Myxomaviral Anti-Inflammatory Serpin Reduces Myeloid-Derived Suppressor Cells and Human Pancreatic Cancer Cell Growth in Mice.
Myxomaviral Anti-Inflammatory Serpin Reduces Myeloid-Derived Suppressor Cells and Human Pancreatic Cancer Cell Growth in Mice.
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DOI：
10.4172/1948-5956.1000219
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发表时间：
2013-08-19
期刊：
影响因子：
--
通讯作者：
Lucas AR
中科院分区：
文献类型：
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作者：
Zheng D;Chen H;Bartee MY;Williams J;Davids JA;Lomas DA;McFadden G;Lucas AR
炎症细胞对肿瘤微环境的修饰代表了新认识的癌症驱动力，在肿瘤侵袭、生长、血管生成和转移中起关键作用。增加的溶血栓级联丝氨酸蛋白酶，特别是尿激酶型纤溶酶原激活剂及其受体，与炎性细胞迁移，胰腺癌生长，侵袭和不利的结果。胰腺癌中的炎症与髓源性抑制细胞（MDSC）活性和癌症进展有关。粘液瘤病毒是一种编码高效免疫调节剂的复杂DNA病毒。Serp-1和M-T7是两种这样的分泌型抗炎粘液瘤病毒蛋白。Serp-1抑制uPA、纤溶酶和凝血因子X，而M-T7抑制C、CC和CXC趋化因子。我们已经探索了这些病毒蛋白用于治疗移植在严重联合免疫缺陷（SCID）小鼠中的一系列人类癌症分离株的潜在用途。用Serp-1、神经丝氨酸蛋白酶抑制剂（一种抑制血栓溶解蛋白酶的相关哺乳动物丝氨酸蛋白酶抑制剂）或M-T7处理移植的肿瘤。Serp-1和neuroserpin在植入后4周抑制胰腺癌细胞系Hs 766 t的生长（分别为P=0.03和P=0.01）。Serp-1还抑制小鼠中第二胰腺癌细胞系MIA PaCa-2的生长（P=0.02）。人乳腺癌细胞系MDA 231的生长不受Serp-1的抑制。相比之下，M-T7在植入SCID小鼠后没有改变任何测试的癌细胞系的生长。丝氨酸蛋白酶抑制剂对胰腺肿瘤生长的抑制与流式细胞术检测的脾细胞MDSC计数的显著降低相关（P=0.009），而在其他脾细胞亚群中未检测到变化。Serp-1和NSP处理也显著减少了肿瘤中的巨噬细胞浸润（P=0.001）。总之，两种抗炎丝氨酸蛋白酶抑制剂减少炎性巨噬细胞侵袭和胰腺肿瘤细胞生长，表明潜在的治疗功效。
Modification of the tumor microenvironment by inflammatory cells represents a newly recognized driving force in cancer with critical roles in tumor invasion, growth, angiogenesis, and metastasis. Increased thrombolytic cascade serine proteases, specifically urokinase-type plasminogen activator and its receptor, correlate with inflammatory cell migration, pancreatic cancer growth, invasion and unfavorable outcomes. Inflammation in pancreatic cancer is linked with myeloid-derived suppressor cell (MDSC) activity and cancer progression. Myxomavirus is a complex DNA virus encoding highly potent immune modulators. Serp-1 and M-T7 are two such secreted anti-inflammatory myxomaviral proteins. Serp-1 inhibits uPA, plasmin and coagulation factor X while M-T7 inhibits C, CC, and CXC chemokines. We have explored the potential use of these viral proteins for treatment of a range of human cancer isolates engrafted in severe combined immunodeficient (SCID) mice. Engrafted tumors were treated with either Serp-1, neuroserpin, a related mammalian serpin that inhibits thrombolytic proteases, or M-T7. Serp-1 and neuroserpin inhibited growth of the pancreatic cancer cell line Hs766t (P=0.03 and P=0.01, respectively) at 4 weeks after implantation. Serp-1 also inhibited growth of a second pancreatic cancer cell line MIA PaCa-2 in mice (P=0.02). Growth of the human breast cancer line MDA231 was not inhibited by Serp-1. M-T7, in contrast, did not alter growth of any of the cancer cell lines tested after implant into SCID mice. Serpin inhibition of pancreatic tumor growth was associated with a significant decrease in splenocyte MDSC counts by flow cytometry (P=0.009), without detected change in other splenocyte subpopulations. Serp-1 and NSP treatment also significantly reduced macrophage infiltration in tumors (P=0.001). In summary two anti-inflammatory serpins reduced inflammatory macrophage invasion and pancreatic tumor cell growth, suggesting potential therapeutic efficacy.