title: A cell-instructive hydrogel to regulate malignancy of 3D tumor spheroids with matrix rigidity.
abstract: Three dimensional (3D) tumor spheroid models are becoming important biomedical tools for both fundamental and applied cancer studies, but current models do not account for different levels of cancer malignancy. Several studies have reported that the mechanical rigidity of a hydrogel plays a significant role in regulating the phenotypes of cancer cells adhered to the gel surface. This finding suggests that matrix rigidity should also modulate the malignancy of 3D tumor spheroids. However, the role of matrix stiffness is often confounded by concurrent changes in 3D matrix permeability. This study reports an advanced strategy to assemble 3D liver tumor spheroids with controlled intercellular organization, phenotypes, and angiogenic activities using hydrogels with controlled stiffness and minimal differences in molecular diffusivity. The elastic moduli of cell-encapsulated collagen gels were increased by stiffening interconnected collagen fibers with varied amounts of poly(ethylene glycol) di-(succinic acid N-hydroxysuccinimidyl ester). Interestingly, hepatocellular carcinoma cells encapsulated in a fat-like, softer hydrogel formed malignant cancer spheroids, while cells cultured in a liver-like, stiffer gel formed compact hepatoids with suppressed malignancy. Overall, both the hydrogel and the 3D tumor spheroids developed in this study will be greatly useful to better understand and regulate the emergent behaviors of various cancer cells.
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Youyun
authors.initials: Y
authors.lastname: Liang
authors.forename: Jaehyun
authors.initials: J
authors.lastname: Jeong
authors.forename: Ross J
authors.initials: RJ
authors.lastname: DeVolder
authors.forename: Chaenyung
authors.initials: C
authors.lastname: Cha
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.forename: Yen Wah
authors.initials: YW
authors.lastname: Tong
authors.forename: Hyunjoon
authors.initials: H
authors.lastname: Kong
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000494:pharmacology; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000494:pharmacology*; D009369:Neoplasms / Q000098:blood supply / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000473:pathology; D010539:Permeability / Q000187:drug effects; D010641:Phenotype; D011092:Polyethylene Glycols / Q000494:pharmacology; D018874:Spheroids, Cellular / Q000187:drug effects* / Q000473:pathology*
chemical_list: D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D011092:Polyethylene Glycols; D003094:Collagen