irculating Exosomal miR-141-p and miR-375 in Metastatic rogression of Rectal Cancer

As many as 30% to 40% of locally advanced rectal cancer (LARC) patients experience metastatic progression of the disease. Recognizing the potential of the genetic cargo in tumor-derived exosomes, we hypothesized that plasma exosomal microRNA (miRNA) may reflect biological aggressiveness in LARC and provide new markers for rectal cancer aggressiveness and risk stratification. In a prospective LARC cohort (NCT01816607), plasma samples were collected from 29 patients at the time of diagnosis, before neoadjuvant therapy and surgery. Exosomes, precipitated from plasma using a commercial kit, were verified by cryo-electron microscopy, nanoparticle tracking analysis, and western blotting. Expression of exosomal miRNAs was profiled using a miRCURY LNA miRNA microarray and validation of six miRNAs associated with pathological and clinical end-points was undertaken in plasma collected at the time of diagnosis from 64 patients in an independent prospective LARC cohort (NCT00278694). In both cohorts, exosomal miR-141-3p and miR-375 were higher in patients with synchronous liver metastasis than in those without (P = .010 and P = .017 respectively in the investigative cohort, and P b .001 for both in the validation cohort). Further, high exosomal miR-141-3p was associated with post-operative metastatic liver progression in the investigative cohort (P = .034). Because both miRNAs are associated with tumor angiogenesis and immune modulation, we propose that these miRNAs in circulating exosomes may reflect rectal cancer aggressiveness and accordingly be candidate biomarkers for further investigations. Translational Oncology (2019) 12, 1038–1044 dress all correspondence to: Sebastian Meltzer, Department of Oncology, Akershus iversity Hospital, 1478 Lørenskog, Norway. E-mail: sebastian.meltzer@medisin.uio.no ceived 22 February 2019; Accepted 17 April 2019 2019 The Authors. Published by Elsevier Inc. on behalf of Neoplasia Press, Inc. This is an n access article under the CCBY-NC-ND license (http://creativecommons.org/licenses/bynd/4.0/). 36-5233/19 ps://doi.org/10.1016/j.tranon.2019.04.014 troduction considerable number of rectal cancer patients experience poor sease outcome due to metastatic progression [1], with the liver pically being the first distant organ affected, followed by the lungs ]. Since total mesorectal excision became the standard surgical ocedure in the mid-nineties and following the introduction of eoadjuvant therapy for the locally-advanced cases, systemic ssemination has remained the main challenge in rectal cancer A U R