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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
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
1945-4589
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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Bhome, Rahul
d7b1e0d3-5925-460a-871d-5f52f69c649b
Goh, Rebecca W
68e91653-f551-4e3e-b831-00f4b1718667
Bullock, Marc D.
e060d2b2-5e6f-449b-b8ae-f411b5a396c2
Pillar, Nir
36dc6f89-c765-4cd7-bfb9-c9a127c424fa
Thirdborough, Stephen M.
161784fb-c8e3-4beb-86b1-cd8bc8ddf8de
Mellone, Massimiliano
b0301b32-14f8-4203-9026-b7f90885cab9
Mirnezami, Reza
d0d4ded7-1d72-4ce4-9ce1-eac5ded0232f
Galea, Dieter
552595c2-b248-4bfe-9ede-4a063af1ccef
Veselkov, Kirill
80ba703a-db99-4181-a813-75aecc478294
Gu, Quan
121eeb78-5e52-4469-befe-716503b3562a
Underwood, Timothy J.
8e81bf60-edd2-4b0e-8324-3068c95ea1c6
Primrose, John N.
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De Wever, Olivier
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Shomron, Noam
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Sayan, A. Emre
d1dbbcad-9c53-47c1-8b7e-1b45cc56e077
Mirnezami, Alex H.
b3c7aee7-46a4-404c-bfe3-f72388e0bc94

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), 2666-2694. (doi:10.18632/aging.101355).

Record type: Article

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
Keywords: Journal Article

Identifiers

Local EPrints ID: 416793
URI: https://eprints.soton.ac.uk/id/eprint/416793
ISSN: 1945-4589
PURE UUID: 7c8ee1f1-5090-4b87-8d55-fc43705fa97a
ORCID for Massimiliano Mellone: ORCID iD orcid.org/0000-0002-4964-9340
ORCID for Timothy J. Underwood: ORCID iD orcid.org/0000-0001-9455-2188
ORCID for John N. Primrose: ORCID iD orcid.org/0000-0002-2069-7605

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Date deposited: 10 Jan 2018 17:30
Last modified: 14 Mar 2019 01:52

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Contributors

Author: Rahul Bhome
Author: Rebecca W Goh
Author: Marc D. Bullock
Author: Nir Pillar
Author: Massimiliano Mellone ORCID iD
Author: Reza Mirnezami
Author: Dieter Galea
Author: Kirill Veselkov
Author: Quan Gu
Author: Olivier De Wever
Author: Noam Shomron
Author: A. Emre Sayan

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