TRANSGENIC MODELS--COOPERATION OF C MYC AND GROWTH FACTORS IN TUMORIGENESIS

我们先前已经证明，c-myc和 转化生长因子α（TGF-α）作为小鼠中的转基因 肝脏导致肿瘤发展的主要增强， 与单独表达这些转基因中的任何一种相比。 尽管在形态上相似的事件之间的顺序 两个转基因株系，显著的加速，程度， c-myc/TGF-α小鼠肝脏病变的严重程度清楚地 证明了这种转基因组合的协同效应。 尽管c-myc/TGF-α和c-myc雌性动物的潜伏期较长， 肿瘤发生率低，病理改变与对照组相同， 在雄性小鼠中观察到，包括肝细胞的形成 肿瘤（HCC），其在TGF-α单转基因中不存在， 女性单转基因和双转基因小鼠的肿瘤显示诱导 内源性c-myc和TGF-α，最常见的是， 或表皮生长因子受体减少，进一步表明 c-myc和TGF-α在提供选择性 独立于表皮生长的肿瘤细胞生长优势 因子受体水平。 为了识别可能的肿瘤前体，我们 特别关注在此之前的发育不良变化， 伴随着肿瘤前病变和肿瘤病变的出现， 双转基因小鼠。 早期，这些变化的特点是 由于出现了大的发育不良的肝细胞， 在中心周围，表达高水平的TGF-α和uPA，以及 TGF-α 1，特别是在凋亡细胞中。 移植 转基因肝组织仅具有发育不良，有或没有 裸鼠血管损伤能够产生由以下组成的HCC： 小的二倍体细胞，这表明启动细胞产生 在早期发育异常阶段，并可进展为HCC。 是 因此很可能大的发育不良肝细胞经历凋亡， 这可能与TGF-131的“上调”密切相关， uPA，而其他细胞演变成HCC的前体群体。 由于c-myc、TGF-α和异型增生同时存在， 我们的转基因小鼠系统出现了 是研究人类肝癌发生的理想模型。

We have previously shown that the coexpression of c-myc and transforming growth factor alpha (TGF-alpha) as transgenes in mouse liver results in major enhancement of neoplastic development in this organ as compared with expression of either of these transgenes alone. Despite morphological similarities in the sequence of events between the two transgenic lines, the dramatic acceleration, extent, and severity of hepatic lesions in c-myc/TGF-alpha mice clearly demonstrated the synergistic effects of this transgenic combination. Although c-myc/TGF-alpha and c-myc females displayed longer latency and lower tumor incidence, the pathological changes were the same as those seen in the male mice, including the formation of hepatocellular carcinomas (HCC), which are absent in TGF-alpha single transgenic females. Tumors in single- and double-transgenic mice showed induction of the endogenous c-myc and TGF-alpha and, most frequently, unchanged or decreased epidermal growth factor receptor, further indicating the collaborative role of c-myc and TGF-alpha in providing a selective growth advantage to tumor cells independently of the epidermal growth factor receptor levels. To identify possible tumor precursors, we focused particularly on the dysplastic changes preceding and accompanying the appearance of preneoplastic and neoplastic lesions in the double-transgenic mice. Early on, these changes were characterized by the appearance of large dysplastic hepatocytes, mostly pericentrally, expressing high levels of TGF-alpha and uPA, as well as TGF-alpha1, particularly in apoptotic cells. Transplantation of the transgenic liver tissues harboring only dysplasia with or without vascular lesions onto nude mice was able to yield HCCs composed of small diploid cells, suggesting that initiated cells are generated during the early dysplastic phase and can progress to HCC. It is therefore likely that large dysplastic hepatocytes undergo apoptosis, which may be closely associated with the "up-regulation" of TGF-131 and uPA, whereas other cells evolve into the precursor population for HCC. Due to the simultaneous presence of c-myc, TGF-alpha, and dysplasia in premalignant human liver diseases, our transgenic mouse system appears to be an appropriate model for studying human hepatocarcinogenesis.