Abstract
EGFR is one of the key oncogenes subjected to targeted therapy for several cancers, as it is known to be amplified and/or mutated in up to 40% of malignant gliomas. EFEMP1, a fibulin-like extracellular protein, exerts both tumor suppressive and oncogenic effects in various cancers and glioma cell models. Although EFEMP1's anti-cancer activity has most commonly been attributed to its anti-angiogenic effects, we showed for gliomas that EFEMP1's binding to EGFR accounts for its suppression of the intracranial tumorigenicity of glioma cells expressing high levels of EGFR. In gliomas where EFEMP1 expression, and thus the anti-EGFR effect of EFEMP1, was suppressed, heightened levels of EGFR expression were associated with unfavorable patient outcomes in prognostic models. Results from the current study clearly demonstrate the impact that the anti-EGFR function of EFEMP1 has on the expression of EGFR and patient prognosis. A glioma prognostic model also suggests EFEMP1's context-dependent oncogenic function in gliomas expressing low levels of EGFR. Hence the level of EFEMP1 expression may have a predictive value for choosing patients for anti-EGFR therapy.
Highlights
EFEMP1 is a member of the fibulin family of secreted glycoproteins containing a series of epidermal growth factor (EGF)-like modules, followed by a carboxyterminal fibulin-type module
We showed that human recombinant EFEMP1 protein reduced the EGFR level and AKT phosphorylation in 48-hr treated glioma cell lines [17]
The experimental data described above demonstrated the tumor suppressive function of EFEMP1, which operates by attenuating and blocking EGF-stimulated EGFR signaling activities, and is consistent with the patient outcomes predicted based on the EGFR level in the subset of gliomas expressing a low level of EFEMP1 (Figure 6A)
Summary
EFEMP1 is a member of the fibulin family of secreted glycoproteins containing a series of epidermal growth factor (EGF)-like modules, followed by a carboxyterminal fibulin-type module. The anti-cancer properties of EFEMP1 were initially thought to be derived from direct targeting of endothelial cell proliferation to suppress angiogenesis www.impactjournals.com/oncoscience in cancer [9]. The tumor suppressive role of EFEMP1 has been confirmed in cancers from several organs, including brain, breast, colon, lung, liver, nasopharynx, and prostate [10-16]. Anti-cancer effects have been confirmed in vitro through characterization of EFEMP1 function in cell lines derived from human lung cancers [10, 18], nasopharyngeal carcinomas [14], and malignant gliomas [17]. In addition to observation of angiostatic effects, additional mechanisms underlying EFEMP1’s tumor suppression function that have since come to light include attenuation of EGFR/AKT-mediated growth signaling activities [14, 17] and reduction of MMP-induced cancer cell invasion [18]
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