Weaponizing human EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) for 21st century cancer therapeutics

Zhou, Yihong; Hu, Yuanjie; Yu, Liping; Ke, Chao; Vo, Christopher; Hsu, Hao Jui; Li, Zhenzhi; Donato, Anne T Di; Chaturbedi, Abhishek; Hwang, Ji Won; Siegel, Eric R.; Linskey, Mark E.

doi:10.18632/oncoscience.306

Cited by 8 publications

(6 citation statements)

References 31 publications

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“…The canonical process of EGF-mediated activation of EGFR includes EGFR internalization, hence reduction of membrane level of EGFR, and increase of AKT phosphorylation (pAKT), which normally occur in synchronized cells by serum starvation for 1-2 days. In U251 cells after serum starvation for 2 days, exposure of cells to EGF (50 ng/ml) for 30 min showed EGFR/AKT activation, whereas adding human recombinant EFEMP1 or induction of ectopic EFEMP1 or ETSP over-expression blocked EGFR activation [ 5 , 8 , 9 ]. Using the same conditions we analyzed ZR30-treated U251.…”

Section: Resultsmentioning

confidence: 99%

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Human fibulin-3 protein variant expresses anti-cancer effects in the malignant glioma extracellular compartment in intracranial xenograft models

Liu

et al. 2017

Oncotarget

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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.

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Section: Resultsmentioning

confidence: 99%

“…EGFR, NOTCH signaling pathways) differentially activated by GBM functional cell subpopulations and their interaction with the tumor-promoting microenvironment (e.g. MMP2) [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Human fibulin-3 protein variant expresses anti-cancer effects in the malignant glioma extracellular compartment in intracranial xenograft models

Liu

et al. 2017

Oncotarget

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“…xenograft model with a survival end‐point following even a single intratumoral administration . The same multifaceted tumor suppression mechanisms of ZR30 were found in treated GBM cell lines and primary cultures, as also shown by induction of h‐fibulin‐3‐v expression in GBM cells . Initially, EFEMP1 was reported to have a role in antiangiogenesis .…”

Section: Introductionmentioning

confidence: 66%

“…Radical surgical resection followed by adjuvant radiotherapy/chemotherapy is standard treatment for malignant gliomas, however, tumor recurrence occurs in nearly all instances. Human fibulin‐3 variant (h‐fibulin‐3‐v), a novel cancer therapeutic agent, has been developed in our laboratory after recognizing that its parental protein EFEMP1 has a role in cancer evolution with a cell context‐dependent dual function . Human fibulin‐3 variant functions in the extracellular compartment through multifaceted tumor suppression mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Dual antivascular function of human fibulin‐3 variant, a potential new drug discovery strategy for glioblastoma

Luo

Cen

et al. 2020

Cancer Science

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The ECM protein EFEMP1 (fibulin‐3) is associated with all types of solid tumor through its cell context‐dependent dual function. A variant of fibulin‐3 was engineered by truncation and mutation to alleviate its oncogenic function, specifically the proinvasive role in glioblastoma multiforme (GBM) cells at stem‐like state. ZR30 is an in vitro synthesized 39‐kDa protein of human fibulin‐3 variant. It has a therapeutic effect in intracranial xenograft models of human GBM, through suppression of epidermal growth factor receptor/AKT and NOTCH1/AKT signaling in GBM cells and extracellular MMP2 activation. Glioblastoma multiforme is highly vascular, with leaky blood vessels formed by tumor cells expressing endothelial cell markers, including CD31. Here we studied GBM intracranial xenografts, 2 weeks after intratumoral injection of ZR30 or PBS, by CD31 immunohistochemistry. We found a 70% reduction of blood vessel density in ZR30‐treated xenografts compared with that of PBS‐treated ones. Matrigel plug assays showed the effect of ZR30 on suppressing angiogenesis. We further studied the effect of ZR30 on genes involved in endothelial transdifferentiation (ETD), in 7 primary cultures derived from 3 GBMs under different culture conditions. Two GBM cultures formed mesh structures with upregulation of ETD genes shortly after culture in Matrigel Matrix, and ZR30 suppressed both. ZR30 also downregulated ETD genes in two GBM cultures with high expression of these genes. In conclusion, multifaceted tumor suppression effects of human fibulin‐3 variant include both suppression of angiogenesis and vasculogenic mimicry in GBM.

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“…EFEMP1 is an important extracellular protein employed in cancer evolution via differential regulation of gene expression in different populations to achieve cell-context dependent dual function [162]. Weaponizing EFEMP1 by enhancing its tumor-suppressing role in TMC and reversing its oncogenic role in STIC of GBM is a promising, new, and novel approach to make cancer therapeutics targeting natural cancer evolution strategies [163].…”

Section: Future Cancer Therapeutics Targeting Natural Cancer Evolutiomentioning

confidence: 99%

Exploiting Cancer’s Tactics to Make Cancer a Manageable Chronic Disease

Afrasiabi

Linskey

Zhou

2020

Cancers

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The history of modern oncology started around eighty years ago with the introduction of cytotoxic agents such as nitrogen mustard into the clinic, followed by multi-agent chemotherapy protocols. Early success in radiation therapy in Hodgkin lymphoma gave birth to the introduction of radiation therapy into different cancer treatment protocols. Along with better understanding of cancer biology, we developed drugs targeting cancer-related cellular and genetic aberrancies. Discovery of the crucial role of vasculature in maintenance, survival, and growth of a tumor opened the way to the development of anti-angiogenic agents. A better understanding of T-cell regulatory pathways advanced immunotherapy. Awareness of stem-like cancer cells and their role in cancer metastasis and local recurrence led to the development of drugs targeting them. At the same time, sequential and rapidly accelerating advances in imaging and surgical technology have markedly increased our ability to safely remove ≥90% of tumor cells. While we have advanced our ability to kill cells from multiple directions, we have still failed to stop most types of cancer from recurring. Here we analyze the tactics employed in cancer evolution; namely, chromosomal instability (CIN), intra-tumoral heterogeneity (ITH), and cancer-specific metabolism. These tactics govern the resistance to current cancer therapeutics. It is time to focus on maximally delaying the time to recurrence, with drugs that target these fundamental tactics of cancer evolution. Understanding the control of CIN and the optimal state of ITH as the most important tactics in cancer evolution could facilitate the development of improved cancer therapeutic strategies designed to transform cancer into a manageable chronic disease.

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Weaponizing human EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) for 21st century cancer therapeutics

Cited by 8 publications

References 31 publications

Human fibulin-3 protein variant expresses anti-cancer effects in the malignant glioma extracellular compartment in intracranial xenograft models

Human fibulin-3 protein variant expresses anti-cancer effects in the malignant glioma extracellular compartment in intracranial xenograft models

Dual antivascular function of human fibulin‐3 variant, a potential new drug discovery strategy for glioblastoma

Exploiting Cancer’s Tactics to Make Cancer a Manageable Chronic Disease

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