Selective secretion of microRNAs from lung cancer cells via extracellular vesicles promotes CAMK1D-mediated tube formation in endothelial cells

Abstract

// James Lawson 1 , Christopher Dickman 1 , Sara MacLellan 1 , Rebecca Towle 1 , James Jabalee 1 , Stephen Lam 1 and Cathie Garnis 1, 2 1 Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada 2 Division of Otolaryngology, Department of Surgery, University of British Columbia, Vancouver, BC, Canada Correspondence to: Cathie Garnis, email: cgarnis@bccrc.ca Keywords: MiRNA, serum miRNA, lung adenocarcinoma, extracellular vesicles Abbreviations: LAC: lung adenocarcinoma; EVs: extracellular vesicles; NTA: nanoparticle tracking analysis Received: February 07, 2017      Accepted: July 23, 2017      Published: August 07, 2017 ABSTRACT Extracellular vesicles (EVs) are key signaling mediators between cancer cells and their supporting stroma, and regulate critical processes such as invasion, metastases, and angiogenesis. We have identified a subset of miRNAs (miR-142-3p, miR-143-3p, miR-145-5p, miR-150-5p, miR-223-3p, miR-451a, miR-486-5p, miR-605-5p) that are enriched in lung adenocarcinoma extracellular vesicles compared to the donor cells from which they were derived. Two well-known tumor suppressors, miR-143-3p and miR-145-5p, were also enriched in serum samples collected during surgery from blood vessels draining directly from lung adenocarcinoma tumor beds. Recently, both miRNAs were found to promote neoangiogenesis in endothelial cells in mouse models of lung adenocarcinoma through targeting of CAMK1D, an inhibitory kinase that can impair angiogenesis when over-expressed. We show that the transfer of miR-143-3p and miR-145-5p within extracellular vesicles from lung adenocarcinoma cells to endothelial cells reduces the levels of CAMK1D and increases tube formation by endothelial cells. This finding suggests that transfer of miRNAs within extracellular vesicles is a method of communication between cancer and endothelial cells which promotes angiogenesis while simultaneously removing tumor suppressive miRNAs within the tumor cells, thus driving tumorigenesis.