Gilg Anne G, Tye Sandra L, Tolliver Lauren B, Wheeler William G, Visconti Richard P, Duncan James D, Kostova Felina V, Bolds Letitia N, Toole Bryan P, Maria Bernard L
Department of Pediatrics, Charles P. Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA.
Clin Cancer Res. 2008 Mar 15;14(6):1804-13. doi: 10.1158/1078-0432.CCR-07-1228.
To determine if hyaluronan oligomers (o-HA) antagonize the malignant properties of glioma cells and treatment-resistant glioma side population (SP) cells in vitro and in vivo.
A single intratumoral injection of o-HA was given to rats bearing spinal cord gliomas 7 days after engraftment of C6 glioma cells. At 14 days, spinal cords were evaluated for tumor size, invasive patterns, proliferation, apoptosis, activation of Akt, and BCRP expression. C6SP were isolated by fluorescence-activated cell sorting and tested for the effects of o-HA on BCRP expression, activation of Akt and epidermal growth factor receptor, drug resistance, and glioma growth in vivo.
o-HA treatment decreased tumor cell proliferation, increased apoptosis, and down-regulated activation of Akt and the expression of BCRP. o-HA treatment of C6SP inhibited activation of epidermal growth factor receptor and Akt, decreased BCRP expression, and increased methotrexate cytotoxicity. In vivo, o-HA also suppressed the growth of gliomas that formed after engraftment of C6 or BCRP+ C6SP cells, although most C6SP cells lost their expression of BCRP when grown in vivo. Interestingly, the spinal cord gliomas contained many BCRP+ cells that were not C6 or C6SP cells but that expressed nestin and/or CD45; o-HA treatment significantly decreased the recruitment of these BCRP+ progenitor cells into the engrafted gliomas.
o-HA suppress glioma growth in vivo by enhancing apoptosis, down-regulating key cell survival mechanisms, and possibly by decreasing recruitment of host-derived BCRP+ progenitor cells. Thus, o-HA hold promise as a new biological therapy to inhibit HA-mediated malignant mechanisms in glioma cells and treatment-resistant glioma stem cells.
确定透明质酸寡聚体（o-HA）在体外和体内是否能拮抗胶质瘤细胞及治疗抵抗性胶质瘤侧群（SP）细胞的恶性特性。
在植入C6胶质瘤细胞7天后，对患有脊髓胶质瘤的大鼠进行瘤内单次注射o-HA。14天时，评估脊髓的肿瘤大小、侵袭模式、增殖、凋亡、Akt激活情况及BCRP表达。通过荧光激活细胞分选分离C6SP细胞，并检测o-HA对BCRP表达、Akt和表皮生长因子受体激活、耐药性及体内胶质瘤生长的影响。
o-HA治疗可降低肿瘤细胞增殖、增加凋亡，并下调Akt激活及BCRP表达。o-HA处理C6SP细胞可抑制表皮生长因子受体和Akt激活，降低BCRP表达，并增加甲氨蝶呤的细胞毒性。在体内，o-HA也可抑制C6或BCRP+C6SP细胞植入后形成的胶质瘤生长，尽管大多数C6SP细胞在体内生长时失去了BCRP表达。有趣的是，脊髓胶质瘤中含有许多BCRP+细胞，这些细胞不是C6或C6SP细胞，但表达巢蛋白和/或CD45；o-HA治疗可显著减少这些BCRP+祖细胞向植入的胶质瘤中的募集。
o-HA通过增强凋亡、下调关键细胞存活机制以及可能通过减少宿主来源的BCRP+祖细胞的募集来抑制体内胶质瘤生长。因此，o-HA有望成为一种新的生物疗法，以抑制胶质瘤细胞和治疗抵抗性胶质瘤干细胞中HA介导的恶性机制。
