Study of the inhibitory effects on invasion and metastasis of human squamous cell carcinoma by intensifying endothelial cell to cell adhesion

增强内皮细胞与细胞粘附抑制人鳞状细胞癌侵袭和转移的研究

• 批准号: 12671960
• 负责人: NAGAYASU Hiroki
• 金额: $ 1.47万
• 依托单位: Health Sciences University of Hokkaido, School of dentistry
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671960/
• 关键词: vascular endothelial cell; cell to cell adhesion; gap junction; connexin43; lung metastasis

Diisoprppyl,1,3-dithiol-2-y1idenemalonate(MT) is clinically used as a hepatoprotective agent. Because we noticed that the differentiation of cultured vascular endothelial cell, we have examined its effects on lung metastasis of the highly metastatic rat mammary carcinoma c-SST-2. MT was orally administered to syngenic SHR rats from 7 days before or after s. c.. inoculation of c-SST-2 cells to the end of the experiments. In the MT treated rats, pulumonary metastasis was markedly suppressed compared with the non-treated rats. In- the rats treated with MT for 19 days after i. v. inoculation of c-SST-2 cells, lung metastasis was also significantly suppressed. An in vitro invasion assay using a rat lung endothelial cell (RLE) monolayer revealed that pretreatment of the RLE with MT, but not c-SST-2 cells, significantly reduced the invasion of the RLE monolayer by c-SST-2 cells. An in vitro vascular permeability assay demonstrated that MT prevented the increase in permeability of the RLE monolayer by serum starvation. On the other hand, in vivo and in vitro growth, gelatinase production and adhesion to the RLE monolayer of c-SST-2 cells were not affected by NT treatment. Electronmicroscopical examination of the RLE monolayer treated with MT showed the development of gap junction Structure. A junction associated protein, cnnexin43 was also elevated at RLE treated with MT. These findings suggests that MT suppressed tumor metastasis by intensifying the cell-cell contact of endothelial cell, thus preventing tumor cells from invading vascular endothelium.

1，3-二巯基-2-亚甲基丙二酸二异丙酯（MT）在临床上用作保肝药。由于我们注意到培养的血管内皮细胞的分化，我们研究了其对高转移性大鼠乳腺癌c-SST-2肺转移的影响。同系SHR大鼠于给药前或给药后7天开始口服MT。C..接种c-SST-2细胞至实验结束。在MT治疗的大鼠，肺转移显着抑制与未处理的大鼠相比。在给大鼠注射MT 19天后，v.接种c-SST-2细胞，肺转移也被显著抑制。使用大鼠肺内皮细胞（RLE）单层的体外侵袭试验显示，MT预处理RLE，而不是c-SST-2细胞，显着降低c-SST-2细胞对RLE单层的侵袭。体外血管通透性测定表明，MT阻止血清饥饿的RLE单层的通透性增加。另一方面，在体内和体外的生长，明胶酶的生产和粘附到RLE单层的c-SST-2细胞不受NT治疗。电镜观察显示MT处理的RLE单层细胞形成了缝隙连接结构。连接相关蛋白cnnexin 43在MT处理的RLE中也升高。提示MT可能通过增强内皮细胞间的细胞接触，阻止肿瘤细胞侵入血管内皮，从而抑制肿瘤转移。

项目成果

中田大地, 柴田敏之, 永易裕樹, 他: "上皮成長因子EGFが退縮型ラット癌細胞ER-1の浸潤, 転移能に及ぼす影響 第3報, EGF長期間処理による酸化ストレスと遺伝的不安定性の誘導"日本口腔外科学会雑誌. 46(9). 511-518 (2000)

Daichi Nakata、Toshiyuki Shibata、Hiroki Nagayoshi 等人：“表皮生长因子 EGF 对消退大鼠癌细胞 ER-1 的侵袭和转移潜力的影响，第 3 部分，长期引起的氧化应激和遗传不稳定性的影响“EGF治疗”“指导”日本口腔颌面外科学会杂志. 46(9). 511-518 (2000)

H. Harada, K. Omura, H. Nggayasu, T. Yanagawa: "Pattern of occult cervical lymph node metastasis and neck dissection in In NO cases of squamous cell carcinoma or the tongue"J. J. O. M. S.. 46 (4). 191-195 (2000)

H. Harada、K. Omura、H. Nggayasu、T. Yanakawa：“鳞状细胞癌或舌癌病例中隐匿性颈部淋巴结转移和颈部清扫术的模式”J。

原田浩之, 小村 健, 永易裕樹, 他: "舌扁平上皮癌NO症例における潜在性頸部リンパ節転移の様相と頸部郭清術式の検討"日本口腔外科学会雑誌. 46(4). 191-195 (2000)

Hiroyuki Harada、Ken Komura、Hiroki Nagayoshi 等：“舌鳞状细胞癌 NO 病例中隐匿性颈部淋巴结转移和颈部清扫技术”，日本口腔颌面外科杂志 46(4)。 191 -195 (2000)

T.Shibata, H.Nagayasu, et al.: "Inhibitory effects of malotilate on in vitro invasion of lung endothelial cell monolayer by human oral squamous cell carcinoma cells"Tumor Biology. 21. 299-308 (2000)

T.Shibata、H.Nagayasu 等人：“马洛替酯对人口腔鳞状细胞癌细胞体外侵袭肺内皮细胞单层的抑制作用”肿瘤生物学。

T. Shhibata, H. Nagayasu et al.: "Inhibitory effects of malotilate on in vitro invasion of lung endothelial cell monolayer by human oral squamous cell carcinoma cells"Tumor Biology. 21. 299-308 (2000)

T. Shibata、H. Nagayasu 等人：“马洛替酯对人口腔鳞状细胞癌细胞体外侵袭肺内皮细胞单层的抑制作用”肿瘤生物学。