Targeting gallbladder cancer: oncolytic virotherapy with myxoma virus is enhanced by rapamycin in vitro and further improved by hyaluronan in vivo.
Targeting gallbladder cancer: oncolytic virotherapy with myxoma virus is enhanced by rapamycin in vitro and further improved by hyaluronan in vivo.
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DOI：
10.1186/1476-4598-13-82
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发表时间：
2014-04-13
期刊：
影响因子：
37.3
通讯作者：
Quan Z
中科院分区：
文献类型：
--
作者：
Weng M;Gong W;Ma M;Chu B;Qin Y;Zhang M;Lun X;McFadden G;Forsyth P;Yang Y;Quan Z
胆囊癌（GBC）具有高度致命性，有效的治疗需要协同抗肿瘤治疗。该研究旨在研究粘液瘤病毒（MYXV）感染对 GBC 的溶瘤价值并优化 MYXV 溶瘤效率。我们检查了 GBC 细胞系对 MYXV 感染的许可性，并在 MYXV +雷帕霉素 (Rap) 处理后比较了 MYXV 对 GBC 和对照许可性神经胶质瘤细胞的细胞活力的影响，已知雷帕霉素 (Rap) 治疗可通过上调 p-Akt 水平来增强细胞对 MYXV 的许可性。我们还通过检查 Akt 激活状态、MMP-9 表达、细胞活力和胶原蛋白分布来评估 MYXV +透明质酸 (HA) 治疗效率。我们进一步比较了 MYXV + Rap 和 MYXV + HA 治疗方案之间的水力传导率、肿瘤面积和荷瘤小鼠的存活率。 MYXV + Rap 处理可显着提高 MYXV 在体外对 GBC 细胞系的溶瘤能力，但在体内对 GBC 异种移植物的溶瘤能力不显着。我们发现 GBC 肿瘤中的 IV 型胶原蛋白水平高于神经胶质瘤肿瘤。扩散分析表明，IV 型胶原蛋白可以物理性地阻碍 MYXV 的瘤内分布。 HA-CD44 相互作用被发现可以激活 Akt 信号通路，从而增加溶瘤率。 HA 还被发现可以增强 MMP-9 的分泌，从而促进 IV 型胶原蛋白的降解。与MYXV + Rap不同，MYXV + HA疗法显着增强了MYXV体内的抗肿瘤作用，并延长了GBC荷瘤小鼠的生存期。 HA 可以通过 HA-CD44 相互作用优化 MYXV 对 GBC 的溶瘤作用，从而促进病毒感染和扩散。
Gallbladder carcinoma (GBC) is highly lethal, and effective treatment will require synergistic anti-tumor management. The study is aimed at investigating the oncolytic value of myxoma virus (MYXV) infection against GBC and optimizing MYXV oncolytic efficiency. We examined the permissiveness of GBC cell lines to MYXV infection and compared the effects of MYXV on cell viability among GBC and control permissive glioma cells in vitro and in vivo after MYXV + rapamycin (Rap) treatment, which is known to enhance cell permissiveness to MYXV by upregulating p-Akt levels. We also assessed MYXV + hyaluronan (HA) therapy efficiency by examinating Akt activation status, MMP-9 expression, cell viability, and collagen distribution. We further compared hydraulic conductivity, tumor area, and survival of tumor-bearing mice between the MYXV + Rap and MYXV + HA therapeutic regimens. MYXV + Rap treatment could considerably increase the oncolytic ability of MYXV against GBC cell lines in vitro but not against GBC xenografts in vivo. We found higher levels of collagen IV in GBC tumors than in glioma tumors. Diffusion analysis demonstrated that collagen IV could physically hinder MYXV intratumoral distribution. HA–CD44 interplay was found to activate the Akt signaling pathway, which increases oncolytic rates. HA was also found to enhance the MMP-9 secretion, which contributes to collagen IV degradation. Unlike MYXV + Rap, MYXV + HA therapy significantly enhanced the anti-tumor effects of MYXV in vivo and prolonged survival of GBC tumor-bearing mice. HA may optimize the oncolytic effects of MYXV on GBC via the HA–CD44 interaction which can promote viral infection and diffusion.
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影响因子：
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