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Clinical Significance of chemokines and its receptors in peritoneal carcinomatosis of gastric cancer

趋化因子及其受体在胃癌腹膜癌变中的临床意义

基本信息

批准号：
16591303
负责人：
YASUMOTO Kazuo
金额：
$ 1.15万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

Peritoneal carcinomatosis is a frequent cause of death in patients with advanced gastric carcinoma. Since chemokines are now considered to play an important role in the metastasis of various malignancies, we hypothesized that they may also be involved in the development of peritoneal carcinomatosis by gastric carcinoma. Human gastric carcinoma cell lines, which were all highly efficient in generating malignant ascites in nude mice upon intraperitoneal inoculation, selectively expressed CXCR4 mRNA and protein. In particular, NUGC4 cells showed vigorous migratory responses to its ligand CXCL12 (also called stromal-derived factor-1a, SDF-1a). CXCL12 enhanced proliferation and rapid increases in phosphorylation of protein kinase B/Akt and extracellular signal-regulated kinase (ERK) of NUGC4 cells. We also demonstrated that AMD3100 (a specific CXCR4 antagonist) effectively reduced tumor growth and ascitic fluid formation in nude mice inoculated with NUGC4 cells. In addition, we examined human clinical samples. Malignant ascites fluids from patients with peritoneal carcinomatosis contained high concentrations of CXCL12 (average, 4.67 ng/mL). Moreover, immunohistochemical analysis demonstrated that 22 of 33 primary gastric tumors with peritoneal metastasis were positive for CXCR4 expression (67%), whereas only 4 of 16 with other distant metastasis were positive (25%). Notably, 22 of 26 CXCR4-expressing primary tumors developed peritoneal metastases (85%). CXCR4-positivity of primary gastric carcinomas significantly correlated with the development of peritoneal carcinomatosis. Collectively, our results strongly suggest that the CXCR4/CXC12 axis plays an important role in the development of peritoneal carcinomatosis from gastric carcinoma. Thus, CXCR4 may be a potential therapeutic target for peritoneal carcinomatosis of gastric carcinoma.

腹膜癌病是进展期胃癌患者常见的死亡原因。由于趋化因子现在被认为在各种恶性肿瘤的转移中起重要作用，我们推测它们也可能参与了胃癌腹膜癌的发生发展。在裸鼠体内接种的人胃癌细胞株均能高效地产生恶性腹水，并选择性表达CXCR4基因和蛋白。特别是，NUGC4细胞对其配体CXCL12(也称为基质衍生因子-1a，SDF-1a)表现出强烈的迁移反应。CXCL12可促进NUGC4细胞的增殖，并使蛋白激酶B/Akt和细胞外信号调节激酶(ERK)的磷酸化水平迅速升高。我们还证明了AMD3100(一种特异性的CXCR4拮抗剂)有效地减少了裸鼠接种NUGC4细胞后的肿瘤生长和腹水形成。此外，我们还检查了人类的临床样本。腹膜癌患者恶性腹水中CXCL12含量较高，平均为4.67 ng/mL。免疫组织化学结果显示，33例有腹膜转移的原发胃肿瘤中有22例表达CXCR4(67%)，而有其他远处转移的16例中仅4例(25%)表达CXCR4。值得注意的是，26例表达CXCR4的原发肿瘤中有22例发生腹膜转移(85%)。CXCR4阳性表达与腹膜癌的发生密切相关。总之，我们的结果强烈表明CXCR4/CXC12轴在胃癌腹膜癌的发生发展中起重要作用。因此，CXCR4可能成为治疗胃癌腹膜癌的潜在靶点。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A pilot study of low dose, divided MTD of OPT-11 on 21 consecutive patients with metastatic colorectal or gastric cancer.

对 21 名连续的转移性结直肠癌或胃癌患者进行低剂量、分开的 OPT-11 MTD 初步研究。

DOI：
发表时间：
2004
期刊：
Surg Today 34
影响因子：
0
作者：
Takahashi Y;Kitakata H;Hirano K;Yamashita K;Yasumoto K;Omote K;Minamoto T;Mai M
通讯作者：
Mai M

Role of the CXCL12/CXCR4 axis in peritoneal carcinomatosis of gastric cancer

DOI：
10.1158/0008-5472.can-05-3393
发表时间：
2006-02-15
期刊：
CANCER RESEARCH
影响因子：
11.2
作者：
Yasumoto, K;Koizumi, K;Saiki, I
通讯作者：
Saiki, I

A case of meningeal carcinomatosis preceded by a rapid increased CA19-9 levels in breast cancer patient serum

乳腺癌患者血清CA19-9水平快速升高的脑膜癌病一例

DOI：
发表时间：
2005
期刊：
International Journal of Clinical Oncology 10
影响因子：
0
作者：
Yasumoto K;Koizumi K;Kawashima A;Saitoh Y;Arita Y;Shinohara K;Minami T;Nakayama T;Sakurai H;Takahashi Y;Yoshie O;Saiki I;Kurachi K. et al.;Inuzuka K. et al.;Yasumoto K;Yasumoto K
通讯作者：
Yasumoto K

Chemotherapy under cachectic conditions and the possibility of cachexia-controlled chemotherapy

恶病质条件下的化疗和恶病质控制化疗的可能性