ABSTRACT
Cancer recurrence can arise owing to rare circulating cancer stem cells (CSCs) that are resistant to chemotherapies and radiotherapies. Here, we show that a double-network hydrogel can rapidly reprogramme differentiated cancer cells into CSCs. Spheroids expressing elevated levels of the stemness genes Sox2, Oct3/4 and Nanog formed within 24 h of seeding the gel with cells from any of six human cancer cell lines or with brain cancer cells resected from patients with glioblastoma. Human brain cancer cells cultured on the double-network hydrogel and intracranially injected in immunodeficient mice led to higher tumorigenicity than brain cancer cells cultured on single-network gels. We also show that the double-network gel induced the phosphorylation of tyrosine kinases, that gel-induced CSCs from primary brain cancer cells were eradicated by an inhibitor of the platelet-derived growth factor receptor, and that calcium channel receptors and the protein osteopontin were essential for the regulation of gel-mediated induction of stemness in brain cancer cells.
Subject(s)
Cellular Reprogramming , Hydrogels/chemistry , Neoplastic Stem Cells/cytology , Animals , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Cell Differentiation , ErbB Receptors/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Glioblastoma/metabolism , Glioblastoma/pathology , Humans , Hydrogels/pharmacology , Mice , Mice, SCID , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/transplantation , Osteopontin/genetics , Osteopontin/metabolism , Phosphorylation/drug effects , Polymers/chemistry , Signal Transduction/drug effects , Signal Transduction/genetics , Tumor Cells, CulturedABSTRACT
Psychological stress is thought to be a risk factor for the onset or accelerate the progression of Parkinson's disease. The main aim of this study is to explore the causative effect of confrontational housing (CH), a paradigm developed as an animal model of psychosocial stress, in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. When mice were housed confrontationally for 24 h, they displayed increased anxiety like-behavior in the light/dark box test. Administration of MPTP after CH for 24 h caused severe damage of striatal dopaminergic neurons as indicated by decreases in dopamine transporter and tyrosine hydroxylase proteins and an increase of glial fibrillary acidic protein levels compared to CH alone. The dose of MPTP used this study slightly affected these protein levels in the striatum of control mice, but they did not significantly change. Our results indicate that the striatal dopaminergic neurons are vulnerable to environmental risk factors that presumably have neurotoxin-like properties under psychological stress condition.
