Tumor angiogenesis is enforced by autocrine regulation of high-mobility group box 1
Tumor angiogenesis is enforced by autocrine regulation of high-mobility group box 1
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DOI：
10.1038/onc.2012.49
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发表时间：
2013-01-17
期刊：
影响因子：
8
通讯作者：
Griffioen, A. W.
中科院分区：
文献类型：
--
作者：
van Beijnum, J. R.;Nowak-Sliwinska, P.;Griffioen, A. W.
内皮细胞在实体肿瘤的发展中起着关键作用，被认为是高度相关的治疗靶点。然而，目前临床上通过抑制肿瘤衍生生长因子发挥作用的血管生成抑制剂很容易产生耐药性。因此，肿瘤内皮细胞的标志物本身提供了吸引人的新的治疗靶点。在肿瘤血管生成标志物的筛选中，我们最近发现了高迁移率族蛋白1(HMGB1)，它是已知的促炎细胞因子和染色质结合分子。在这里，我们报告了HMGB1在血管生成中的作用，表明它的过度表达与内皮细胞血管生成潜力的增加有关。HMGB1在体外和体内均能刺激血管内皮细胞生长因子和血小板衍生生长因子信号转导分子的表达。重要的是，我们发现HMGB1在内皮细胞中触发并帮助维持这种促血管生成的基因表达程序，此外，我们还发现HMGB1参与了几种自分泌和/或旁分泌反馈机制，导致HMGB1及其受体、RAGE(晚期糖基化终产物受体)和Toll样受体4(TLR4)的活性增加。通过基因敲除和抗体介导的靶向干扰HMGB1的表达和/或功能，以打破这种恶性循环，导致内皮细胞的迁移和萌发受到抑制。采用不同的体内模型，证实了HMGB1靶向治疗的有效性。首先，我们证明了在光动力治疗和肿瘤攻击后，HMGB1在鸡胚绒毛尿囊膜(CAM)新生血管中的诱导表达。我们随后发现，在这两种模型中，抗HMGB1抗体抑制了血管密度，同时血管新生生长因子受体的表达减少。总之，这些数据证实HMGB1是肿瘤血管生成的重要调节因子，并提示靶向HMGB1用于多水平癌症治疗的可行性。Oncogene(2013年)32,363-374；doi：10.1038/onc.2012.49；2012年3月5日在线发布
The endothelium plays a pivotal role in the progression of solid tumors and is considered a highly relevant target for therapy. However, it emerges that current clinical angiogenesis inhibitors that act through inhibition of tumor-derived growth factors are prone to inducing drug resistance. Therefore, markers of tumor endothelial cells (ECs) themselves provide attractive novel therapeutic targets. In a screen for markers of tumor angiogenesis, we recently identified high-mobility group box 1 (HMGB1), known to act as proinflamnnatory cytokine and chromatin-binding molecule. Here we report on the role of HMGB1 in angiogenesis by showing that its overexpression is associated with an increased angiogenic potential of ECs. HMGB1 stimulates the expression of players in vascular endothelial growth factor and platelet-derived growth factor signaling, both in vitro and in vivo. Importantly, we show that HMGB1 triggers and helps to sustain this proangiogenic gene expression program in ECs, additionally characterized by increased activity of matrix metalloproteinases, integrins and nuclear factor-kappa B. Moreover, we found that HMGB1 is involved in several autocrine and/or paracrine feedback mechanisms resulting in positive enforcement of HMGB1 expression, and that of its receptors, RAGE (receptor for advanced glycation end products) and Toll-like receptor 4 (TLR4). Interference in HMGB1 expression and/or function using knockdown approaches and antibody-mediated targeting to break this vicious circle resulted in inhibited migration and sprouting of ECs. Using different in vivo models, therapeutic efficacy of HMGB1 targeting was confirmed. First, we demonstrated induction of HMGB1 expression in the chicken embryo chorioallantoic membrane (CAM) neovasculature following both photodynannic therapy and tumor challenge. We subsequently showed that anti-HMGB1 antibodies inhibited vessel density in both models, accompanied by a reduced vascular expression of angiogenic growth factor receptors. Collectively, these data identify HMGB1 as an important modulator of tumor angiogenesis and suggest the feasibility of targeting HMGB1 for multi-level cancer treatment. Oncogene (2013) 32, 363-374; doi:10.1038/onc.2012.49; published online 5 March 2012