Tumorigenicity of cortical astrocyte cell line induced by the protease ADAM17
Mark Katakowski1, Feng Jiang, XuGuang Zheng
1Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA.
Abstract:
The metalloprotease ADAM17 (a.k.a. TACE) plays a pivotal role in the cleavage and activation of membrane-anchored receptor ligands. More recently, it has been revealed that ADAM17 is a potent sheddase of the epidermal growth factor (EGF) family of ligands and regulates epidermal growth factor receptor (EGFR) activity in a variety of tumors. EGFR is a key component of autonomous growth signaling in several tumors, and correlates with the malignancy grade of astrocytoma. In this study, we tested the hypothesis that over-expression of ADAM17 in cortical astrocytes derived from normal brain would induce a progression towards a malignant phenotype. Over-expression of human ADAM17 (hADAM17) in the CTX-TNA2 cortical astrocyte cell line resulted in non-adherent growth, increased proliferation, invasiveness, production of angiogenic factors, and expression of genes associated with immature and/or neoplastic cells. hADAM17 up-regulated EGFR and AKT phosphorylation, and increased proliferation and cell invasion were significantly dependent upon EGFR activity. When implanted in the nude mouse brain, CTX-TNA2 cells induced low histological grade, benign intraventricular gliomas. In contrast, the same astrocytes with hADAM17 formed large malignant gliomas. Taken together, these findings suggest that unregulated ADAM17 activity induces functional changes in astrocytes that significantly advance the malignant phenotype.
Insights
Overexpressing ADAM17 in astrocytes promotes malignant glioma development by activating EGFR signaling. This metalloprotease drives tumor growth, invasion, and angiogenesis, advancing the malignant phenotype.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Research
Background:
- ADAM17 (a.k.a. TACE) is a metalloprotease crucial for cleaving membrane-bound ligands.
- ADAM17 sheds epidermal growth factor (EGF) ligands, regulating epidermal growth factor receptor (EGFR) activity in tumors.
- EGFR signaling is vital for tumor growth and correlates with astrocytoma malignancy.
Purpose of the Study:
- To investigate if ADAM17 overexpression in normal astrocytes induces malignant transformation.
- To determine the role of ADAM17 in regulating astrocyte proliferation, invasion, and tumor formation.
Main Methods:
- Overexpression of human ADAM17 (hADAM17) in the CTX-TNA2 astrocyte cell line.
- Analysis of cellular phenotypes: growth, proliferation, invasion, and gene expression.
- Assessment of signaling pathways: EGFR and AKT phosphorylation.
- In vivo studies involving implantation of modified astrocytes into nude mouse brains.
Main Results:
- hADAM17 overexpression led to non-adherent growth, increased proliferation, invasiveness, and production of angiogenic factors.
- hADAM17 upregulated EGFR and AKT phosphorylation; EGFR activity was essential for proliferation and invasion.
- CTX-TNA2 cells with hADAM17 formed malignant gliomas in vivo, unlike control cells which formed benign gliomas.
Conclusions:
- Unregulated ADAM17 activity in astrocytes drives malignant transformation.
- ADAM17 promotes a malignant phenotype through EGFR signaling.
- ADAM17 is a potential therapeutic target for gliomas.