Cancer-associated fibroblasts support vascular growth through mechanical force

Mary Kathryn Sewell-Loftin, Samantha Van Hove Bayer, Elizabeth Crist, Taylor Hughes, Sofia M. Joison, Gregory D. Longmore, Steven George

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The role of cancer-associated fibroblasts (CAFs) as regulators of tumor progression, specifically vascular growth, has only recently been described. CAFs are thought to be more mechanically active but how this trait may alter the tumor microenvironment is poorly understood. We hypothesized that enhanced mechanical activity of CAFs, as regulated by the Rho/ROCK pathway, contributes to increased blood vessel growth. Using a 3D in vitro tissue model of vasculogenesis, we observed increased vascularization in the presence of breast cancer CAFs compared to normal breast fibroblasts. Further studies indicated this phenomenon was not simply a result of enhanced soluble signaling factors, including vascular endothelial growth factor (VEGF), and that CAFs generated significantly larger deformations in 3D gels compared to normal fibroblasts. Inhibition of the mechanotransductive pathways abrogated the ability of CAFs to deform the matrix and suppressed vascularization. Finally, utilizing magnetic microbeads to mechanically stimulate mechanically-inhibited CAFs showed partial rescue of vascularization. Our studies demonstrate enhanced mechanical activity of CAFs may play a crucial and previously unappreciated role in the formation of tumor-associated vasculature which could possibly offer potential novel targets in future anti-cancer therapies.

Original languageEnglish (US)
Article number12574
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

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Blood Vessels
Growth
Fibroblasts
Neoplasms
Tumor Microenvironment
Cancer-Associated Fibroblasts
Microspheres
Vascular Endothelial Growth Factor A
Breast
Gels
Breast Neoplasms

ASJC Scopus subject areas

  • General

Cite this

Sewell-Loftin, M. K., Bayer, S. V. H., Crist, E., Hughes, T., Joison, S. M., Longmore, G. D., & George, S. (2017). Cancer-associated fibroblasts support vascular growth through mechanical force. Scientific Reports, 7(1), [12574]. https://doi.org/10.1038/s41598-017-13006-x

Cancer-associated fibroblasts support vascular growth through mechanical force. / Sewell-Loftin, Mary Kathryn; Bayer, Samantha Van Hove; Crist, Elizabeth; Hughes, Taylor; Joison, Sofia M.; Longmore, Gregory D.; George, Steven.

In: Scientific Reports, Vol. 7, No. 1, 12574, 01.12.2017.

Research output: Contribution to journalArticle

Sewell-Loftin, MK, Bayer, SVH, Crist, E, Hughes, T, Joison, SM, Longmore, GD & George, S 2017, 'Cancer-associated fibroblasts support vascular growth through mechanical force', Scientific Reports, vol. 7, no. 1, 12574. https://doi.org/10.1038/s41598-017-13006-x
Sewell-Loftin MK, Bayer SVH, Crist E, Hughes T, Joison SM, Longmore GD et al. Cancer-associated fibroblasts support vascular growth through mechanical force. Scientific Reports. 2017 Dec 1;7(1). 12574. https://doi.org/10.1038/s41598-017-13006-x
Sewell-Loftin, Mary Kathryn ; Bayer, Samantha Van Hove ; Crist, Elizabeth ; Hughes, Taylor ; Joison, Sofia M. ; Longmore, Gregory D. ; George, Steven. / Cancer-associated fibroblasts support vascular growth through mechanical force. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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