Resistance of Glioblastoma-Initiating Cells to Radiation Mediated by the Tumor Microenvironment Can Be Abolished by Inhibiting Transforming Growth Factor-beta

Department of Radiation Oncology, New York University School of Medicine, New York, New York 10016, USA.
Cancer Research (Impact Factor: 9.33). 06/2012; 72(16):4119-29. DOI: 10.1158/0008-5472.CAN-12-0546
Source: PubMed


The poor prognosis of glioblastoma (GBM) routinely treated with ionizing radiation (IR) has been attributed to the relative radioresistance of glioma-initiating cells (GIC). Other studies indicate that although GIC are sensitive, the response is mediated by undefined factors in the microenvironment. GBM produce abundant transforming growth factor-β (TGF-β), a pleotropic cytokine that promotes effective DNA damage response. Consistent with this, radiation sensitivity, as measured by clonogenic assay of cultured murine (GL261) and human (U251, U87MG) glioma cell lines, increased by approximately 25% when treated with LY364947, a small-molecule inhibitor of TGF-β type I receptor kinase, before irradiation. Mice bearing GL261 flank tumors treated with 1D11, a pan-isoform TGF-β neutralizing antibody, exhibited significantly increased tumor growth delay following IR. GL261 neurosphere cultures were used to evaluate GIC. LY364947 had no effect on the primary or secondary neurosphere-forming capacity. IR decreased primary neurosphere formation by 28%, but did not reduce secondary neurosphere formation. In contrast, LY364947 treatment before IR decreased primary neurosphere formation by 75% and secondary neurosphere formation by 68%. Notably, GL261 neurospheres produced 3.7-fold more TGF-β per cell compared with conventional culture, suggesting that TGF-β production by GIC promotes effective DNA damage response and self-renewal, which creates microenvironment-mediated resistance. Consistent with this, LY364947 treatment in irradiated GL261 neurosphere-derived cells decreased DNA damage responses, H2AX and p53 phosphorylation, and induction of self-renewal signals, Notch1 and CXCR4. These data motivate the use of TGF-β inhibitors with radiation to improve therapeutic response in patients with GBM.

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    • "However, if cancer cells are commonly out of regulation and have relatively higher plasticity, conventional therapies may have to be revisited to check if the introduced disturbances have the potential to modulate cell plasticity. In addition to the identification of CSCs, we need to investigate how CSCs and differentiated bulk tumor cells dynamically respond to microenvironmental changes [44]. For example, hypoxia (HIF1α) [45, 46], epithelial-mesenchymal transition [47], inflammatory cytokines (e.g., IL-6 and TGFβ) [48, 49], and embryonic microenvironments [50] can all promote the reprogramming of CCs and increase the overall stemness of the tumor. "
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    ABSTRACT: Enrichment of cancer stem cells (CSCs) is thought to be responsible for glioblastoma multiforme (GBM) recurrence after radiation therapy. Simulation results from our agent-based cellular automata model reveal that the enrichment of CSCs may result either from an increased symmetric self-renewal division rate of CSCs or a reprogramming of non-stem cancer cells (CCs) to a stem cell state. Based on plateau-to-peak ratio of the CSC fraction in the tumor following radiation, a downward trend from peak to subsequent plateau (i.e., a plateau-to-peak ratio exceeding 1.0) was found to be inconsistent with increased symmetric division alone and favors instead a strong reprogramming component. The two contributions together are seen to be the product of a dynamic equilibrium between CSCs and CCs that is highly regulated by the kinetics of single cells, including the potential for CCs to reacquire a stem cell state and confer phenotypic plasticity to the population as a whole. We conclude that tumor malignancy can be gauged by a degree of cancer cell plasticity.
    Stem cell International 05/2014; 2014:249309. DOI:10.1155/2014/249309 · 2.81 Impact Factor
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    • "In this network, the ten genes were coregulated by the six miRNAs, suggesting that the six miRNAs and ten genes may play important roles in the NPC radioresistance. Previous studies strongly support our views: (1) the three miRNAs (miRNA-23a, miRNA-203 and miRNA-660) target IL-8, a inflammatory factor, not only played an important role in the pathogenesis of NPC [53], but also could activate NF-κB and Stats signaling pathways related to tumor radioresistance [49], [54]; (2) the four miRNAs (miRNA-23a, miRNA-203, miRNA-30a, miRNA-545) target JAK1 is an upstream factor of Stats, and a Stat signaling pathway played an important role in the pathogenesis of NPC [55] and radioresistance of tumors including NPC [14], [54]; (3) the five miRNAs (miRNA-23a, miRNA-203, miRNA-24, miR30a, miRNA-545) target SMAD2 is one member of TGF-β signaling pathway, and activation of this pathway was associated with tumor radioresistance [56], [57]; (4) the five miRNAs (miRNA-23a, miRNA-203, miRNA-30a, miRNA-24, miRNA-545) target SOCS6 is one member of SOCS family, and reciprocal regulation of SOCS1 and SOCS3 enhanced glioblastoma multiforme radioresistance [58]; (5) the two miRNA (miRNA-203, miRNA-24) target FOS, a component of transcriptional factor AP1, was associated with tumor chemoresistance [59], [60]. "
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    ABSTRACT: The purpose of this study was to identify miRNAs and genes involved in nasopharyngeal carcinoma (NPC) radioresistance, and explore the underlying mechanisms in the development of radioresistance. We used microarrays to compare the differences of both miRNA and mRNA expression profiles in the radioresistant NPC CNE2-IR and radiosensitive NPC CNE2 cells, applied qRT-PCR to confirm the reliability of microarray data, adopted databases prediction and anticorrelated analysis of miRNA and mRNA expression to identify the miRNA target genes, and employed bioinformatics tools to examine the functions and pathways in which miRNA target genes are involved, and construct a miRNA-target gene regulatory network. We further investigated the roles of miRNA-23a and its target gene IL-8 in the NPC radioresistance. THE MAIN FINDINGS WERE FOURFOLD: (1) fifteen differential miRNAs and 372 differential mRNAs were identified, and the reliability of microarray data was validated for randomly selected eight miRNAs and nine genes; (2) 174 miRNA target were identified, and most of their functions and regulating pathways were related to tumor therapeutic resistance; (3) a posttranscriptional regulatory network including 375 miRNA-target gene pairs was constructed, in which the ten genes were coregulated by the six miRNAs; (4) IL-8 was a direct target of miRNA-23a, the expression levels of IL-8 were elevated in the radioresistant NPC tissues and showed inverse correlation with miRNA-23a expression, and genetic upregulation of miRNA-23a and antibody neutralization of secretory IL-8 could reduce NPC cells radioresistance. We identified fifteen differential miRNAs and 372 differential mRNAs in the radioresistant NPC cells, constructed a posttranscriptional regulatory network including 375 miRNA-target gene pairs, discovered the ten target genes coregulated by the six miRNAs, and validated that downregulated miRNA-23a was involved in NPC radioresistance through directly targeting IL-8. Our data form a basis for further investigating the mechanisms of NPC radioresistance.
    PLoS ONE 01/2014; 9(1):e87767. DOI:10.1371/journal.pone.0087767 · 3.23 Impact Factor
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    • "Galli et al. similarly demonstrated that glioblastoma cell lines possess molecular, cytologic, and histologic characteristics similar to neural stem cells (NSCs) [13]. Like other CSCs, GSCs are especially endowed with the ability to resist radiation therapy [14] [15] [16] [17]. For example, GSCs were shown to possess higher capacity to activate DNA damage checkpoint proteins and thereby are more radiation resistant than non-GSCs [14]. "
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    ABSTRACT: Glioblastoma multiforme (GBM) is the most malignant form of central nervous system tumor, and current therapies are largely ineffective at treating the cancer. Developing a more complete understanding of the mechanisms controlling the tumor is important in order to explore new possible treatment options. It is speculated that the presence of glioblastoma stem or stem-like cells (GSCs), a rare type of pluripotent cancer cell that possesses the ability to self-renew and generate tumors, could be an important factor contributing to the resistance to treatment and deadliness of the cancer. A comprehensive knowledge of the mechanisms controlling the expression and properties of GSCs is currently lacking, and one promising area for further exploration is in the influence of basic fibroblast growth factor (FGF-2) on GSCs. Recent studies reveal that FGF-2 plays a significant part in regulating GBM, and the growth factor is commonly included as a supplement in media used to culture GSCs in vitro. However, the particular role that FGF-2 plays in GSCs has not been as extensively explored. Therefore, understanding how FGF-2 is involved in GSCs and in GBMs could be an important step towards a more complete comprehension of the managing the disease. In this review, we look at the structure, signaling pathways, and specific role of FGF-2 in GBM and GSCs. In addition, we explore the use of FGF-2 in cell culture and using its synthetic analogs as a potential alternative to the growth factor in culture medium.
    Cancer letters 12/2013; 346(1). DOI:10.1016/j.canlet.2013.12.003 · 5.62 Impact Factor
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