Institute of Polymer Science and Engineering, National Taiwan University, Taipei, Taiwan.
Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
Biomaterials. 2019 Aug;213:119202. doi: 10.1016/j.biomaterials.2019.05.013. Epub 2019 May 13.
Pancreatic stromal cells especially pancreatic stellate cells (PSCs) play a critical role in the progression of human pancreatic ductal adenocarcinoma (PDAC). However, the exact interaction between cancer cells and PSCs remains to be elucidated in order to develop more effective therapeutic approaches to treat PDAC. The microenvironment of PDAC shows higher hyaluronan (HA) levels, which is associated with poor prognosis of PDAC patients. In the current study, an efficient three-dimensional tumor spheroid model for PDAC was established. The pancreatic cancer cells and PSCs were co-cultured on hyaluronan grafted chitosan (CS-HA) coated plates to generate 3D tumor-like co-spheroids. The pancreatic cancer cells and PSCs (1:9 ratio) co-cultured on CS-HA coated plates were assembled into tumor-like co-spheroids with 3D core-shell structure in 48 h. These spheroids displayed potent in vitro tumorigenicity such as up-regulated expression of stemness and migration markers. The migration rate of cancer cells in spheroids (from 1:9 cell ratio) was much faster (3.2-fold) than that of cancer cells alone. Meanwhile, this unique co-spheroidal cancer cell structure with the outer wrap of PSCs contributed to the chemo-resistance of pancreatic cancer cells to gemcitabine as well as sensitivity to the combined gemcitabine and Abraxane treatment in vitro. The metastatic nature of the spheroids was confirmed by the zebrafish xenograft model in vivo. The compact and dynamic pancreatic cancer-PSC co-spheroids generated by the unique 3D co-culture platform on CS-HA biomaterials can mimic the PSC-constituting microenvironment of PDAC and demonstrate the chemo-resistant, invasive, and metastatic phenotypes. They have potential applications in personalized and high-throughput drug screening.
胰腺基质细胞，特别是胰腺星状细胞（PSCs），在人类胰腺导管腺癌（PDAC）的进展中起着关键作用。然而，为了开发更有效的治疗 PDAC 的方法，仍需要阐明癌细胞和 PSCs 之间的确切相互作用。PDAC 的微环境表现出更高的透明质酸（HA）水平，这与 PDAC 患者的预后不良有关。在本研究中，建立了一种有效的 PDAC 三维肿瘤球体模型。胰腺癌细胞和 PSCs 共培养在透明质酸接枝壳聚糖（CS-HA）涂层板上，以生成 3D 肿瘤样共球体。胰腺癌细胞和 PSCs（1:9 比例）共培养在 CS-HA 涂层板上，在 48 小时内组装成具有 3D 核壳结构的肿瘤样共球体。这些球体表现出强大的体外致瘤性，例如干性和迁移标志物的上调表达。球体中癌细胞的迁移率（来自 1:9 细胞比例）比单独的癌细胞快得多（3.2 倍）。同时，这种独特的共球体癌细胞结构，外覆 PSCs，有助于胰腺癌细胞对吉西他滨的化疗耐药性以及对吉西他滨和 Abraxane 联合治疗的敏感性。体内斑马鱼异种移植模型证实了球体的转移性。在 CS-HA 生物材料上独特的 3D 共培养平台生成的紧密且动态的胰腺癌细胞-PSC 共球体可以模拟 PDAC 中由 PSC 构成的微环境，并表现出化疗耐药性、侵袭性和转移性表型。它们在个性化和高通量药物筛选方面具有应用潜力。
