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Atay S , Banskota S , Crow J , Sethi G , Rink L , Godwin AK
Oncogenic KIT-containing exosomes increase gastrointestinal stromal tumor cell invasion
Proc Natl Acad Sci U S A. 2014 Jan 14;111(2) :711-6
PMID: 24379393    PMCID: PMC3896203    URL: https://www.ncbi.nlm.nih.gov/pubmed/24379393
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During tumor development, constant interplay occurs between tumor cells and surrounding stromal cells. We report evidence that gastrointestinal stromal tumor (GIST) cells invade the interstitial stroma through the release of the oncogenic protein tyrosine kinase (KIT)-containing exosomes, which triggers the phenotypic conversion of progenitor smooth muscle cells to tumor-promoting cells. These recipient cells display morphologic changes and acquire tumor-associated phenotypes, including enhanced adhesion to extracellular matrix proteins, activation of intracellular pathways downstream of KIT, expression of Interstitial Cell of Cajal-like markers, and release of various matrix metalloproteinases (MMPs), particularly MMP1. This report shows stimulation of MMP1 production by stromal cells via uptake of tumor-derived exosomes, which leads to tumor cell invasion. Exosomes derived from GIST patients but not healthy donors show enhanced MMP1 secretion by smooth muscle cells and tumor cell invasion, whereas selective blocking of exosome-mediated MMP1 secretion decreases tumor invasiveness. Our study indicates that exosome release and subsequent MMP1 induction creates a positive feedback mechanism established between tumor and stromal cells that drives GIST development and offers unique insights for potential therapeutic strategies to block GIST progression and metastatic spread.
Atay, Safinur Banskota, Samagya Crow, Jennifer Sethi, Geetika Rink, Lori Godwin, Andrew K eng P30 CA168524/CA/NCI NIH HHS/ R01 CA106588/CA/NCI NIH HHS/ UL1 TR000001/TR/NCATS NIH HHS/ UL1 TR000001-02S1/TR/NCATS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Proc Natl Acad Sci U S A. 2014 Jan 14;111(2):711-6. doi: 10.1073/pnas.1310501111. Epub 2013 Dec 30.