NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Luxembourg, Luxembourg, Sweden.
Neuro Oncol. 2013 Sep;15(9):1200-11. doi: 10.1093/neuonc/not054. Epub 2013 May 30.
Deregulated growth factor signaling is a major driving force in the initiation and progression of glioblastoma. The tumor suppressor and stem cell marker Lrig1 is a negative regulator of the epidermal growth factor receptor (EGFR) family. Here, we addressed the therapeutic potential of the soluble form of Lrig1 (sLrig1) in glioblastoma treatment and the mechanism of sLrig1-induced growth inhibition.
With use of encapsulated cells, recombinant sLrig1 was locally delivered in orthotopic glioblastoma xenografts generated from freshly isolated patient tumors. Tumor growth and mouse survival were evaluated. The efficacy of sLrig1 and the affected downstream signaling was studied in vitro and in vivo in glioma cells displaying variable expression of wild-type and/or a constitutively active EGFR mutant (EGFRvIII).
Continuous interstitial delivery of sLrig1 in genetically diverse patient-derived glioma xenografts led to strong tumor growth inhibition. Glioma cell proliferation in vitro and tumor growth in vivo were potently inhibited by sLrig1, irrespective of EGFR expression levels. Of importance, tumor growth was also suppressed in EGFRvIII-driven glioma. sLrig1 induced cell cycle arrest without changing total receptor level or phosphorylation. Affected downstream effectors included MAP kinase but not AKT signaling. Of importance, local delivery of sLrig1 into established tumors led to a 32% survival advantage in treated mice.
To our knowledge, this is the first report demonstrating that sLrig1 is a potent inhibitor of glioblastoma growth in clinically relevant experimental glioma models and that this effect is largely independent of EGFR status. The potent anti-tumor effect of sLrig1, in combination with cell encapsulation technology for in situ delivery, holds promise for future treatment of glioblastoma.
失调的生长因子信号是胶质母细胞瘤发生和进展的主要驱动力。肿瘤抑制因子和干细胞标志物 Lrig1 是表皮生长因子受体（EGFR）家族的负调节剂。在这里，我们研究了可溶性 Lrig1（sLrig1）在胶质母细胞瘤治疗中的治疗潜力及其诱导生长抑制的机制。
使用包封细胞，在从新鲜分离的患者肿瘤中生成的原位胶质母细胞瘤异种移植中局部递送电融合可溶性 Lrig1（sLrig1）。评估肿瘤生长和小鼠存活。研究了 sLrig1 的功效及其在显示野生型和/或组成型激活的 EGFR 突变（EGFRvIII）的 EGFR 表达水平不同的神经胶质瘤细胞中的受影响的下游信号。
在遗传上多样化的患者来源的胶质母细胞瘤异种移植中持续的间质递送电融合可溶性 Lrig1 导致强烈的肿瘤生长抑制。sLrig1 在体外和体内均能有效抑制神经胶质瘤细胞的增殖和肿瘤的生长，而与 EGFR 表达水平无关。重要的是，sLrig1 还抑制了 EGFRvIII 驱动的神经胶质瘤的生长。sLrig1 诱导细胞周期停滞，而不改变总受体水平或磷酸化。受影响的下游效应物包括 MAP 激酶，但不包括 AKT 信号。重要的是，sLrig1 局部递送至已建立的肿瘤中，可使治疗小鼠的存活率提高 32%。
据我们所知，这是第一项证明 sLrig1 是临床上相关的实验性神经胶质瘤模型中胶质母细胞瘤生长的有效抑制剂的报告，并且这种作用在很大程度上独立于 EGFR 状态。sLrig1 的强大抗肿瘤作用，结合用于原位递送的细胞包封技术，为胶质母细胞瘤的未来治疗提供了希望。
