Research Paper Volume 9, Issue 12 pp 2666—2694
Exosomal microRNAs derived from colorectal cancer-associated fibroblasts: role in driving cancer progression
- 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.101355How to Cite
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.