The soluble form of the tumor suppressor Lrig1 potently inhibits in vivo glioma growth irrespective of EGF receptor status

摘要

Background. 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 Lrigl (sLrigl) in glioblastoma treatment and the mechanism of sLrig1-induced growth inhibition. Methods. With use of encapsulated cells, recombinant sLrigl was locally delivered in orthotopic glioblastoma xenografts generated from freshly isolated patient tumors. Tumor growth and mouse survival were evaluated. The efficacy of sLrigl and the affected downstream signaling was studied in vitro and in vivo in glioma cells displaying variable expression of wild-type and/or a con-stitutively active EGFR mutant (EGFRvⅢ). Results. Continuous interstitial delivery of sLrigl 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 sLrigl, irrespective of EGFR expression levels. Of importance, tumor growth was also suppressed in EGFRvⅢ-driven glioma. sLrigl induced cell cycle arrest without changing total receptor level or phosphor-ylation. Affected downstream effectors included MAP kinase but not AKT signaling. Of importance, local delivery of sLrigl into established tumors led to a 32% survival advantage in treated mice. Conclusions. To our knowledge, this is the first report demonstrating that sLrigl 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 sLrigl, in combination with cell encapsulation technology for in situ delivery, holds promise for future treatment of glioblastoma.