The Effect of Matrix Stiffness on Breast Cancer Response to Chemotherapeutic Drugs

Khuu, Nancy (University of Toronto)
Li, Yunfeng (University of Toronto)
Gevorkian, Albert (University of Toronto)
Alizadehgiashi, Moien (University of Toronto)
Kumacheva, Eugenia (University of Toronto)

Introduction

It is currently established that the variation in the mechanical properties of the extracellular matrix (ECM) can contribute to the development and progression of breast cancer. 1-3 Consequently, several studies have examined the effect of varying stiffness on the growth and malignant phenotype progression of cancer cells.4-5 The variation in the mechanical properties of the hydrogels was achieved by either changing the polymer chain length, or concentration. However, changing the polymer chain length or concentration may affect other ECM properties, such as pore size and integrin ligand density, which may undermine the validity of conclusions drawn from these systems. In addition, the question of how the stiffness independently affects breast cancer response to chemotherapeutic drugs remains to be answered.

To this end, we have developed a collagen-alginate hydrogel, with the capability of tuning hydrogel stiffness independent of ligand density, fibrillar structure and pore size. We utilized this hydrogel to study the effect of stiffness on cancer cell growth and explore how stiffness affects breast cancer tumors’ response to drugs.

Materials and Methods

In order to achieve the decoupling of mechanical properties from other ECM properties, we have developed a nanofibrillar interpenetrating network (IPN) hydrogel consisting of collagen and alginate. Collagen was used to provide intrinsic cell binding sites and to help recapitulate the in vivo communication between the cells and the ECM. Alginate was used to control the mechanical properties of the composite hydrogel by varying the concentration of Ca2+. MCF-7 breast cancer cells were encapsulated in this collagen-alginate hydrogel, in order for the exclusive effects of varying stiffness on cancer cell growth and response to drugs to be studied.

Results

Through mechanical, permeation and structural characterization of the hydrogel, it was demonstrated that the mechanical properties of the hydrogel could be tuned from the range of stiffness of healthy mammary tissue to that of the malignant mammary tissue without changing the pore size or the fibrillar structure of the hydrogel. Growth of MCF-7 cells into multicellular spheroids within the hydrogel revealed that the size and number of spheroids decreased with increasing hydrogel stiffness increased. Treatment of these spheroids with doxorubicin revealed preliminary differences in the metabolic activity of breast cancer spheroids grown in hydrogels of different stiffness.

Discussion and Conclusion

We have developed a collagen-alginate IPN hydrogel with the mechanical properties tuned independently of ligand density, fibrillar structure and pore size to investigate the effect of hydrogel stiffness on breast cancer growth and the response of multicellular cancer spheroids to chemotherapy drugs.

Growth of multicellular cancer spheroids in this hydrogel and treatment with doxorubicin revealed differences in the size, number and metabolic activity of the spheroids with the varying stiffness of the hydrogel matrix. To explain these differences, current work is focused on understanding the mechanism by which matrix stiffness affects breast cancer cell growth and response to doxorubicin.

Acknowledgements

The authors would like to acknowledge and thank NSERC CREATE Organ-on-a-Chip for financial support on this work. 

References

1. Bissell, M. J.; Hines, W. C. Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nature Med.  2011, 17, 320–329.

2.Paszek MJ, et al. Tensional homeostasis and the malignant phenotype. Cancer
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3. Levental KR, et al. Matrix crosslinking forces tumor progression by enhancing 
integrin signaling. Cell. 2009, 139, 891–906.

4. . Liu et al. Soft fibrin gels promote selection and growth of tumorigenic cells. Nat. Mater. 2012, 11, 734–741.

5. Y. Liang et al. A cell-instructive hydrogel to regulate malignancy of 3D tumor spheroids with matrix rigidity. Biomaterials. 2011, 32, 9308–9315.

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