TRANSGENIC MODELS--COOPERATION OF ONCOGENES AND GROWTH FACTORS IN TUMORIGENESIS

该项目的目标是开发转基因小鼠模型，以 核癌基因与生长因子相互作用的研究 肿瘤发生学。我们最初的模型旨在定义相互作用， 以及c-myc和转化蛋白可能的协同作用。 生长因子-α在肝癌发生中的作用 C-myc和转化生长因子-`作为转基因在小鼠肝脏中的共表达 在这个器官肿瘤发展的巨大加速中 与单独表达这两种转基因之一相比。两个人 在双胞胎的肝脏中发生的明显的细胞反应 肝肿瘤出现前转基因小鼠发育不良 和现有肝细胞的凋亡变化，随后出现 包括增生性和非增生性的多发性局灶性病变 细胞群。我们产生了双转基因小鼠，它们同时携带c- 白蛋白作用下MYC与肝细胞生长因子 启动子/增强子。之所以选择HGF，是因为众所周知它是一种重要的 体内肝再生调节剂和成熟的有效有丝分裂原 肝细胞体外培养。目前的研究结果表明， 显然，如果HGF和转化生长因子-α共同表达，它们的作用方式是不同的 在转基因小鼠模型中使用c-myc。而转化生长因子-α/myc小鼠 很早就表现出肝脏发育不良和肿瘤性改变 随着年龄的增长，HGF/myc小鼠在 相同甚至更晚的时间点。然而，这两种双转基因模型 (HGF/myc和转化生长因子-α/myc)的形态证据表明 有丝分裂活性和细胞凋亡增加。这是特别的 利息，因为有建议说，平衡的比率 增殖和凋亡信号是预防致癌的关键 进步。我们预测这些双转基因小鼠模型将 有助于分析在多步骤过程中起作用的因素 致癌的可能性。

The objective of this project is to develop transgenic mouse models to study the interaction of nuclear oncogenes and growth factors in tumorigenesis. Our initial model was aimed at defining the interaction, as well as the possible synergistic effect of c-myc and transforming growth factor-alpha (TGF-alpha) during hepatocarcinogenesis. Coexpression of c-myc and TGF-` as transgenes in the mouse liver resulted in a tremendous acceleration of neoplastic development in this organ as compared to expression of either of these transgenes alone. The two distinct cellular reactions that occurred in the liver of the double transgenic mice prior to the appearance of liver tumors were dysplastic and apoptotic changes in the existing hepatocytes followed by emergence of multiple focal lesions composed of both hyperplastic and dysplastic cell populations. We generated double-transgenic mice harboring both c- myc and hepatocyte growth factor (HGF) under the albumin promoter/enhancer. HGF was chosen because it is known to be an important regulator of liver regeneration in vivo and a potent mitogen for mature hepatocytes in vitro. The results of the current study demonstrate clearly that HGF and TGF-alpha act in a different way if co-expressed with c-myc in a transgenic mouse model. Whereas TGF-alpha/myc mice exhibited dysplastic and neoplastic changes in the liver at a very early age, the HGF/myc mice show no signs of neoplastic transformations at the same and even later time points. However, both double-transgenic models (HGF/myc and TGF-alpha/myc) exhibit morphological evidence for an increase in mitotic activity and apoptosis. This is of particular interest since it has been proposed that a balanced ratio between proliferating and apoptotic signals is critical to prevent a carcinogenic progression. We predict that these double-transgenic mouse models will be useful to analyze the factors acting throughout the multistep process of carcinogenesis.