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Aging (Albany NY). 2017 Dec 28;9(12):2666-2694. doi: 10.18632/aging.101355.

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

Author information

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.

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.

KEYWORDS:

cancer-associated fibroblasts; colorectal cancer; exosomes; microRNA; stroma

PMID:
29283887
PMCID:
PMC5764398
DOI:
10.18632/aging.101355
[Indexed for MEDLINE]
Free PMC Article

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