Cancer-associated fibroblasts support vascular growth through mechanical force

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.

Patient-derived small intestinal myofibroblasts direct perfused, physiologically responsive capillary development in a microfluidic Gut-on-a-Chip Model

“…1A). This suggested patient-derived ISEMFs are indeed capable of supporting vasculogenesis, similar to fibroblast cell types that have been explored in similar systems 7,10,11 .…”

“…The referenced Moya et al study involved co-culture of commercially available normal human lung fibroblasts and ECs embedded in fibrin gels adjacent to microfluidic media lines 7 . To date, other stromal populations such as mesenchymal stem cells and cancer-associated fibroblasts have been used in this system to support perfused capillary network formation via secreted and/or mechanical stimuli on ECs 7,10,11 .…”

A Gelatin Hydrogel to Study Endometrial Angiogenesis and Trophoblast Invasion

“…Other labs have demonstrated that although a stromal component featuring stromal cells or other support cells (pericytes, astrocytes, etc.) is necessary for the establishment of stable endothelial networks, specific stromal features, including their tissue source, expression of soluble factors, and mechanical activity, can inhibit or promote vascularization [67][68][69]. While increasing local presentation of VEGF within the GelMA hydrogel could increase the extent of the endothelial cell network formation, there is also potential to utilize endometrial-specific endothelial cells to create a tissue-specific model of endometrial angiogenesis and alter stromal cell decidualization status to determine the effects of stromal differentiation on endothelial network complexity.…”

The Role of Cancer-Associated Fibroblasts and Extracellular Vesicles in Tumorigenesis

“…Moreover, the up-regulation of PDGF-C was demonstrated as an alternative mechanism by which tumors presenting resistance to anti-VEGF-A therapy might promote angiogenesis [50]. In addition to soluble signaling factors, CAFs are also able to regulate vascular growth and may contribute to tumor neovascularization by their biomechanical behaviors, which differ from normal fibroblasts [51].…”