AGE DEPENDENT LIVER TUMOR SUPPRESSION IN THE LIVER

肝脏中年龄依赖性肝肿瘤抑制

基本信息

批准号：
2871832
负责人：
GARY Joseph SMITH
金额：
$ 20.32万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-04-15 至 2001-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2871832
关键词：
age difference carcinogenesis carcinogenesis inhibitor cell differentiation cell transplantation gender difference hormone regulation /control mechanism laboratory rat liver cells liver function liver neoplasms molecular cloning neoplasm /cancer transplantation neoplastic growth sex hormones tissue /cell culture transfection

项目摘要

This application will characterize how age decreases the ability of the normal tissue microenvironment to regulate cellular differentiation/function, suppressing expression of the tumorigenic phenotype. This project will utilize a unique experimental system in which rat liver epithelial tumor cells that carry a transfected bacterial beta- galactosidase reporter gene are transplanted into the liver parenchymal or subcutaneous tissue compartments of syngeneic rats. The ability of the normal hepatic parenchyma to suppress the tumorigenic potential of transplanted, neoplastically transformed rat liver epithelial cells can be evaluated directly using beta-galactosidase histochemistry. We have previously characterized the transplantation site-specific tumorigenic potential of two rat liver epithelial tumor cell lines. In the young adult rat (3-months old), these cell lines form undifferentiated spindle-cell carcinomas with short latency at subcutaneous transplantation sites, but in the liver form slow-growing hepatocellular carcinomas or no tumors at all. Suppressed tumor cells incorporate into hepatic plates and morphologically differentiate into hepatocyte-like cells. The tumor cell line that is suppressed in the livers of young adult males forms undifferentiated carcinomas in the livers of 100% of 24-month old rats. These results demonstrate that age of host and transplantation site are strong determinants in the tumorigenic potential of transplanted tumor cells. We hypothesize that the liver microenvironment exerts a strong regulatory (suppressive) capacity over transplanted cells and that this capacity-is lost With age. The transplantation site-specificity of tumor suppression was evidenced by tumor formation at extrahepatic sites of animals that formed no hepatic tumors following transplantation of cells directly into the hepatic parenchyma. The first goal of this project is to extend our observations on the loss of liver-specific tumor suppression in older male rats to a full range of ages of recipient rats, and to evaluate the hormonal component of the male predominance of liver cancer using female and castrated male rats of various ages. The second goal is to investigate the role of Kupffer and pit cells on hepatic tumor formation by examining their numbers/distribution in vivo. We will also evaluate the effects of growth modulating factors produced by these cells on tumor cell proliferation/differentiation in vitro. The third goal is to develop an in vitro system for evaluating the interaction of tumor cells with specific extracellular matrix and cell membrane components, and .humoral factors, isolated from rats of different ages and gender. The final goal is to characterize, using the technique of differential display, changes in gene expression patterns that accompany the transplantation of tumor cells into different tissue microenvironments.

该应用将表征年龄如何降低正常组织微环境调节细胞分化/功能，抑制肿瘤的表达表型。该项目将利用独特的实验系统大鼠肝上皮肿瘤细胞，携带转染的细菌β- 半乳糖苷酶报告基因被移植到肝实质或合成大鼠的皮下组织室。能力正常肝实质以抑制肿瘤性的潜力移植的，肿瘤转化的大鼠肝上皮细胞可以是直接使用β-半乳糖苷酶组织化学进行评估。我们有先前表征了移植部位特异性肿瘤的特异性两种大鼠肝上皮肿瘤细胞系的电势。在年轻人大鼠（3个月大），这些细胞系形成未分化的纺锤体细胞癌在皮下移植部位的潜伏期短，但在肝脏中形成缓慢生长的肝细胞癌或无肿瘤全部。抑制肿瘤细胞掺入肝板，并形态学上分化为肝细胞样细胞。肿瘤细胞在年轻男性形式的肝脏中被抑制的线 24个月大大鼠的肝脏中未分化的癌。这些结果表明，宿主和移植部位的年龄是移植肿瘤的致瘤潜能中的强决定因素细胞。我们假设肝微环境施加了强大的对移植细胞的调节（抑制）能力，这是能力 - 随着年龄的增长而失去。肿瘤的移植部位特异性肿瘤在肝外部位的形成证明了抑制细胞移植后未形成肝肿瘤的动物直接进入肝实质。该项目的第一个目标是扩展我们对肝特异性肿瘤抑制丧失的观察结果年龄较大的男性大鼠到全年的接受者大鼠，并评估使用肝癌的男性占主导地位的荷尔蒙成分雌性和cast割的雄性大鼠。第二个目标是研究Kupffer和Pit细胞在肝肿瘤形成中的作用通过检查其体内数量/分布。我们还将评估这些细胞产生的生长调节因子对肿瘤细胞的影响体外增殖/分化。第三个目标是开发体外系统用于评估肿瘤细胞与特定的相互作用细胞外基质和细胞膜成分以及.Humoral因子，从不同年龄和性别的大鼠中分离出来。最终目标是表征，使用差分显示技术，基因的变化伴随肿瘤细胞移植到不同的组织微环境。