Weaponizing human EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) for 21st century cancer therapeutics
| Autor: | Anne T. Di Donato, Ji Won Hwang, Zhenzhi Li, Liping Yu, Eric R. Siegel, Yi-Hong Zhou, Chao Ke, Yuanjie Hu, Hao Hsu, Mark E. Linskey, Christopher Vo, Abhishek Chaturbedi |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research MMP2 Angiogenesis EGFR Integrin Cell Notch signaling pathway Extracellular matrix 03 medical and health sciences Extracellular matrix protein 1 0302 clinical medicine NOTCH1 tumor vascularization glioma medicine education education.field_of_study EFEMP1 biology orthotopic tumors tumor cell subpopulation cell invasion Molecular biology Fibulin 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer research biology.protein |
| Zdroj: | Oncoscience, vol 3, iss 7-8 |
| ISSN: | 2331-4737 |
| DOI: | 10.18632/oncoscience.306 |
| Popis: | De-regulated EFEMP1 gene expression in solid tumors has been widely reported with conflicting roles. We dissected EFEMP1 to identify domains responsible for its cell context-dependent dual functions, with the goal being to construct an EFEMP1-derived tumor-suppressor protein (ETSP) that lacked tumor-promoting function. Exon/intron boundaries of EFEMP1 were used as boundaries of functional modules in constructing EFEMP1 variants, with removal of various module(s), and/or mutating an amino acid residue to convert a weak integrin binding-site into a strong one. A series of in vitro assays on cancerous features, and subcutaneous and intracranial xenograft-formation assays, were carried out for effects from overexpression of wild-type and variant forms of EFEMP1 in two glioma subpopulations characterized as tumor mass-forming cells (TMCs) or stem-like tumor initiating cells (STICs), where EFEMP1 showed cellcontext- dependent dual functions. One of the EFEMP1 variants was identified as the sought-after ETSP, which had a stronger tumor-suppression function in TMCs by targeting EGFR and angiogenesis, and a new tumor-suppression function in STICs by targeting NOTCH signaling and MMP2-mediated cell invasion. Therefore, ETSP may form the basis for further important research to develop a novel cancer therapy to treat many types of cancer by its tumor suppressor effect in the extracellular matrix compartment. |
| Databáze: | OpenAIRE |
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