The development of early diagnostic marker for peritoneal metastasis, and the management of tumor fibrosis through angiotensin II type I (AT1) receptor in gastric cancer.

腹膜转移早期诊断标记物的开发，以及通过胃癌血管紧张素 II I 型 (AT1) 受体控制肿瘤纤维化。

• 批准号: 17591383
• 负责人: FUSHIDA Sachio
• 金额: $ 1.73万
• 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: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591383/
• 关键词: serum type IV collagen; peritoneal metastasis (recurrence); peritoneal fibrosis; Angiotensin II type 1 receptor; candesartan; 腹膜繊維化; 腹膜転移

Evaluation of the serum type IV collagen for early diagnosis of peritoneal metastases (recurrence)The purpose of this study is to determine whether the type IV collagen, which is marker of hepatic fibrosis, could be useful biomarker for peritoneal metastasis. Type IV collagen was measured in 112 patients who were diagnosed wit gastric cancer : early cancer 55 (Group A), advanced cancer 43 (Group B), patients with peritoneal metastasis 27 (Group C). And they were compared with conventional biomarker (CEA, CA19-9, CAl25). The median type IV collagen levels in Group C was significantly higher than Group A and B (p<0.0001). In the clinical course of 13 patients with peritoneal metastasis, all of the serum type IV collagen levels were increasing according to their tumor progression. Furthermore, 3 of 5 patients, who were in the high risk group for peritoneal recurrence, were found peritoneal recurrence by laparoscopy without clinical, radiological, biochemical symptoms. These findings sugge … More st that the serum type IV collagen is a useful marker for early diagnosis of peritoneal metastasis with gastric cancer.4Angiotensin II activates MAP kinase and NF-kB through angiotensin II type I receptor in gastric cancer cellsFour of 5 gastric cancer cell lines were found angiotensis II type 1 (AT1) receptor expression using western blot analysis. Angiotensin II stimulated growth of AT1 positive gastric cancer cell and this proliferative response was inhibited by candesartan, a specific AT1 receptor antagonist. Angiotensin II plays a role in the growth of AT1 positive gastric cancer cells through MAP kinase activation by ERK1/2 phosphorylation and surviving induction as antiapoptotic molecule by NF-kB activation.One of the AT1 receptor expressing cell lines, OCUM2MD3, which had a very high peritoneal metastatic potential, was used as in vivo experiment. OCUM2MD3 made peritoneal metastasis including massive ascites and metastatic nodules 4weeks after intraperitoneal injection of 1×107 cells in nude mice. To elucidate whether over-expression of AT1 correlate to tumor progression, AT1 receptor antagonist, candesartan, has been treated everyday from 1 week after tumor injection. The candesartan group showed a significant longer survival than control group. These finding suggest that AT1 activation correlates tumor progression and its receptor antagonist may be a candidate for the molecule targeting therapy Less

血清IV型胶原蛋白对腹膜转移（复发）早期诊断的评估本研究的目的是确定IV型胶原蛋白作为肝纤维化的标志物，是否可以作为腹膜转移的有用生物标志物。对112例确诊为胃癌的患者进行IV型胶原蛋白测定，其中早期55例（A组），晚期43例（B组），腹膜转移27例（C组）。并与常规生物标志物（CEA、CA19-9、CAl25）进行比较。C组IV型胶原中位数水平显著高于A、B组（p<0.0001）。在13例腹膜转移患者的临床过程中，血清IV型胶原蛋白水平均随肿瘤进展而升高。5例腹膜复发高危组中有3例经腹腔镜检查发现腹膜复发，无临床、影像学、生化症状。提示血清IV型胶原是早期诊断胃癌腹膜转移的有效标志物。4 .血管紧张素II通过血管紧张素II I型受体在胃癌细胞中激活MAP激酶和NF-kB。western blot分析5株胃癌细胞株中有4株的血管紧张素II I型受体表达。血管紧张素II刺激AT1阳性胃癌细胞的生长，这种增殖反应被坎地沙坦（一种特异性AT1受体拮抗剂）抑制。血管紧张素II通过ERK1/2磷酸化激活MAP激酶，并通过NF-kB活化作为抗凋亡分子诱导存活，参与AT1阳性胃癌细胞的生长。其中一种AT1受体表达细胞系OCUM2MD3具有很高的腹膜转移潜力，被用于体内实验。OCUM2MD3在裸鼠腹腔注射1×107细胞4周后发生腹膜转移，包括大量腹水和转移结节。为了阐明AT1的过表达是否与肿瘤进展相关，AT1受体拮抗剂坎地沙坦从肿瘤注射后1周开始每天治疗。坎地沙坦组的生存期明显长于对照组。这些发现表明AT1激活与肿瘤进展相关，其受体拮抗剂可能是分子靶向治疗的候选药物