Zhou Naizhen, Ma Xiaoe, Bernaerts Katrien V, Ren Pengfei, Hu Wanjun, Zhang Tianzhu
State Key Lab of Bioelectronics, National Demonstration Center for Experimental Biomedical Engineering Education, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China.
Aachen-Maastricht Institute for Biobased Materials (AMIBM), Faculty of Science and Engineering, Maastricht University, Brightlands Chemelot Campus, Urmonderbaan 22, 6167 RD Geleen, The Netherlands.
ACS Biomater Sci Eng. 2020 Jun 8;6(6):3310-3326. doi: 10.1021/acsbiomaterials.9b01967. Epub 2020 Apr 21.
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 cross-linked poly(methyl vinyl ether--maleic acid) (P(MVE--MA)) (network 1, denoted as PEMM) and Sr (or Ca, Fe) 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. 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.
深入了解癌症干细胞（CSCs）对于癌症治疗和耐药性研究至关重要。目前，越来越多的研究致力于获取癌症干细胞以研究其恶性程度增强的机制。在本研究中，制备了三种双网络水凝胶（PEMM/藻酸盐），它们由共价交联的聚（乙二醇）（PEG）和聚（甲基乙烯基醚 - 马来酸）（P(MVE - MA)）（网络1，记为PEMM）以及Sr（或Ca、Fe）离子交联的藻酸盐（网络2，记为SrAlg、CaAlg或FeAlg）组成。系统研究了PEMM/藻酸盐水凝胶的硬度、形态和成分，以了解它们对癌症干细胞富集的影响。只有PEMM/FeAlg水凝胶能够支持SK - OV - 3细胞的长期生长、增殖和球状体形成。在不同阶段通过蛋白质和基因水平评估了癌症干细胞相关标志物的表达。在PEMM/FeAlg水凝胶中培养的细胞球状体获得了某些类似癌症干细胞的特性，从而增强了耐药性，尤其是在PEMM - 1/FeAlg水凝胶中。致瘤性实验也证实了PEMM - 1/FeAlg水凝胶中存在更多的癌症干细胞。结果表明，基质硬度、形态和阳离子协同作用于上皮 - 间质转化（EMT）、白细胞介素 - 6（IL - 6）和Wnt信号通路的调节，影响卵巢癌的侵袭性以及非癌症干细胞向癌症干细胞的转化。具有较低弹性模量、更具大孔形态和更高溶胀率的PEMM - 1/FeAlg水凝胶可显著增强SK - OV - 3细胞的干性、恶性程度和致瘤性。
