Amphiregulin exosomes increase cancer cell invasion
Open accessAbstract
Autocrine, paracrine, and juxtacrine are recognized modes of action for mammalian EGFR ligands including EGF, TGF-α (TGFα), amphiregulin (AREG), heparin-binding EGF-like growth factor (HB-EGF), betacellulin, epiregulin, and epigen. We identify a new mode of EGFR ligand signaling via exosomes. Human breast and colorectal cancer cells release exosomes containing full-length, signaling-competent EGFR ligands. Exosomes isolated from MDCK cells expressing individual full-length EGFR ligands displayed differential activities; AREG exosomes increased invasiveness of recipient breast cancer cells 4-fold over TGFα or HB-EGF exosomes and 5-fold over equivalent amounts of recombinant AREG. Exosomal AREG displayed significantly greater membrane stability than TGFα or HB-EGF. An average of 24 AREG molecules are packaged within an individual exosome, and AREG exosomes are rapidly internalized by recipient cells. Whether the composition and behavior of exosomes differ between nontransformed and transformed cells is unknown. Exosomes from DLD-1 colon cancer cells with a mutant KRAS allele exhibited both higher AREG levels and greater invasive potential than exosomes from isogenically matched, nontransformed cells in which mutant KRAS was eliminated by homologous recombination. We speculate that EGFR ligand signaling via exosomes might contribute to diverse cancer phenomena such as field effect and priming of the metastatic niche.
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Breast cancer cells incubated with exosomes containing high levels of AREG show significantly enhanced invasiveness compared to low AREG exosomes or recombinant EGFR ligands.
“Further, significantly enhanced levels of invasiveness are observed when breast cancer cells are incubated with exosomes containing high levels of AREG compared to incubation of cells with exosomes containing low levels of AREG or recombinant EGFR ligands (Higginbotham et al., 2011), suggesting a gain-of-function mode of EGFR signaling that might act in more distant environments.”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Higginbotham et al., 2011
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ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics
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- Authors
- Higginbotham, J. N., Demory Beckler, M., Gephart, J. D., Franklin, J. L., Bogatcheva, G., Kremers, G.-J., Piston, D. W., Ayers, G. D., McConnell, R. E., Tyska, M. J., & Coffey, R. J.
- Affiliations
- Vanderbilt University Medical Center (US)
- Nashville VA Medical Center (US)
- Corresponding author
- Coffey, Robert J.
- ORCID
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 21
- Issue
- 9
- Pages
- 779-786
- ISSN
- 0960-9822 (ISSN-L)
- PMC
- PMC3417320
- OpenAlex
- W2063508984
- Cited by
- 360
- References
- 32
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 15 · 2023: 17 · 2022: 22 · 2021: 19 · 2020: 37 · 2019: 27 · 2018: 28 · 2017: 27 · 2016: 37 · 2015: 39 · 2014: 22 · 2013: 21 · 2012: 20
- FWCI
- 9.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Public Health Service (P50 95103)
- National Cancer Institute (P30 CA 68485, CA46413, R25CA092043, P50CA095103, 1R25 CA92043, R01CA163563, R01CA046413, T32CA009582, P30CA068485)
- National Institute of General Medical Sciences (GM72048, P20GM072048)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK058404, R01DK075555, DK075555, P30DK058404)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007502)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Keywords
- amphiregulin, exosomes, EGFR ligands, tumor invasion, transforming growth factor-alpha, HB-EGF, KRAS mutation, breast cancer, colorectal cancer, exosome internalization, metastatic niche, field effect
- MeSH terms
- Animals, Centrifugation, Dogs, Electrophoresis, Polyacrylamide Gel, Enzyme-Linked Immunosorbent Assay, Glycoproteins, Humans, Microscopy, Electron, Neoplasm Invasiveness, Immunoblotting, Signal Transduction, Transforming Growth Factor alpha, Intercellular Signaling Peptides and Proteins, Cell Line, Tumor, Exosomes, ErbB Receptors, EGF Family of Proteins, Heparin-binding EGF-like Growth Factor, Amphiregulin
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