TY - JOUR
T1 - Expansion of Ovarian Cancer Stem-like Cells in Poly(ethylene glycol)-Cross-Linked Poly(methyl vinyl ether-alt-maleic acid) and Alginate Double-Network Hydrogels
AU - Zhou, Naizhen
AU - Ma, Xiaoe
AU - Bernaerts, Katrien
AU - Ren, Pengfei
AU - Hu, Wanjun
AU - Zhang, Tianzhu
N1 - Funding Information:
The work is supported by the Special Project on Development of National Key Scientific Instruments and Equipment of China (2011YQ03013403), National Natural Science Youth Foundation of China (81600407), Open Project from Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application (Soochow University), and the Fundamental Research Funds for the Central Universities.
Publisher Copyright:
Copyright © 2020 American Chemical Society.
PY - 2020/6
Y1 - 2020/6
N2 - A better understanding of cancer stem cells (CSCs) is essential for research on cancer therapy and drug resistance. Currently, increasingly more investigations are focused on obtaining CSCs to study the mechanism of their enhanced malignancy. In this work, three kinds of double-network hydrogels (PEMM/alginate), consisting of poly(ethylene glycol) (PEG) covalently crosslinked poly(methyl vinyl ether-alt-maleic acid) (P(MVE-alt-MA)) (network 1, denoted as PEMM) and Sr2+ (or Ca2+, Fe3+) ionically cross-linked alginates (network 2, denoted as SrAlg, CaAlg, or FeAlg), were prepared. The stiffness, morphology, and components of the PEMM/alginate hydrogels were systematically investigated to understand their effects on CSC enrichment. Only the PEMM/FeAlg hydrogels could support the long-term growth, proliferation, and spheroid formation of SK-OV-3 cells. The expression of CSC-related markers was evaluated with the levels of protein and gene at different stages. The cell spheroids cultured in the PEMM/FeAlg hydrogels acquired certain CSC-like properties, thus drug resistance was enhanced, especially in the PEMM-1/FeAlg hydrogel. In vivo tumorigenicity experiments also confirmed the presence of more CSCs in the PEMM-1/FeAlg hydrogel. The results suggest that matrix stiffness, morphology, and cations act synergistically on the regulation of the epithelial-mesenchymal transition (EMT), interleukin-6 (IL-6), and Wnt pathways, affecting the invasiveness of ovarian cancer and the conversion of the non-CSCs into CSCs. The PEMM-1/FeAlg hydrogel with lower elastic modulus, a more macroporous morphology, and higher swelling rate can significantly enhance the stemness, malignancy, and tumorigenicity of SK-OV-3 cells.
AB - A better understanding of cancer stem cells (CSCs) is essential for research on cancer therapy and drug resistance. Currently, increasingly more investigations are focused on obtaining CSCs to study the mechanism of their enhanced malignancy. In this work, three kinds of double-network hydrogels (PEMM/alginate), consisting of poly(ethylene glycol) (PEG) covalently crosslinked poly(methyl vinyl ether-alt-maleic acid) (P(MVE-alt-MA)) (network 1, denoted as PEMM) and Sr2+ (or Ca2+, Fe3+) ionically cross-linked alginates (network 2, denoted as SrAlg, CaAlg, or FeAlg), were prepared. The stiffness, morphology, and components of the PEMM/alginate hydrogels were systematically investigated to understand their effects on CSC enrichment. Only the PEMM/FeAlg hydrogels could support the long-term growth, proliferation, and spheroid formation of SK-OV-3 cells. The expression of CSC-related markers was evaluated with the levels of protein and gene at different stages. The cell spheroids cultured in the PEMM/FeAlg hydrogels acquired certain CSC-like properties, thus drug resistance was enhanced, especially in the PEMM-1/FeAlg hydrogel. In vivo tumorigenicity experiments also confirmed the presence of more CSCs in the PEMM-1/FeAlg hydrogel. The results suggest that matrix stiffness, morphology, and cations act synergistically on the regulation of the epithelial-mesenchymal transition (EMT), interleukin-6 (IL-6), and Wnt pathways, affecting the invasiveness of ovarian cancer and the conversion of the non-CSCs into CSCs. The PEMM-1/FeAlg hydrogel with lower elastic modulus, a more macroporous morphology, and higher swelling rate can significantly enhance the stemness, malignancy, and tumorigenicity of SK-OV-3 cells.
KW - P(MVE-alt-MA)
KW - alginate
KW - cation
KW - double-network hydrogel
KW - cancer stem-like cell
KW - CARCINOMA-CELLS
KW - TUMORSPHERE FORMATION
KW - EXTRACELLULAR-MATRIX
KW - IRON TRAFFICKING
KW - ENRICHMENT
KW - CULTURE
KW - PROLIFERATION
KW - IDENTIFICATION
KW - THERAPY
KW - GEL
U2 - 10.1021/acsbiomaterials.9b01967
DO - 10.1021/acsbiomaterials.9b01967
M3 - Article
C2 - 33463174
SN - 2373-9878
VL - 6
SP - 3310
EP - 3326
JO - ACS Biomaterial Science and Engineering
JF - ACS Biomaterial Science and Engineering
IS - 6
ER -