Abstract
BackgroundDecades of cytotoxic and more recently immunotherapy treatments for malignant glioma have had limited success due to dynamic intra-tumoral heterogeneity. The dynamic interplay of cancer cell subpopulations has been found to be under the control of proteins in the cancer microenvironment. EGF-containing fibulin-like extracellular matrix protein (EFEMP1) (also fibulin-3) has the multiple functions of suppressing cancer growth and angiogenesis, while promoting cancer cell invasion. EFEMP1-derived tumor suppressor protein (ETSP) retains EFEMP1’s anti-growth and anti-angiogenic functions while actually inhibiting cancer cell invasion.MethodsIn this study, we examined the therapeutic effect on glioblastoma multiforme (GBM) of an in vitro synthesized protein, ZR30, which is based on the sequence of ETSP, excluding the signaling peptide.ResultsZR30 showed the same effects as ETSP in blocking EGFR/NOTCH/AKT signaling pathways, when applied to cultures of multiple GBM cell lines and primary cultures. ZR30’s inhibition of MMP2 activation was shown not only for GBM cells, but also for other types of cancer cells having overexpression of MMP2. A significant improvement in survival of mice with orthotopic human GBM xenografts was observed after a single, intra-tumoral injection of ZR30. Using a model mimicking the intra-tumoral heterogeneity of GBM with cell subpopulations carrying different invasive and proliferative phenotypes, we demonstrated an equal and simultaneous tumor suppressive effect of ZR30 on both tumor cell subpopulations, with suppression of FOXM1 and activation of SEMA3B expressions in the xenografts.ConclusionOverall, the data support a complementary pleiotrophic therapeutic effect of ZR30 acting in the extracellular compartment of GBM.
Highlights
glioblastoma multiforme (GBM) is a deadly form of brain cancer, for which there has been marginal improvement on survival despite 40 years of research/clinical trials
In this study, we examined the therapeutic effect on glioblastoma multiforme (GBM) of an in vitro synthesized protein, ZR30, which is based on the sequence of EFEMP1-derived tumor suppressor protein (ETSP), excluding the signaling peptide
ZR30 used in this study was provided by Ziren Research, LLC, produced by an in vitro cell-free system based on ETSP but excluding the signal peptide (Figure 1A), fused to GST tag for purification, has a size of 38.61 kDa after GST removal in SDS-PAGE gel (Figure 1B) and detectable in immunoblotting by an antibody for human EFEMP1 (Figure 1C)
Summary
GBM is a deadly form of brain cancer, for which there has been marginal improvement on survival despite 40 years of research/clinical trials. Most GBMs are found to have over-expression of cell membrane receptor EGFR, pro-angiogenic protein VEGFA, and pro-invasive protein MMP2, there has been no success in improving survival with drugs targeting MMP2, EGFR and VEGFA alone or in combination [1, 2]. Invasive STIC in GBM are commonly found to lack the high expression of EGFR shown in TMC subpopulations, but to have activation of NOTCH signaling, which has been demonstrated to maintain “stemness” [3] and other features associated with cancer stem cells and their resistance to radiation therapy [4]. Using a model mimicking the intra-tumoral heterogeneity of GBM with cell subpopulations carrying different invasive and proliferative phenotypes, we demonstrated an equal and simultaneous tumor suppressive effect of ZR30 on both tumor cell subpopulations, with suppression of FOXM1 and activation of SEMA3B expressions in the xenografts. Conclusion: Overall, the data support a complementary pleiotrophic therapeutic effect of ZR30 acting in the extracellular compartment of GBM
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