Amphiregulin exosomes increase cancer cell invasion.

Higginbotham JN, Demory Beckler M, Gephart JD, Franklin JL, Bogatcheva G, Kremers GJ, Piston DW, Ayers GD, McConnell RE, Tyska MJ, Coffey RJ
Curr Biol. 2011 21 (9): 779-86

PMID: 21514161 · PMCID: PMC3417320 · DOI:10.1016/j.cub.2011.03.043

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.

Copyright © 2011 Elsevier Ltd. All rights reserved.

MeSH Terms (19)

Amphiregulin Animals Cell Line, Tumor Centrifugation Dogs EGF Family of Proteins Electrophoresis, Polyacrylamide Gel Enzyme-Linked Immunosorbent Assay ErbB Receptors Exosomes Glycoproteins Heparin-binding EGF-like Growth Factor Humans Immunoblotting Intercellular Signaling Peptides and Proteins Microscopy, Electron Neoplasm Invasiveness Signal Transduction Transforming Growth Factor alpha

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