Research Paper Volume 9, Issue 12 pp 2666—2694

Exosomal microRNAs derived from colorectal cancer-associated fibroblasts: role in driving cancer progression

Rahul Bhome 1, 2, , Rebecca W. Goh 1, , Marc D. Bullock 1, 2, , Nir Pillar 3, , Stephen M. Thirdborough 1, , Massimiliano Mellone 1, , Reza Mirnezami 4, , Dieter Galea 4, , Kirill Veselkov 4, , Quan Gu 5, , Timothy J. Underwood 1, 2, , John N. Primrose 2, , Olivier De Wever 6, , Noam Shomron 3, , A. Emre Sayan 1, , Alex H. Mirnezami 1, 2, ,

  • 1 Cancer Sciences, University of Southampton, Somers Building, Southampton General Hospital, Southampton, SO16 6YD, UK
  • 2 University Surgical Unit, University of Southampton, Southampton General Hospital, Southampton, SO16 6YD, UK
  • 3 Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel
  • 4 Department of Surgery and Cancer, Imperial College London, Sir Alexander Fleming Building, London, SW7 2BB, UK
  • 5 University of Glasgow Centre for Virus Research, 117 Sir Michael Stoker Building, Glasgow, G61 1QH, UK
  • 6 Department of Experimental Cancer Research, Ghent University, Radiotherapiepark, Ghent, 9000, Belgium

received: October 30, 2017 ; accepted: December 17, 2017 ; published: December 24, 2017 ;

https://doi.org/10.18632/aging.101355
How to Cite

Copyright: Bhome et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Colorectal cancer is a global disease with increasing incidence. Mortality is largely attributed to metastatic spread and therefore, a mechanistic dissection of the signals which influence tumor progression is needed. Cancer stroma plays a critical role in tumor proliferation, invasion and chemoresistance. Here, we sought to identify and characterize exosomal microRNAs as mediators of stromal-tumor signaling. In vitro, we demonstrated that fibroblast exosomes are transferred to colorectal cancer cells, with a resultant increase in cellular microRNA levels, impacting proliferation and chemoresistance. To probe this further, exosomal microRNAs were profiled from paired patient-derived normal and cancer-associated fibroblasts, from an ongoing prospective biomarker study. An exosomal cancer-associated fibroblast signature consisting of microRNAs 329, 181a, 199b, 382, 215 and 21 was identified. Of these, miR-21 had highest abundance and was enriched in exosomes. Orthotopic xenografts established with miR-21-overexpressing fibroblasts and CRC cells led to increased liver metastases compared to those established with control fibroblasts. Our data provide a novel stromal exosome signature in colorectal cancer, which has potential for biomarker validation. Furthermore, we confirmed the importance of stromal miR-21 in colorectal cancer progression using an orthotopic model, and propose that exosomes are a vehicle for miR-21 transfer between stromal fibroblasts and cancer cells.

Abbreviations

CRC: colorectal cancer; miRNA: microRNA; CAF: cancer-associated fibroblast; NOF: normal fibroblast.