A subset of myofibroblastic cancer-associated fibroblasts regulate collagen fiber elongation, which is prognostic in multiple cancers

Collagen structure has been shown to influence tumor cell invasion, metastasis and clinical outcome in breast cancer. However, it remains unclear how it affects other solid cancers. Here we utilized multi-photon laser scanning microscopy and Second Harmonic Generation to identify alterations to coll...

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Main Authors:	Hanley, Christopher J., Noble, Fergus, Ward, Matthew, Bullock, Marc, Drifka, Cole, Mellone, Massimiliano, Manousopoulou, Antigoni, Johnston, Harvey E., Hayden, Annette, Thirdborough, Steve, Liu, Yuming, Smith, David M., Mellows, Toby, Kao, W. John, Garbis, Spiros D., Mirnezami, Alex, Underwood, Tim J., Eliceiri, Kevin W., Thomas, Gareth J.
Format:	Online
Language:	English
Published:	Impact Journals LLC 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868747/

id	pubmed-4868747
recordtype	oai_dc
spelling	pubmed-48687472016-05-20 A subset of myofibroblastic cancer-associated fibroblasts regulate collagen fiber elongation, which is prognostic in multiple cancers Hanley, Christopher J. Noble, Fergus Ward, Matthew Bullock, Marc Drifka, Cole Mellone, Massimiliano Manousopoulou, Antigoni Johnston, Harvey E. Hayden, Annette Thirdborough, Steve Liu, Yuming Smith, David M. Mellows, Toby Kao, W. John Garbis, Spiros D. Mirnezami, Alex Underwood, Tim J. Eliceiri, Kevin W. Thomas, Gareth J. Research Paper Collagen structure has been shown to influence tumor cell invasion, metastasis and clinical outcome in breast cancer. However, it remains unclear how it affects other solid cancers. Here we utilized multi-photon laser scanning microscopy and Second Harmonic Generation to identify alterations to collagen fiber structure within the tumor stroma of head & neck, esophageal and colorectal cancers. Image segmentation algorithms were then applied to quantitatively characterize these morphological changes, showing that elongated collagen fibers significantly correlated with poor clinical outcome (Log Rank p < 0.05). We used TGF-β treatment to model fibroblast conversion to smooth muscle actin SMA-positive cancer associated fibroblasts (CAFs) and found that these cells induce the formation of elongated collagen fibers in vivo. However, proteomic/transcriptomic analysis of SMA-positive CAFs cultured ex-vivo showed significant heterogeneity in the expression of genes with collagen fibril organizing gene ontology. Notably, stratifying patients according to stromal SMA-positivity and collagen fiber elongation was found to provide a highly significant correlation with poor survival in all 3 cancer types (Log Rank p ≤ 0.003). In summary, we show that increased collagen fiber length correlates with poor patient survival in multiple tumor types and that only a sub-set of SMA-positive CAFs can mediate the formation of this collagen structure. Impact Journals LLC 2015-12-23 /pmc/articles/PMC4868747/ /pubmed/26716418 http://dx.doi.org/10.18632/oncotarget.6740 Text en Copyright: © 2016 Hanley et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Hanley, Christopher J. Noble, Fergus Ward, Matthew Bullock, Marc Drifka, Cole Mellone, Massimiliano Manousopoulou, Antigoni Johnston, Harvey E. Hayden, Annette Thirdborough, Steve Liu, Yuming Smith, David M. Mellows, Toby Kao, W. John Garbis, Spiros D. Mirnezami, Alex Underwood, Tim J. Eliceiri, Kevin W. Thomas, Gareth J.
spellingShingle	Hanley, Christopher J. Noble, Fergus Ward, Matthew Bullock, Marc Drifka, Cole Mellone, Massimiliano Manousopoulou, Antigoni Johnston, Harvey E. Hayden, Annette Thirdborough, Steve Liu, Yuming Smith, David M. Mellows, Toby Kao, W. John Garbis, Spiros D. Mirnezami, Alex Underwood, Tim J. Eliceiri, Kevin W. Thomas, Gareth J. A subset of myofibroblastic cancer-associated fibroblasts regulate collagen fiber elongation, which is prognostic in multiple cancers
author_facet	Hanley, Christopher J. Noble, Fergus Ward, Matthew Bullock, Marc Drifka, Cole Mellone, Massimiliano Manousopoulou, Antigoni Johnston, Harvey E. Hayden, Annette Thirdborough, Steve Liu, Yuming Smith, David M. Mellows, Toby Kao, W. John Garbis, Spiros D. Mirnezami, Alex Underwood, Tim J. Eliceiri, Kevin W. Thomas, Gareth J.
author_sort	Hanley, Christopher J.
title	A subset of myofibroblastic cancer-associated fibroblasts regulate collagen fiber elongation, which is prognostic in multiple cancers
title_short	A subset of myofibroblastic cancer-associated fibroblasts regulate collagen fiber elongation, which is prognostic in multiple cancers
title_full	A subset of myofibroblastic cancer-associated fibroblasts regulate collagen fiber elongation, which is prognostic in multiple cancers
title_fullStr	A subset of myofibroblastic cancer-associated fibroblasts regulate collagen fiber elongation, which is prognostic in multiple cancers
title_full_unstemmed	A subset of myofibroblastic cancer-associated fibroblasts regulate collagen fiber elongation, which is prognostic in multiple cancers
title_sort	subset of myofibroblastic cancer-associated fibroblasts regulate collagen fiber elongation, which is prognostic in multiple cancers
description	Collagen structure has been shown to influence tumor cell invasion, metastasis and clinical outcome in breast cancer. However, it remains unclear how it affects other solid cancers. Here we utilized multi-photon laser scanning microscopy and Second Harmonic Generation to identify alterations to collagen fiber structure within the tumor stroma of head & neck, esophageal and colorectal cancers. Image segmentation algorithms were then applied to quantitatively characterize these morphological changes, showing that elongated collagen fibers significantly correlated with poor clinical outcome (Log Rank p < 0.05). We used TGF-β treatment to model fibroblast conversion to smooth muscle actin SMA-positive cancer associated fibroblasts (CAFs) and found that these cells induce the formation of elongated collagen fibers in vivo. However, proteomic/transcriptomic analysis of SMA-positive CAFs cultured ex-vivo showed significant heterogeneity in the expression of genes with collagen fibril organizing gene ontology. Notably, stratifying patients according to stromal SMA-positivity and collagen fiber elongation was found to provide a highly significant correlation with poor survival in all 3 cancer types (Log Rank p ≤ 0.003). In summary, we show that increased collagen fiber length correlates with poor patient survival in multiple tumor types and that only a sub-set of SMA-positive CAFs can mediate the formation of this collagen structure.
publisher	Impact Journals LLC
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868747/
_version_	1613579900811214848

A subset of myofibroblastic cancer-associated fibroblasts regulate collagen fiber elongation, which is prognostic in multiple cancers

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