Biomaterial considerations for ovarian cancer models

Ovarian cancer is the 5th most common and the deadliest gynecological cancer, with a 5-year survival rate of less than 50 percent. Most deaths due to ovarian cancer are caused by recurrent disease, which typically corresponds to an increase in chemoresistance of the tumor cells. However, little is known about how ovarian tumor chemoresponse changes and if such changes are regulated by the tumor microenvironment (TME). Moreover, the ovarian TME, including the tissue compositions and biomechanical features, is not well-characterized primarily due to a lack of optimal models. To more effectively characterize the TME of ovarian cancer, which may help develop innovative treatment strategies, appropriate models are desperately needed. The most utilized models include mouse models with both patient-derived xenografts and mouse or human tumor cell line derivatives, and more recently microphysiological systems (MPS). While mouse models provide high levels of physiological complexity, there is virtually no control over the TME components after tumor initiation or implantation. On the other hand, MPS or organoid models permit high levels of control of initial composition but lack many features of in vivo models. Selection of appropriate components to create a TME model is paramount for generating a physiologically relevant in vitro and ex vivo systems. The importance of biomaterial or matrix selection in ovarian TME models lies in the role of these components to activate oncogenic signaling pathways either through receptor-ligand interactions or mechanotransduction. Recent studies suggest that off-target or post-target effects of chemotherapies may interfere with mechanotransductive pathways. In ovarian cancer, changes in fibrous proteins, adhesive glycoproteins, and glycosaminoglycans can remodel the mechanical environment, further altering mechanotransductive pathways. Therefore, the next-generation of ovarian tumor models should incorporate relevant biomaterials including hyaluronic acid (HA), collagens, fibrinogen, and fibronectin to investigate the link between matrix properties and mechanobiology with metastasis and chemoresistance

Cancer-associated fibroblasts support vascular growth through mechanical force.

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

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