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 tumorderived 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.ICC | crosstalk | microvesicles | tumor microenvironment

The αvβ6 Integrin Is Transferred Intercellularly via Exosomes

“…Conversely, ␤ 1 integrin subunit levels do not show any detectable change upon exosome uptake in the recipient cells; the reasons why this occurs remain to be investigated. Third, this is the only study showing surface re-expression of a transmembrane receptor of the integrin family; two previous studies have shown that two different transmembrane receptors, MET and KIT, are transferred and re-expressed on the surface of recipient cells (9,38). Finally, our study is the first to show that the ␣ v ␤ 6 integrin that is transferred between different subsets of PrCa cells is functional and promotes cell adhesion and migration on LAP-TGF␤ in an ␣ v ␤ 6 integrin-dependent manner.…”

The exosomes in tumor immunity

“…These exosomes contain large amount of tumorpromoting RNAs (mRNAs, miRNAs and other non-coding RNAs) and proteins (EGFR, HSPs, KIT, etc.). [14][15][16] Exosomemediated exchange of mRNAs and miRNAs (named as exosomal shuttle RNA, esRNA) is believed to be a novel way for genetic intervention between cells. 17 Plenty of miRNAs had been detected in exosomes.…”

Emerging roles of exosomes during epithelial–mesenchymal transition and cancer progression

“…Recent evidence highlights the role of EVs, in particular exosomes, to stimulate invasion and migration in various cancer models [151]. For example, breast MCF-7-derived exosomes were shown to foster tumour growth, migration, and matrix degradation, via secretory Rab27b [152].…”