EVs can promote the dissemination of cancer cells through body fluids, the formation of pre-/pro-metastatic niche, and the education of myeloid cells. EV-mediated molecular transfer is essential for several events in tumor progression, including epithelial–mesenchymal transition (EMT), tumor–stroma interaction, and metastasis. Recent studies have shown that extracellular vesicles (EVs) released from the cells can transfer bioactive molecules to neighboring cells and deliver them to distant organs through body fluids such as the bloodstream. Poor prognosis in cancer patients is associated with rapid tumor progression, a permissive tumor–stroma interactive microenvironment, and the dissemination of tumor cells to blood circulation and distant organs where metastatic secondary tumors are formed. These data newly demonstrate that oncogenic EVs-derived MMP is a transmissive trans-activator for the cellular communication network gene and promotes tumorigenesis at distant sites.Ĭancer is one of the most common causes of death, with its lethality involving metastasis and therapy resistance. A high expression level of MMP3 or CCN2/CTGF mRNA was prognostic and unfavorable in particular types of cancers including head and neck, lung, pancreatic, cervical, stomach, and urothelial cancers. The CRISPR/Cas9-mediated knockout of MMP3 showed significant anti-tumor effects such as the inhibition of migration and invasion of tumor cells, and a reduction in CCN2/CTGF promoter activity and fragmentations in vitro. TRENDIC and other cis-elements in the CCN2/CTGF promoter were essential for the oncosomal responsivity. Oncosome-derived MMP3 was transferred into recipient cell nuclei and thereby trans-activated the CCN2/CTGF promoter, and induced CCN2/CTGF production in vitro. MMP3-rich, LuM1-derived EVs were disseminated to multiple organs through body fluid and were pro-tumorigenic in an allograft mouse model, which prompted us to define LuM1-EVs as oncosomes in the present study. EVs derived from a rapidly metastatic cancer cell line (LuM1) were enriched in MMP3 and a C-terminal half fragment of CCN2/CTGF. We here investigated the roles of MMP3-rich EVs in tumor progression, molecular transmission, and gene regulation. Moreover, several members of the MMP family have been found within tumor-derived extracellular vesicles (EVs). Indeed, connective tissue growth factor (CTGF, aka cellular communication network factor 2 (CCN2)) is transcriptionally induced as well as cleaved by MMP3. Matrix metalloproteinase 3 (MMP3) plays multiple roles in extracellular proteolysis as well as intracellular transcription, prompting a new definition of moonlighting metalloproteinase (MMP), according to a definition of protein moonlighting (or gene sharing), a phenomenon by which a protein can perform more than one function.
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