Cellular plasticity regulated cancer stem cell niche: a possible new mechanism of chemoresistance.

The cancer stem cell (CSC) theory is an emerging concept that proposes a hierarchical nature of carcinogenesis, where a small number of tumor cells are capable of driving tumor growth. Despite many unanswered questions surrounding the cancer stem cell model, the hypothesis has rejuvenated hopes for formulating a novel therapeutic strategy for targeting the roots of cancer. This model predicts that cancer stem cells have the capacity to resist conventional radio- and chemotherapy and initiate disease recurrence. We recently investigated the mechanisms of chemoresistance in glioblastoma (GBM), the most common and aggressive adult human brain tumor. Exposure of patient derived glioma xenograft lines to a therapeutic dose of temolozolomide (TMZ), the most commonly used chemotherapy for patients with GBM, consistently increased the glioma stem cell (GSC) frequency over time. Lineage tracing analysis at the single sell level revealed unprecedented cellular plasticity within the glioma cells, allowing them to reprogram from a differentiated state to an undifferentiated CSC-like state. This reprogramming, mediated by cellular plasticity, is driven by TMZ-induced hypoxia inducible factors (HIFs), and provides a novel mechanism for chemoresistance acquisition. We herein discuss the possible role of temozolomide in regulating a cancer stem cell niche that supports GSC resistance, proliferation, and subsequent therapeutic relapse.