Development and biological analysis of peritoneal metastasis mouse models for human scirrhous stomach cancer
Development and biological analysis of peritoneal metastasis mouse models for human scirrhous stomach cancer
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DOI：
10.1111/j.1349-7006.2005.00054.x
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发表时间：
2005-06-01
期刊：
影响因子：
5.7
通讯作者：
Hirohashi, S
中科院分区：
文献类型：
--
作者：
Yanagihara, K;Takigahira, M;Hirohashi, S
由于缺乏高度重复的动物模型，已发表的关于硬质胃癌腹膜播散的研究数量非常少。将HSC-44PE和HSC-58（硬质胃癌细胞系）细胞原位植入裸鼠体内，导致肿瘤细胞向大网膜、肠系膜、腹膜等部位播散，并导致少数动物出现腹水。对动物依次重复腹水肿瘤细胞的分离和这些细胞的原位接种的循环。这是为了分离具有强大诱导腹水形成能力的高度转移细胞系（来自HSC-44PE的44As3；来自HSC-58的58As1和58As9）。所有三种细胞系均在原位注射部位诱导肿瘤形成，并在接种后约 3-5 周在 90-100% 的动物中引起致命的癌性腹膜炎和血性腹水。当亲代细胞被植入后，动物在大约 12-18 周内变得濒临死亡，然而，没有动物出现腹水。互补DNA微阵列和免疫组织化学分析揭示了高转移性细胞系和亲本细胞系之间编码基质蛋白酶、细胞粘附、运动、血管生成和增殖的基因表达水平的差异。通过分析细胞转移潜力的稳定性和重现性来评估该模型在药物评估中的有用性。用 CPT-11 和 GEM 静脉注射治疗的动物显示出肿瘤生长受到抑制并显着延长了生存期。本研究建立的转移细胞系和体内模型有望作为原发灶发展为癌性腹膜炎的模型，并作为阐明硬质胃癌腹膜播散的病理生理学及其治疗药物开发的有用手段。
The number of published studies on peritoneal dissemination of scirrhous gastric carcinoma is very small as a result of the unavailability of highly reproducible animal models. Orthotopic implantation of HSC-44PE and HSC-58 (scirrhous gastric carcinoma-derived cell lines) cells into nude mice led to dissemination of the tumor cells to the greater omentum, mesenterium, peritoneum and so on, and caused ascites in a small number of animals. Cycles of isolation of the ascitic tumor cells and orthotopic inoculation of these cells were repeated in turn to animals. This was to isolate highly metastatic cell lines with a strong capability of inducing the formation of ascites (44As3 from HSC-44PE; 58As1 and 58As9 from HSC-58). All three cell lines induced tumor formation at the site of orthotopic injection, and caused fatal cancerous peritonitis and bloody ascites in 90-100% of the animals approximately 3-5 weeks after the inoculation. When the parent cells were implanted, the animals became moribund in approximately 12-18 weeks, however, none of the animals developed ascites. Complementary DNA microarray and immunohistochernical analyses revealed differences in the expression levels of genes coding for the matrix proteinase, cell adhesion, motility, angiogenesis and proliferation between the highly metastatic- and parent-cell lines. The usefulness of this model for the evaluation of drugs was assessed by analyzing the stability of the metastatic potential of the cells and the reproducibility. Animals intravenously treated with CPT-11 and GEM showed suppressed tumor growth and significantly prolonged survival. The metastatic cell lines and the in vivo model established in the present study are expected to serve as a model of cancerous peritonitis developing from primary lesions, and as a useful means of clarifying the pathophysiology of peritoneal dissemination of scirrhous gastric carcinoma and the development of drugs for its treatment.