Rationale of hypoxic condition in Development of Liver Cancer

肝癌发生过程中缺氧的原理

基本信息

批准号：
12670901
负责人：
KISHI Kazushi
金额：
$ 2.05万
依托单位：
Wakayama Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670901/
关键词：
Liver cancer CCl4 Wister Rat Hypoxia induced factor 1alpha Hypoxia Hepatitis Liver cirrhosis Cox-2 inhibitor ラット肝がん肝炎肝硬変四塩化炭素

项目摘要

The liver is one of the most hypoxia-sensitive and hypoxic organs because of the energy consumptive cellular functions and that the 80% of the blood supply is portal venous flow. The most human liver cancer is known arising from the chronic hepatitis base or cirrhotic base. And several experimental liver cancers in the rat develop among inflammatory regenerative process.In the present experiment carcinogenetic model applied to Wister rat did not show any evidence of carcinogenesis with repeated injection of CCl4. Instead of the expected carcinogenic process they showed a course of inflammatory reaction and fibrotic reaction that was a common process with the liver cirrhosis. The inflammatory course showed transient hypoxia in the liver parenchyma bottomed at the 4^<th> week followed by V-shaped rebound while the CCl4 was still administrated. Then the rebound was not because the toxin (CCl4) was ceased but supposedly because due to tissue reaction including repairing process such as angiogenesis. This was coincided with the fact that, in the molecular research, this hypoxia was reflected to increase of the HIF1alpha. In the control group and a group in which CCl4 and anti-inflammatory drug (a cox-2 inhibitor) group showed less intensive hypoxia, and the less intensive induction of the HIF1alpha, correspondingly. Though this observation is very limited but is suggesting that inflammatory process involved in carcinogenic condition and that hypoxia is related to severity of inflammation. This also suggest a possibility of a hypothesis that anti-inflammatory drug (especially, cox-2 inhibitor) may be useful in reducing the cancer induction though hypoxic process in the liver. This project will be succeeded with a new budget by the same head investigator.

肝脏是对缺氧最敏感和缺氧的器官之一，因为肝脏具有消耗能量的细胞功能，并且80%的血液供应是门静脉血流。已知大多数人类肝癌源自慢性肝炎或肝硬化。大鼠中的几种实验性肝癌是在炎症再生过程中发生的。在目前应用于Wister大鼠的致癌模型中，没有显示出任何重复注射CCl4的致癌证据。他们没有表现出预期的致癌过程，而是表现出炎症反应和纤维化反应过程，这是肝硬化的常见过程。炎症过程显示肝实质短暂缺氧，在第4周触底，随后在仍施用CCl 4 时出现V形反弹。那么反弹并不是因为毒素（CCl4）停止，而是因为组织反应，包括血管生成等修复过程。这与分子研究中这种缺氧反映为HIF1α的增加这一事实相吻合。在对照组和CCl4和抗炎药(cox-2抑制剂)组中，缺氧程度较低，HIF1α的诱导程度也相应较低。尽管这一观察结果非常有限，但表明炎症过程涉及致癌情况，并且缺氧与炎症的严重程度有关。这也表明抗炎药（特别是cox-2抑制剂）可能有助于通过肝脏缺氧过程减少癌症诱导的假设。该项目将由同一位首席研究员通过新的预算来完成。