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Therapeutic Gene Delivery and Transfection in Human Pancreatic Cancer Cells using Epidermal Growth Factor Receptor-targeted Gelatin Nanoparticles
Published on: January 4, 2012
Epidermal growth factor receptor-related protein: a potential therapeutic agent for colorectal cancer
Dorota J Marciniak1, Lathika Moragoda, Ramzi M Mohammad
1Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan, USA.
Background & Aims:
Epidermal growth factor receptor is frequently implicated in epithelial cancers and is, therefore, being considered as a potential target for therapy. Recently, we reported the isolation and characterization of epidermal growth factor receptor-related protein, a negative regulator of epidermal growth factor receptor. To discern whether epidermal growth factor receptor-related protein could be an effective therapeutic agent for colorectal cancer, we generated epidermal growth factor receptor-related protein fusion protein and studied its effect on the growth of colon cancer cells in vivo and in vitro. We also studied whether epidermal growth factor receptor-related protein expression is altered in colorectal cancer.
Methods:
A 55-kilodalton epidermal growth factor receptor-related protein fusion protein with V5 and His tags was generated in a drosophila expression system and subsequently purified by a His antibody affinity column. Rabbit polyclonal antibodies against epidermal growth factor receptor-related protein were used to examine the expression of epidermal growth factor receptor-related protein.
Results:
Epidermal growth factor receptor-related protein expression was found to be high in benign human colonic epithelium but low in adenocarcinoma. Exposure of the colon cancer cell lines HCT-116 and Caco-2 to purified recombinant epidermal growth factor receptor-related protein caused a marked inhibition of proliferation, as well as attenuation of basal and ligand-induced stimulation of epidermal growth factor receptor phosphorylation. Epidermal growth factor receptor-related protein-induced inhibition of proliferation of colon cancer cells was prevented by epidermal growth factor receptor-related protein antibodies. Reduced epidermal growth factor receptor phosphorylation was partly due to sequestration of epidermal growth factor receptor ligands by epidermal growth factor receptor-related protein, resulting in the formation of inactive heterodimers with epidermal growth factor receptor. Intratumoral or subcutaneous (away from the tumor site) injections of purified epidermal growth factor receptor-related protein caused regression of palpable colon cancer xenograft tumors in some severely compromised immunodeficient mice and arrested tumor growth in others.
Conclusions:
We propose that epidermal growth factor receptor-related protein inhibits cellular growth by attenuating epidermal growth factor receptor signaling processes and is an effective therapeutic agent for colorectal cancer.
Insights
Epidermal growth factor receptor-related protein inhibits colon cancer growth by blocking epidermal growth factor receptor signaling. This protein shows therapeutic potential for colorectal cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Epidermal growth factor receptor (EGFR) is a key target in epithelial cancers.
- Epidermal growth factor receptor-related protein (EGFRRP) negatively regulates EGFR.
- EGFRRP's therapeutic potential for colorectal cancer requires investigation.
Purpose of the Study:
- To evaluate EGFRRP as a therapeutic agent for colorectal cancer.
- To assess EGFRRP's effect on colon cancer cell growth in vitro and in vivo.
- To determine alterations in EGFRRP expression in colorectal cancer.
Main Methods:
- Generated and purified a 55-kDa EGFRRP fusion protein.
- Utilized rabbit polyclonal antibodies to examine EGFRRP expression.
- Studied the effects of EGFRRP on colon cancer cell lines (HCT-116, Caco-2) and xenografts in mice.
Main Results:
- EGFRRP expression was high in benign colonic epithelium but low in adenocarcinoma.
- Recombinant EGFRRP inhibited colon cancer cell proliferation and EGFR phosphorylation.
- EGFRRP treatment led to regression or growth arrest of colon cancer xenografts in mice.
Conclusions:
- EGFRRP inhibits cellular growth by attenuating EGFR signaling.
- EGFRRP demonstrates efficacy as a therapeutic agent for colorectal cancer.
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