Exosomal microRNAs derived from colorectal cancer-associated fibroblasts:: role in driving cancer progression
Exosomal microRNAs derived from colorectal cancer-associated fibroblasts:: role in driving cancer progression
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.
Journal Article
2666-2694
Bhome, Rahul
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Goh, Rebecca W.
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Bullock, Marc D.
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Pillar, Nir
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Thirdborough, Stephen M.
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Mellone, Massimiliano
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Mirnezami, Reza
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Galea, Dieter
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Veselkov, Kirill
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Gu, Quan
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Underwood, Timothy J.
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Primrose, John N.
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De Wever, Olivier
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Shomron, Noam
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Sayan, A. Emre
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Mirnezami, Alex H.
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24 December 2017
Bhome, Rahul
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Goh, Rebecca W.
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Bullock, Marc D.
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Pillar, Nir
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Thirdborough, Stephen M.
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Mellone, Massimiliano
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Mirnezami, Reza
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Galea, Dieter
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Veselkov, Kirill
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Gu, Quan
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Underwood, Timothy J.
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Primrose, John N.
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De Wever, Olivier
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Shomron, Noam
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Sayan, A. Emre
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Mirnezami, Alex H.
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Bhome, Rahul, Goh, Rebecca W., Bullock, Marc D., Pillar, Nir, Thirdborough, Stephen M., Mellone, Massimiliano, Mirnezami, Reza, Galea, Dieter, Veselkov, Kirill, Gu, Quan, Underwood, Timothy J., Primrose, John N., De Wever, Olivier, Shomron, Noam, Sayan, A. Emre and Mirnezami, Alex H.
(2017)
Exosomal microRNAs derived from colorectal cancer-associated fibroblasts:: role in driving cancer progression.
Aging, 9 (12), .
(doi:10.18632/aging.101355).
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.
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Accepted/In Press date: 17 December 2017
e-pub ahead of print date: 24 December 2017
Published date: 24 December 2017
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Journal Article
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Local EPrints ID: 416793
URI: http://eprints.soton.ac.uk/id/eprint/416793
ISSN: 1945-4589
PURE UUID: 7c8ee1f1-5090-4b87-8d55-fc43705fa97a
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Date deposited: 10 Jan 2018 17:30
Last modified: 16 Mar 2024 04:14
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Author:
Rebecca W. Goh
Author:
Marc D. Bullock
Author:
Nir Pillar
Author:
Massimiliano Mellone
Author:
Reza Mirnezami
Author:
Dieter Galea
Author:
Kirill Veselkov
Author:
Quan Gu
Author:
Olivier De Wever
Author:
Noam Shomron
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