Tumor activation alters the mechano-responsiveness, capillary formation, and drug sensitivity of endothelial cells in synthetic matrices. The study uses synthetic hydrogel cell culture platforms to show that activation of human umbilical endothelial cells (HUVECs) by tumor factors changes the cells' responses to matrix stiffness. Without activation, HUVECs prefer a substrate of appropriate stiffness for optimal capillary formation. However, tumor activation disrupts this mechano-responsive behavior and capillary formation depends less on matrix stiffness. The response of HUVECs to an anti-angiogenic drug was also substrate dependent, with increased drug sensitivity on more compliant gels.

1. Tumor activation alters the mechano-responsiveness, capillary formation, and drug sensitivity of endothelial
cells in synthetic matrices
Yang Wu, Bingxin Guo, and Gargi Ghosh
Bioengineering Program, Department of Mechanical Engineering
University of Michigan - Dearborn
Introduction
Solid cancers induce the formation of new blood vessels to promote
growth and metastasis. 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.
2).Poro size
3). Diffusion
4) . Morphology images in HR and HCR media
5) . Sprout images on with and W/O cancer cells scaffolds
Goals
 Understand how tumor activation affect mechanosensitivity of
endothelial cells
 Understand how matrix stiffness and tumor activation affect
response of endothelial cells to vandetanib inhibition
Materials and Methods
Cancer cells
Pre-polymer solution
Cancer cell laden scaffolds
UV curing
Addition of
HUVECs on
the top of cell
laden scaffolds
Capillary sprouts
+
Results
11 kPa 78 kPa36 kPa
0
200
400
600
800
1000
1200
0 10 20 30
Cummulativerelease
ofFITC-dextran(ng)
Time (hour)
11 kPa
36 kPa
78 kPa
Conclusion/ Future Studies
Acknowledgement
Authors would like to thank University of Michigan, Dearborn and
Office of Vice President of Research, University of Michigan, Ann
Arbor for their financial support
Our study revealed that while in absence of activation, HUVECs
prefer a substrate of appropriate stiffness for optimal capillary
network formation; tumor activation disrupts the mechano-
responsive behavior of HUVECs.
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.
6). Vandetanib inhibition on with and W/O cancer cells
scaffolds
7). IC50 of Vandetanib (µM)
1. Scaffold characterization
1). Compression modulus and swelling ratio
0
5
10
15
20
25
11 36 78
SwellingRatio
Compression Modulus (kPa)
0
10
20
30
40
50
60
70
80
90
5% 10% 15%
Compression
modulus(KPa)
Concentration of PEGDA
Compression
Modulus (kPa)
Without cancer
cells
With cancer cells
11 0.14 0.24
36 0.16 0.36
78 0.21 0.57
11 KPa 36 KPa 78 KPa
36 KPa11 KPa 78 KPa
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
**
*
*
*
*
*
*
11 KPa 36 KPa 78 KPa
36 KPa11 KPa 78 KPa
HR media
HCR media
With
cancer
cells
Without
cancer
cells
0
1
2
3
4
5
0 0.5 1 2
Sproutspernodes
(withcancercells)
Drug concentration ( µM)
11 kPa
36 kPa
78 kPa
0
0.5
1
1.5
2
2.5
3
3.5
4
0 0.5 1 2
Sproutspernodes
(withoutcancercells)
Drug concentrtion (µM)
11 kPa
36 kPa
78 kPa