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

Abstract

BackgroundDeregulated 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.MethodsWith 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).ResultsContinuous 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.ConclusionsTo 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.

MicroRNA-590-3p enhances the radioresistance in glioblastoma cells by targeting LRIG1

“…Previous studies have indicated that LRIG1 was frequently decreased in gliomas (21), and the expression level of LRIG1 is significantly correlated with the malignancy of glioma (21,33). It has also been reported that upregulation of LRIG1 expression suppresses malignant glioma cell growth and induces cell apoptosis (21,(34)(35)(36), whereas downregulation of LRIG1 expression promotes the proliferation and aggressive properties of glioma cells (37,38). Furthermore, previous studies have suggested that LRIG1 is associated with the regulation of chemosensitivity of human cancer cells (39,40).…”

LRIG1 inhibits hypoxia-induced vasculogenic mimicry formation via suppression of the EGFR/PI3K/AKT pathway and epithelial-to-mesenchymal transition in human glioma SHG-44 cells

“…Inhibition of EGFR signaling by LRIG1 results from the physical interaction between both proteins, which subsequently induces the recruitment of E3 ubiquitin ligases to promote lysosomal degradation of the EGFR-LRIG1 complex (Johansson et al 2013). In glioma cells, EGFR is usually overexpressed and its downstream signaling cascades are frequently activated during the development of malignancy (Ye et al 2010).…”

LRIG1 Extracellular Domain: Structure and Function Analysis

“…Similarly, Johansson et al observed an anti-proliferative effect of LRIG1, whether or not glioma cells expressed the EGFR [10]. Nor could we detect an effect of soluble, purified LRIG1-ECD, or coexpressed, full-length LRIG1 on the levels of EGFR, the phosphorylation of the EGFR kinase, or on the activation of EGFR signalling.…”

“…It contains 19 β-strands with 16 LRRs (numbered [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. There are 15 complete LRRs [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15], each with 23-27 residues, where 11 LRRs have the 24-residue repeat [LxxLxLxxNxLxxLxxxx(Hφ)xx(Hφ)xx, where Hφ is any hydrophobic amino acid residue]. LRR16 is only a partial repeat with a new pattern LxxLxIxSxxFx, where Ser appears to replace Asn in the consensus repeat (LxxLxLxxNxLxx).…”

“…Mutations to the intracellular domain of LRIG1 reduce its effects on EGFR degradation [7], and LRIG1 also increases the degradation of an oncogenic form of the EGFR(vIII), which is missing domain I and most of domain II [8]. Although it has been reported that cell-surface EGFR is necessary for the anti-proliferative action of the soluble ectodomain of LRIG1 [9], more recent reports indicate that the soluble form of LRIG1 inhibits the proliferation of glioma cells irrespective of the levels of the EGFR [10].…”