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 cellsPre-polymer solution

Cancer cell laden scaffolds

UV curing

Addition of

HUVECs on

the top of cell

laden scaffolds

Capillary sprouts

+

Results

11 kPa 78 kPa 36 kPa

0

200

400

600

800

1000

1200

0 10 20 30

Cu

mm

ula

tive r

ele

ase

o

f F

ITC

-de

xtr

an

(n

g)

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

Sw

ell

ing

Ra

tio

Compression Modulus (kPa)

0102030405060708090

5% 10% 15%

Co

mp

ress

ion

m

od

ulu

s(K

Pa)

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 KPa 11 KPa

78 KPa

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

* *

*

*

*

*

*

*

11 KPa 36 KPa

78 KPa

36 KPa 11 KPa

78 KPa

HR media

HCR media

With

cancer

cells

Without

cancer

cells

0

1

2

3

4

5

0 0.5 1 2

Sp

rou

ts p

er

no

des

(w

ith

can

cer

cell

s)

Drug concentration ( µM)

11 kPa

36 kPa

78 kPa

00.5

11.5

22.5

33.5

4

0 0.5 1 2

Sp

rou

ts p

er

no

de

s

(wit

ho

ut

can

cer

cell

s)

Drug concentrtion (µM)

11 kPa

36 kPa

78 kPa