Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy

Abstract

Glioblastoma multiforme patients have a poor prognosis due to therapeutic resistance and tumor relapse. It has been suggested that gliomas are driven by a rare subset of tumor cells known as glioma stem cells (GSCs). This hypothesis states that only a few GSCs are able to divide, differentiate, and initiate a new tumor. It has also been shown that this subpopulation is more resistant to conventional therapies than its differentiated counterpart. In order to understand glioma recurrence post therapy, we investigated the behavior of GSCs after primary chemotherapy. We first show that exposure of patient-derived as well as established glioma cell lines to therapeutic doses of temozolomide (TMZ), the most commonly used antiglioma chemotherapy, consistently increases the GSC pool over time both in vitro and in vivo. Secondly, lineage-tracing analysis of the expanded GSC pool suggests that such amplification is a result of a phenotypic shift in the non-GSC population to a GSC-like state in the presence of TMZ. The newly converted GSC population expresses markers associated with pluripotency and stemness, such as CD133, SOX2, Oct4, and Nestin. Furthermore, we show that intracranial implantation of the newly converted GSCs in nude mice results in a more efficient grafting and invasive phenotype. Taken together, these findings provide the first evidence that glioma cells exposed to chemotherapeutic agents are able to interconvert between non-GSCs and GSCs, thereby replenishing the original tumor population, leading to a more infiltrative phenotype and enhanced chemoresistance. This may represent a potential mechanism for therapeutic relapse.

WITHDRAWN: Intranasal GM-CSF enhances efficacy of local ACNU delivery rendezvousing with TMZ plus irradiation in glioblastoma

“…B Auffinger et al [23] provided evidence that glioma cells exposed to chemotherapeutic agents are able to convert into stem-like cells, replenishing the original tumor population, and leading to enhanced chemoresistance. According to our previous in vitro studies, the application of GM-CSF targeting glioma stem cells could sensitize chemotherapy, and thereby increase the clearance rate for GSCs.…”

miRNA-182 and the regulation of the glioblastoma phenotype - toward miRNA-based precision therapeutics

“…We envision using 182-SNAs as adjuvant for TMZ. As TMZ increases the glioma stem cell compartment, 63 we will test the hypothesis that due to the prodifferentiation effects of miR182, 182-SNAs, in addition to its ability to regulate Bcl2L12, will increase TMZ effectiveness by promoting a more differentiated tumor phenotype. In addition, we will evaluate whether miR-9 and miR-34a, 2 additional high-priority miRNAs show enhanced antitumor effects when combined with miR-182 (Fig.…”

The role of cancer stem cells in glioblastoma

“…Stimuli such as hypoxia and acidic stress, as well as therapeutic agents such as TMZ, can induce some non-CSCs to adopt a CSC phenotype. 5,16,39,60 Furthermore, research on CSCs has failed thus far to discover universally informative biomarkers, mutations, or gene-expression patterns. 3 Biomarkers used to identify and enrich CSCs have been shown to exhibit variable cell cycle-dependent expression.…”