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Updated: Aug 6, 2026
Modeling Spontaneous Metastatic Renal Cell Carcinoma (mRCC) in Mice Following Nephrectomy
Published on: April 29, 2014
Multiple acquired renal carcinoma tumor capabilities abolished upon silencing of ADAM17
Aleksandra Franovic1, Isabelle Robert, Karlene Smith
1Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Abstract:
Malignancy is a manifestation of acquired defects in regulatory circuits that direct normal cell proliferation and homeostasis. Most of these circuits operate through cell autonomous pathways, whereas others potentially involve the neighboring microenvironment. We report that the metalloprotease ADAM17 plays a pivotal role in several acquired tumor cell capabilities by mediating the availability of soluble transforming growth factor-alpha, an epidermal growth factor receptor (EGFR) ligand, and thus the establishment of a key autocrine signaling pathway. Silencing of ADAM17 in human renal carcinoma cell lines corrects critical features associated with cancer cells, including growth autonomy, tumor inflammation, and tissue invasion. Highly malignant renal carcinoma cancer cells fail to form in vivo tumors in the absence of ADAM17, confirming the essential function of this molecule in tumorigenesis. These data show that ligand shedding is a crucial step in endogenous EGFR activation and endorse prospective therapeutic strategies targeting ADAM17 in human cancer.
Insights
The metalloprotease ADAM17 is crucial for tumor growth by enabling cancer cells to signal themselves. Inhibiting ADAM17 stops renal carcinoma cells from growing and invading, highlighting its potential as a cancer therapy target.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Malignancy arises from defects in cell proliferation and homeostasis regulatory circuits.
- These regulatory circuits can be cell-autonomous or involve the tumor microenvironment.
Purpose of the Study:
- To investigate the role of the metalloprotease ADAM17 in acquired tumor cell capabilities.
- To determine if ADAM17 is essential for tumorigenesis and cancer progression.
Main Methods:
- Silencing of ADAM17 in human renal carcinoma cell lines.
- Assessment of cancer cell features such as growth autonomy, inflammation, and invasion.
- In vivo tumor formation assays in the absence of ADAM17.
Main Results:
- ADAM17 mediates the availability of soluble transforming growth factor-alpha, an epidermal growth factor receptor (EGFR) ligand.
- Silencing ADAM17 corrected growth autonomy, tumor inflammation, and tissue invasion in renal carcinoma cells.
- Highly malignant renal carcinoma cells failed to form in vivo tumors without ADAM17.
Conclusions:
- ADAM17 plays a pivotal role in key autocrine signaling pathways essential for cancer progression.
- Ligand shedding mediated by ADAM17 is a crucial step in endogenous EGFR activation.
- Targeting ADAM17 represents a prospective therapeutic strategy for human cancers, particularly renal carcinoma.
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