Differential Effects of Tumor Secreted Factors on Mechanosensitivity, Capillary Branching, and Drug Responsiveness in PEG Hydrogels.

Solid cancers induce the formation of new blood vessels to promote growth and metastasis. Unlike the normal vascular networks, the tumor induced vasculatures exhibit abnormal shape and function. Past efforts have been focused on characterizing the altered growth factor signaling pathway in tumor capillary endothelial cells; however, the mechanical microenvironment of tumor also plays a significant role in regulating the formation of vascular patterns. Here, we used synthetic hydrogel based cell culture platforms to probe how activation of human umbilical endothelial cells (HUVECs) by tumor secreted factors alters the responses to matrix modulus and in turn the capillary network formation and drug sensitivity. Our study revealed that while in absence of activation, HUVECs prefer a substrate of appropriate stiffness for optimal capillary network formation; stimulation by tumor cells disrupts the mechano-responsive behavior of HUVECs. Additionally, the effect of vandetanib on reducing the capillary network was also investigated. The response of HUVECs to the anti-angiogenic agent was substrate modulus dependent displaying increased sensitivity on the compliant gels. Stimulation by tumor cells reduced the responsiveness to vandetanib, particularly when plated on stiffer gels.