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首页> 外文期刊>World Journal of Gastroenterology >Suppression of human colon tumor growth by adenoviral vector-mediated NK4 expression in an athymic mouse model
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Suppression of human colon tumor growth by adenoviral vector-mediated NK4 expression in an athymic mouse model

机译：腺病毒载体介导的NK4在无胸腺小鼠模型中抑制人结肠肿瘤的生长

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摘要

AIM: To investigate the suppressive effects of adenoviral vector-mediated expression of NK4, an antagonist of hepatocyte growth factor (HGF), on human colon cancer in an athymic mouse model to explore the possibility of applying NK4 to cancer gene therapy. METHODS: A human colon tumor model was developed by subcutaneous implantation of tumor tissue formed by LS174T cells grown in athymic mice. Fifteen tumor-bearing mice were randomized into three groups (n = 5 in each group) at d 3 after tumor implantation and mice were injected intratumorally with phosphate-buffered saline (PBS) or with recombinant adenovirus expressing β-galactosidase (Ad-LacZ) or NK4 (rvAdCMV/NK4) at a 6-d interval for total 5 injections in each mouse. Tumor sizes were measured during treatment to draw a tumor growth curve. At d 26 after the first treatment, all animals were sacrificed and the tumors were removed to immunohistochemically examine proliferating cell nuclear antigen (PCNA), microvessel density (represented by CD31), and apoptotic cells. In a separate experiment, 15 additional athymic mice were employed to develop a tumor metastasis model by intraperitoneal injection (ip) of LS174T cells. These mice were randomized into 3 groups (n = 5 in each group) at d 1 after injection and were treated by ip injection of PBS, or Ad-LacZ, or rvAdCMV/NK4 at a 6-d interval for total two injections in each mouse. All animals were sacrificed at d 14 and the numbers and weights of disseminated tumors within the abdominal cavity were measured. RESULTS: Growth of human colon tumors were significantly suppressed in the athymic mice treated with rvAdCMV/NK4 (2537.4 ± 892.3 mm~3) compared to those treated by either PBS (5175.2 ± 1228.6 mm~3) or Ad-LacZ (5578.8 ± 1955.7 mm~3) (P < 0.05). The tumor growth inhibition rate was as high as 51%. Immunohistochemical staining revealed a similar PCNA labeling index (75.1% ± 11.2% in PBS group vs 72.8% ± 7.6% in Ad-LacZ group vs 69.3% ± 9.4% in rvAdCMV/ NK4 group) in all groups, but significantly lower microvessel density (10.7 ± 2.4 in rvAdCMV/NK4 group vs 25.6 ± 3.8 in PBS group or 21.3 ± 3.5 in Ad-LacZ group, P < 0.05), and a markedly higher apoptotic index (7.3% ± 2.4% in rvAdCMV/NK4 group vs 2.6 ± 1.1% in PBS group or 2.1% ± 1.5% in Ad-LacZ group, P < 0.05) in the rvAdCMV/NK4 group compared to the two control groups. In the tumor metastasis model, the number and weight of disseminated tumors of mice treated with rvAdCMV/NK4 were much lower than those of the control groups (tumor number: 6.2 ± 3.3 in rvAdCMV/ NK4 group vs 22.9 ± 7.6 in PBS group or 19.8 ± 8.5 in Ad-LacZ group, P < 0.05; tumor weight: 324 ± 176 mg in rvAdCMV/NK4 group vs 962 ± 382 mg in PBS group or 1116 ± 484 mg in Ad-LacZ group, P < 0.05). CONCLUSION: The recombinant adenovirus, rvAdCMV/ NK4, can attenuate the growth of colon cancer in vivo, probably by suppressing angiogenesis and inducing tumor cell apoptosis, but not by direct suppression of tumor cell proliferation. Moreover, rvAdCMV/NK4 may inhibit peritoneal dissemination of colon cancer cells in a murine tumor metastasis model. These findings indicate that NK4 gene transfer may be an effective tool for the treatment of colon cancer.
机译：目的：在无胸腺小鼠模型中研究腺病毒载体介导的NK4（肝细胞生长因子（HGF）的拮抗剂）对人结肠癌的抑制作用，以探讨将NK4应用于癌症基因治疗的可能性。方法：通过皮下植入无胸腺小鼠体内生长的LS174T细胞形成的肿瘤组织，建立人结肠肿瘤模型。将15只荷瘤小鼠在肿瘤植入后第3天随机分为三组（每组n = 5），并向小鼠瘤内注射磷酸盐缓冲液（PBS）或表达β-半乳糖苷酶（Ad-LacZ）的重组腺病毒。或NK4（rvAdCMV / NK4），间隔6天，每只小鼠总共注射5次。在治疗期间测量肿瘤大小以绘制肿瘤生长曲线。第一次治疗后第26天，处死所有动物，并切除肿瘤以进行免疫组织化学检查增殖细胞核抗原（PCNA），微血管密度（以CD31表示）和凋亡细胞。在一个单独的实验中，通过腹膜内注射（ip）LS174T细胞，另外15只无胸腺小鼠被用于建立肿瘤转移模型。将这些小鼠在注射后第1天随机分为3组（每组n = 5），并以ip注射PBS或Ad-LacZ或rvAdCMV / NK4的方式在6 d间隔进行治疗，每组总共注射两次老鼠。在第14天处死所有动物，并测量腹腔内扩散的肿瘤的数量和重量。结果：与PBS（5175.2±1228.6 mm〜3）或Ad-LacZ（5578.8±1955.7）处理的无胸腺小鼠相比，rvAdCMV / NK4（2537.4±892.3 mm〜3）处理的无胸腺小鼠的人结肠肿瘤的生长得到了显着抑制。 mm〜3）（P <0.05）。肿瘤生长抑制率高达51％。免疫组化染色显示所有组的PCNA标记指数相似（PBS组为75.1％±11.2％，Ad-LacZ组为72.8％±7.6％，rvAdCMV / NK4组为69.3％±9.4％），但微血管密度明显降低（ rvAdCMV / NK4组为10.7±2.4，而PBS组为25.6±3.8，Ad-LacZ组为21.3±3.5，P <0.05），且凋亡指数明显更高（rvAdCMV / NK4组为7.3％±2.4％，而2.6±与两个对照组相比，rvAdCMV / NK4组的PBS组为1.1％，Ad-LacZ组为2.1％±1.5％，P <0.05）。在肿瘤转移模型中，接受rvAdCMV / NK4治疗的小鼠的弥散性肿瘤数量和重量远低于对照组（rvAdCMV / NK4组的肿瘤数量为6.2±3.3，而PBS组为22.9±7.6或19.8） Ad-LacZ组为±8.5，P <0.05;肿瘤重量：rvAdCMV / NK4组为324±176 mg，而PBS组为962±382 mg，Ad-LacZ组为1116±484 mg，P <0.05）。结论：重组腺病毒rvAdCMV / NK4可以通过抑制血管生成和诱导肿瘤细胞凋亡来减弱体内结肠癌的生长，但不能直接抑制肿瘤细胞的增殖。此外，在鼠肿瘤转移模型中，rvAdCMV / NK4可能抑制结肠癌细胞的腹膜扩散。这些发现表明NK4基因转移可能是治疗结肠癌的有效工具。

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