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 C. George

Research output: Contribution to journalArticle

17 Scopus citations

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
Article number12574
JournalScientific reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017
Externally publishedYes

Fingerprint Dive into the research topics of 'Cancer-associated fibroblasts support vascular growth through mechanical force'. Together they form a unique fingerprint.

  • Cite this

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