TY - JOUR
T1 - Cancer-associated fibroblasts support vascular growth through mechanical force
AU - Sewell-Loftin, Mary Kathryn
AU - Bayer, Samantha Van Hove
AU - Crist, Elizabeth
AU - Hughes, Taylor
AU - Joison, Sofia M.
AU - Longmore, Gregory D.
AU - George, Steven C.
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health (F32 CA203284 (M.K.S.L.), F30 CA200386 (S.V.H.B.), R01 CA196205 (G.D.L.), U54 CA210173 (G.D.L.), UH3 TR000481 (S.C.G.), R01 CA170879 (S.C.G.), and UC4 DK104202 (S.C.G.)). We would also like to thank Drew Glaser and Priscilla Hwang for assistance with experimental setups.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85030556573&partnerID=8YFLogxK
U2 - 10.1038/s41598-017-13006-x
DO - 10.1038/s41598-017-13006-x
M3 - Article
C2 - 28974764
AN - SCOPUS:85030556573
SN - 2045-2322
VL - 7
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 12574
ER -