脂肪酸转运蛋白2抑制剂对人乳腺癌MDA-MB-231移植瘤生长的影响

Effect of Lipofermata on Transplanted Tumor growth of Human Breast Cancer MDA-MB-231

目的探讨Lipofermata通过抑制脂肪酸转运蛋白2(fatty acid transport protein 2,FATP2)对小鼠人乳腺癌MDA-MB-231移植瘤生长的影响及其机制。方法通过小鼠构建人乳腺癌移植瘤模型后随机分成实验组(10只)和对照组(10只),实验组小鼠皮下注射Lipofermata,2 mg/kg,每天两次,连续给药2周。对照组小鼠皮下注射溶媒(10%DMSO)2 mg/kg,每天两次,连续给药2周。给药后第8天、第11天、第14天、第17天使用游标卡尺测量并计算各组小鼠移植瘤的体积。给药结束后,取两组小鼠脾脏组织制作组织匀浆,检测各组小鼠脾脏内花生四烯酸(Arachidonicacid,AA)和前列腺素E2的含量。取两组小鼠脾脏组织和肿瘤组织,研磨形成单个细胞,过筛除去多余组织块,流式细胞仪检测CD8+T细胞占总细胞的比例。结果给药后第8天,实验组小鼠移植瘤体积(904.55±62.50)mm 3,对照组小鼠移植瘤体积(907.21±11.07)mm 3,两组无显著差异(t=-0.13,P=0.90)。第11天、第14天及第17天测量发现,实验组小鼠移植瘤体积明显小于对照组,且差异均有统计学意义(P<0.01)。实验组小鼠脾脏内花生四烯酸含量(23.98±1.65)ng/mL,对照组为(45.63±1.85)ng/mL,差异有统计学意义(t=-27.62,P<0.01)。实验组小鼠脾脏内前列腺素E2含量(0.98±0.24)ng/mL,对照组为(1.62±0.18)ng/mL,差异有统计学意义(t=-6.76,P<0.01)。实验组小鼠脾脏内CD8+T细胞比例(0.42±0.07)%,对照组(0.27±0.05)%,差异有统计学意义(t=5.68,P<0.01)。实验组小鼠肿瘤组织内CD8+T细胞比例(0.24±0.06)%,对照组(0.13±0.04)%,差异有统计学意义(t=4.65,P<0.01)。结论Lipofermata通过靶向抑制FATP2来解除髓系抑制细胞(Myeloid-derived suppressor cells,MDSCs)的免疫抑制,提高CD8+T细胞,从而抑制小鼠人乳腺癌MDA-MB-231移植瘤的生长。

Objective To investigate the effect and mechanism of Lipofermata on the growth of human breast cancer MDA-MB-231 xenografts tumor by inhibiting fatty acid transporter 2(FATP2).Methods Human breast cancer xenograft tumor model mice were randomly divided into experimental group and control group,with 10 mice in each group.The mice were administered Lipofermata(2 mg/kg)or 10%DMSO twice a day for 2 weeks by subcutaneous injection.The volumes of transplanted tumors were measure using a vernier caliper on day 8,day 11,day 14 and day 17 after administration.After the administration,the spleen tissues of mice in the two groups were taken to prepare tissue homogenates,and then the contents of arachidonic acid and PGE2 were detected.Spleen tissues and tumor tissues of mice in the two groups were ground to form single cells,and the excess tissue blocks were removed by sieving.The proportion of CD8+T cells in the total cells was detected by flow cytometry.Results On day 8 after administration,the tumor volume of mice in experimental group was(904.55±62.50)mm 3,and that in control group was(907.21±11.07)mm 3,there was no significant difference between the two groups(t=-0.13,P=0.90).On days 11,14 and 17,the tumor volume in the experimental group was significantly smaller than that in the control group(P<0.01).The content of AA in spleen was(23.98±1.65)ng/mL in experimental group and(45.63±1.85)ng/mL in control group,the difference was statistically significant(t=-27.62,P<0.01).The content of PEG2 in spleen of experimental group was(0.98±0.24)ng/mL,and that in control group was(1.62±0.18)ng/mL,the difference was statistically significant(t=-6.76,P<0.01).The proportion of CD8+T cells in spleen of experimental group was(0.42±0.07)%,and that of control group was(0.27±0.05)%,the difference was statistically significant(t=5.68,P<0.01).The proportion of CD8+T cells in tumor tissue in experimental group was(0.24±0.06)%,and that in control group was(0.13±0.04)%,the difference was statistically significant(t=4.65,P<0.01).Conclusion Lipofermata can relieve the immunosuppression of myeloid-derived suppressor cells by targeting FATP2 and increase CD8+T cells,thereby inhibiting the growth of human breast cancer MDA-MB-231 xenografts in mice.