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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2666-2694
Number of pages29
JournalAging
Volume9
Issue number12
DOIs
StatePublished - 1 Dec 2017

Keywords

  • Cancer-associated fibroblasts
  • Colorectal cancer
  • Exosomes
  • MicroRNA
  • Stroma

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