Stmc-34. role of interleukin-8/cxcr2 regulated epigenetic plasticity in gbm recurrence

Emerging evidence has revealed the enrichment of cancer stem cells (CSCs) in glioblastoma (GBM) and other cancers post-therapy. This can occur by dedifferentiation of non-CSCs to CSCs within the tumor population, which may be responsible for promoting the therapeutic resistance. To elucidate the molecular mechanisms of post-therapy cellular plasticity, a gene expression analysis, comparing the pre- and the post-therapy GBM CSCs (GSCs), revealed that Interleukin-8 (IL-8) transcripts are significantly elevated in post-therapy CD133+ GSCs. IL-8 is a pro-inflammatory chemokine that is upregulated both at mRNA and protein level upon therapeutic stress. The IL8 cognate receptor CXCR2 positive non-GSC population converts to CD133+ GSCs during chemotherapy. Exposure to IL8 significantly enhanced the self-renewing capacity of PDX GBMs (average 3-fold, p<0.0005), and shRNA-mediated knockdown of IL8 significantly delayed PDX GBM tumor growth in vivo (p<0.0005). Analysis of the Cancer Genome Atlas data demonstrated that IL8 transcript expression is negatively correlated with GBM patient survival (p=0.001). Gene expression analysis in different anatomic regions of GBM, in the Ivy Glioblastoma Atlas Project, indicates that IL8 expression is positively correlated with stemness genes such as CD133 and SOX2 within pseudopalisading cells around necrotic areas, and also in the leading edge region within patient GBM (p<0005, r=0.7; p=0.03, r=0.48). In sicilo analysis indicates that IL8 ...
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: STEM CELLS Source Type: research