Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Sapporo, Japan.
Global Station for Soft Matter, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Japan.
Nat Biomed Eng. 2021 Aug;5(8):914-925. doi: 10.1038/s41551-021-00692-2. Epub 2021 Mar 29.
Cancer recurrence can arise owing to rare circulating cancer stem cells (CSCs) that are resistant to chemotherapies and radiotherapies. Here, we show that a double-network hydrogel can rapidly reprogramme differentiated cancer cells into CSCs. Spheroids expressing elevated levels of the stemness genes Sox2, Oct3/4 and Nanog formed within 24 h of seeding the gel with cells from any of six human cancer cell lines or with brain cancer cells resected from patients with glioblastoma. Human brain cancer cells cultured on the double-network hydrogel and intracranially injected in immunodeficient mice led to higher tumorigenicity than brain cancer cells cultured on single-network gels. We also show that the double-network gel induced the phosphorylation of tyrosine kinases, that gel-induced CSCs from primary brain cancer cells were eradicated by an inhibitor of the platelet-derived growth factor receptor, and that calcium channel receptors and the protein osteopontin were essential for the regulation of gel-mediated induction of stemness in brain cancer cells.
癌症复发可能是由于对化疗和放疗有抵抗力的罕见循环肿瘤干细胞 (CSC) 引起的。在这里，我们表明双网络水凝胶可以快速将分化的癌细胞重编程为 CSC。在将来自六种人类癌细胞系或从胶质母细胞瘤患者切除的脑癌细胞接种到凝胶中 24 小时内，就会形成表达高水平干性基因 Sox2、Oct3/4 和 Nanog 的球体。在双网络水凝胶上培养并颅内注射免疫缺陷小鼠的人脑癌细胞比在单网络凝胶上培养的人脑癌细胞具有更高的致瘤性。我们还表明，双网络凝胶诱导了酪氨酸激酶的磷酸化，血小板衍生生长因子受体抑制剂可以消除由凝胶诱导的原代脑癌细胞中的 CSC，钙通道受体和蛋白骨桥蛋白对于调节脑癌细胞中凝胶介导的干性诱导至关重要。
