Microencapsulation of engineered cells to deliver sustained high circulating levels of interleukin-6 to study hepatocellular carcinoma progression
Microencapsulation of engineered cells to deliver sustained high circulating levels of interleukin-6 to study hepatocellular carcinoma progression
复制标题
DOI：
10.3727/000000006783981477
复制
发表时间：
2006-01-01
影响因子：
3.3
通讯作者：
McKillop, Iain H.
中科院分区：
文献类型：
--
作者：
Moran, Diarmuid M.;Koniaris, Leonidas G.;McKillop, Iain H.
白细胞介素-6（IL-6）是一种多效细胞因子，在正常和异常的肝功能和反应中起核心作用。本研究的目的是确定使用细胞包封技术引入遗传修饰的异种（CHO）细胞群以提高大鼠模型中rhIL-6的循环水平的可行性，并确定持续高水平的rhIL-6对体内肝细胞癌（HCC）进展的影响。将藻酸盐基质与转染的CHO细胞组合，根据其合成rhIL-6的能力进行选择，并用于产生均匀的藻酸盐细胞珠。一旦包封，转染细胞继续进行复制，在珠内形成集落，并在体外合成/释放大量rhIL-6到培养基中。腹腔内植入珠到大鼠导致显着增加的循环和肝内rhIL-6的水平高达4天postimplantation。长时间植入导致CHO细胞从微珠中逃逸，导致微珠内的宿主反应和CHO细胞死亡。随后，将CHO-IL-6包封的细胞植入预先肝内接种H4 IIE HCC细胞系的大鼠中。这些研究证明了在该模型中维持高循环/肝内rhIL-6水平。尽管rhIL-6显著增加，但该技术并未显著改变净肿瘤进展速率。然而，Stat 3活性在从植入CHO-IL-6细胞的动物切除的正常肝脏和HCC组织中均显著增加。总的来说，这些数据证明了使用细胞包封技术产生高水平的活性循环和肝内细胞因子的短期可行性，并提高了修饰在肿瘤进展期间被鉴定为重要的特定信号转导级联的可能性。
Interlukin-6 (IL-6) is a pleitropic cytokine that plays a central role in normal and abnormal hepatic function and response. The aims of the current study were to determine the viability of using cell encapsulation technology to introduce a genetically modified xenogeneic (CHO) cell population to elevate circulating levels of rhIL-6 in a rat model and determine the effects of sustained high rhIL-6 levels on hepatocellular carcinoma (HCC) progression in vivo. An alginate matrix was combined with transfected CHO cells, selected for their ability to synthesize rhIL-6, and used to generate uniform alginate-cell beads. Once encapsulated transfected cells continued to undergo replication, formed colonies within the bead, and synthesized/released large quantities of rhIL-6 into culture medium in vitro. Intraperitoneal implantation of beads into rats resulted in significantly increased circulating and intrahepatic levels of rhIL-6 up to 4 days postimplantation. Prolonged implantation led to the escape of CHO cells from the bead, resulting in a host response and CHO cell death within the bead. Subsequently CHO-IL-6 encapsulated cells were implanted into rats previously inoculated intrahepatically with the H4IIE HCC cell line. These studies demonstrated the maintenance of high circulating/intrahepatic rhIL-6 levels in this model. Despite significantly increased rhlL-6, this technique did not significantly alter the rate of net tumor progression. However, Stat3 activity was significantly increased in both normal liver and HCC tissue resected from animals implanted with CHO-IL-6 cells. Collectively these data demonstrate the short-term viability of using cell encapsulation technology to generate high levels of active circulating and intrahepatic cytokines and raise the possibility of modifying specific signal transduction cascades identified to be important during tumor progression.