Research Papers:
3D hydrogel breast cancer models for studying the effects of hypoxia on epithelial to mesenchymal transition
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Abstract
Ying Wang1,2, Sameer Mirza3, Shaohua Wu1,6, Jiping Zeng2, Wen Shi1,6, Hamid Band3,4,5, Vimla Band3,5 and Bin Duan1,6,7,8
1Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE, USA
2Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan, China
3Department of Genetics, Cell Biology and Anatomy University of Nebraska Medical Center, Omaha, NE, USA
4Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
5Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
6Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
7Department of Surgery, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
8Department of Mechanical and Materials Engineering, University of Nebraska-Lincoln, Lincoln, NE, USA
Correspondence to:
Bin Duan, email: [email protected]
Vimla Band, email: [email protected]
Keywords: lysyl oxidase; epithelial-mesenchymal transition; hydrogel; hypoxia
Received: March 07, 2018 Accepted: July 21, 2018 Published: August 14, 2018
ABSTRACT
Solid tumors are 3D assemblies of cancer cells, together with multiple stromal cell types within an extracellular matrix. Yet, the vast majority of cell-based studies to characterize oncogenesis and discovery of new anti-cancer drugs is conducted using conventional 2D monolayer culture systems, where cells are grown on plastic substratum under normoxic environments. In current study, we generated 3D breast cancer cell culture platform consists of photocrosslinkable hydrogels and encapsulated isogenic primary (21PT) and a metastatic (21MT-2) breast cancer cell lines derived from the primary tumor and pleural effusion from the same patient. We demonstrated that hypoxia decreased cellular assembly size and density, and promoted epithelial to mesenchymal transition (EMT) process, without affecting cell viability. Next, we showed hypoxia enhanced breast cancer cell migration, and expression and secretion of lysyl oxidase (LOX), which is copper-dependent amine oxidase and has the primary function to drive the crosslinking of collagen and elastin and is regulated by hypoxia. Furthermore, to recapitulate in vivo situation, we generated breast cancer and lung cells (derived from the same patient) contact model by stacking 3D hydrogel constructs with breast cancer cells onto lung mesenchymal cells (LMC) laden-hydrogel and then showed breast cancer cells migrated towards LMC during hypoxia. Lastly, as a validation of this model for future screen of therapeutic agents, we demonstrated that LOX inhibitor exhibited a significant decrease in breast cancer cell viability, migration, and EMT. Taken together, these results validate the use of hydrogels based models to examine hypoxia related EMT in breast cancer cells.
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