including SP cell-derived ones with distinctively greater ability to retain xenobiotics than host VECs. Iron is stored in tumor infiltrating host macrophages (Mφs), whose protumoral activity is potently enhanced by SP cell-secreted soluble factor(s). Finally, coexpression of ECM-, iron-, and Mφ-related genes is found to be predictive of glioma patients' outcome. Our polymer-based approach reveals the intrinsic capacities of GSCs, to adapt the environment to organize a self-advantageous microenvironment niche, for their maintenance and expansion, which redefines the current concept of anti-CSC niche therapy and has the potential to accelerate cancer therapy development. Stem Cells 2016;34:1151-1162.
Subject(s)
Brain Neoplasms/pathology , Glioma/pathology , Polymers/pharmacology , Stem Cell Niche , Tissue Scaffolds/chemistry , Animals , Brain Neoplasms/genetics , Cell Differentiation/drug effects , Cell Line, Tumor , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Extracellular Matrix/drug effects , Extracellular Matrix/metabolism , Female , Gene Expression Regulation, Neoplastic/drug effects , Glioma/genetics , Humans , Iron/metabolism , Macrophages/drug effects , Macrophages/metabolism , Male , Mice, Inbred C57BL , Models, Biological , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Polyurethanes/pharmacology , Rats , Scavenger Receptors, Class A/genetics , Scavenger Receptors, Class A/metabolism , Side-Population Cells/cytology , Side-Population Cells/drug effects , Stem Cell Niche/drug effects , Stem Cell Niche/genetics , Transferrin/metabolism , Treatment OutcomeABSTRACT
A chemically defined thermoresponsive hydrogel, poly(AEtMA-Cl-co-DEAEA) cross-linked with N,N'-methylenebisacrylamide, which allows enzyme-free passaging, was used as a substrate to culture murine embryonic stem cells (mESCs) under defined and undefined conditions. Analysis of 14 stem cell markers showed that the mESCs remained in a "naïve" state of pluripotency with differentiation potential to form endoderm, mesoderm, and ectoderm derived lineages. These results validate the use of a chemically defined hydrogel for standardised and inexpensive mESC culture.