title: Oncogenic KIT-containing exosomes increase gastrointestinal stromal tumor cell invasion.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160.
authors.forename: Safinur
authors.initials: S
authors.lastname: Atay
authors.forename: Samagya
authors.initials: S
authors.lastname: Banskota
authors.forename: Jennifer
authors.initials: J
authors.lastname: Crow
authors.forename: Geetika
authors.initials: G
authors.lastname: Sethi
authors.forename: Lori
authors.initials: L
authors.lastname: Rink
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D055354:Exosomes / Q000378:metabolism / Q000502:physiology*; D005434:Flow Cytometry; D046152:Gastrointestinal Stromal Tumors / Q000503:physiopathology*; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D053758:Nanoparticles / Q000032:analysis; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D034741:RNA, Small Interfering; D019009:Proto-Oncogene Proteins c-kit; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1
keywords: ICC; crosstalk; microvesicles; tumor microenvironment