Resistance of glioblastoma-initiating cells to radiation mediated by the tumor microenvironment can be abolished by inhibiting transforming growth factor-β.
Resistance of glioblastoma-initiating cells to radiation mediated by the tumor microenvironment can be abolished by inhibiting transforming growth factor-β.
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DOI：
10.1158/0008-5472.can-12-0546
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发表时间：
2012-08-15
期刊：
影响因子：
11.2
通讯作者：
Barcellos-Hoff MH
中科院分区：
文献类型：
--
作者：
Hardee ME;Marciscano AE;Medina-Ramirez CM;Zagzag D;Narayana A;Lonning SM;Barcellos-Hoff MH
胶质母细胞瘤（GBM）常规电离辐射（IR）治疗的预后不良归因于胶质瘤起始细胞（GIC）的相对辐射抗性。其他研究表明，GIC是敏感的，但反应是由微环境中不确定的因素介导的。GBM产生丰富的转化生长因子-β（TGFβ），这是一种多效性细胞因子，可促进有效的DNA损伤反应。与此一致，通过克隆形成试验测量的培养的鼠（GL 261）和人（U251，U87 MG）胶质瘤细胞系的辐射敏感性在辐射前用LY 364947（一种TGFβ I型受体激酶的小分子抑制剂）处理时增加约25%。用1D 11（一种泛同种型TGFβ中和抗体）处理的携带GL 261侧腹肿瘤的小鼠在IR后表现出显著增加的肿瘤生长延迟。使用GL 261神经球培养物来评估GIC。LY 364947对初级或次级神经球形成能力没有影响。IR使原发性神经球形成减少28%，但不减少继发性神经球形成。相比之下，IR之前的LY 364947使初级神经球形成减少75%，次级神经球形成减少68%。值得注意的是，与传统培养物相比，GL 261神经球每个细胞产生的TGFβ多3.7倍，这表明GIC产生的TGFβ促进了DNA损伤反应和自我更新，并产生了微环境介导的抗性。与此一致，LY 364947处理在辐照的GL 261神经球衍生细胞中降低了DNA损伤反应、H2 AX和p53磷酸化，以及自我更新信号、Notch 1和CXCR 4的诱导。这些数据促使TGFβ抑制剂与放射一起使用，以改善GBM患者的治疗反应。
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 suggest that GIC are sensitive but the response is mediated by undefined factors in the microenvironment. GBM produce abundant transforming growth factor-β (TGFβ), 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 approximately 25% when treated with LY364947, a small molecule inhibitor of TGFβ type I receptor kinase, prior to irradiation. Mice bearing GL261 flank tumors treated with 1D11, a pan-isoform TGFβ neutralizing antibody, exhibited significantly increased tumor growth delay following IR. GL261 neurosphere cultures were used to evaluate GIC. LY364947 had no effect on primary or secondary neurosphere-forming capacity. IR decreased primary neurosphere formation by 28%, but did not reduce secondary neurosphere formation. In contrast, LY364947 prior to IR decreased primary neurosphere formation by 75% and secondary neurosphere formation by 68%. Notably, GL261 neurospheres produced 3.7-fold more TGFβ per cell compared to traditional culture, suggesting that TGFβ production by GIC promotes the DNA damage response and self-renewal and 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 TGFβ inhibitors with radiation to improve therapeutic response in GBM patients.