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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    • "These findings suggest that inhibition of TGF-β signaling may inhibit the capacity of GSCs to initiate brain tumors. Indeed, TGF-β receptor inhibitors decreased the CD44(high)/ Id1(high) GSC population through the repression of DNA-binding proteins and the transcriptional regulators Id1 and Id3[64], and treatment with LY364947, a selective ATP-competitive inhibitor of TGF-βRI, reversed GSC radiation resistance and improve therapeutic response in patients[65]. "

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    • "Additionally, the clinical Abl/PDGFR inhibitor imatinib mesylate was reported to inhibit homologous recombination repair of IR-induced DNA double strand breaks, which, in turn, increased radiation sensitivity[40]. Comparable data have been published for TGFβ receptor inhibition increasing radiation sensitivity of glioblastoma and breast cancer cell lines[17,31,41]. However, in our dataset, the absence of TGFβ receptor type 1 and low expression levels of TGFβ receptor type 2 may have resulted in only small effects of the selective inhibitor LY2109761 on the tested MSC samples. "
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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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