Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Oncogene. 2013 Jan 17;32(3):363-74. doi: 10.1038/onc.2012.49. Epub 2012 Mar 5.
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 proinflammatory 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-κB. 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 photodynamic 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.
内皮细胞在实体瘤的进展中起着关键作用，被认为是治疗的一个非常相关的靶点。然而，目前通过抑制肿瘤衍生的生长因子来发挥作用的临床血管生成抑制剂容易产生耐药性。因此，肿瘤内皮细胞（EC）本身的标志物提供了有吸引力的新的治疗靶点。在筛选肿瘤血管生成标志物的过程中，我们最近发现高迁移率族蛋白 B1（HMGB1），已知作为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，表明其过表达与 EC 的血管生成潜力增加有关。HMGB1 刺激血管内皮生长因子和血小板衍生生长因子信号通路中蛋白的表达，无论是在体外还是体内。重要的是，我们表明 HMGB1 在 EC 中触发并有助于维持这种促血管生成基因表达程序，其特征还包括基质金属蛋白酶、整合素和核因子-κB 的活性增加。此外，我们发现 HMGB1 参与了几个自分泌和/或旁分泌反馈机制，导致 HMGB1 表达及其受体 RAGE（晚期糖基化终产物受体）和 Toll 样受体 4（TLR4）的表达增强。使用敲低方法和抗体靶向进行的 HMGB1 表达和/或功能的干扰导致 EC 的迁移和发芽受到抑制。使用不同的体内模型，证实了 HMGB1 靶向的治疗效果。首先，我们证明了在鸡胚绒毛尿囊膜（CAM）新生血管中，光动力疗法和肿瘤挑战后 HMGB1 的表达均被诱导。随后，我们表明抗 HMGB1 抗体抑制了两种模型中的血管密度，同时降低了血管中血管生成生长因子受体的表达。总之，这些数据表明 HMGB1 是肿瘤血管生成的重要调节剂，并表明靶向 HMGB1 进行多层次癌症治疗的可行性。
