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

我们之前已经证明，c-myc和c-myc的共同表达 转化生长因子-α在小鼠体内的转基因研究 肝脏导致了肿瘤发展的主要增强。 与单独表达这两种转基因中的任何一种相比，该基因在器官中的表达。 尽管事件顺序在形态上相似，但 这两个转基因品系，戏剧性的加速，范围和 C-myc/转化生长因子-α小鼠肝脏病变的严重程度 展示了这种转基因组合的协同效应。 尽管c-myc/转化生长因子-α和c-myc女性表现出更长的潜伏期和 肿瘤发生率较低，病理改变与 在雄性小鼠中可见，包括肝细胞的形成 转化生长因子-α单一转基因缺失的肿瘤 女性。单转基因和双转基因小鼠的肿瘤呈诱导性 内源性c-myc和转化生长因子-α，最常见的是没有变化 或表皮生长因子受体减少，进一步表明 C-myc和转化生长因子-α在提供选择性 对肿瘤细胞的生长优势不依赖于表皮生长 因子受体水平。为了确定可能的肿瘤前体，我们 特别关注之前的发育异常变化和 伴随癌前病变和肿瘤性病变的出现 双转基因小鼠。在早期，这些变化是有特征的 通过出现大的发育不良的肝细胞，主要是 在中心周围，高水平表达转化生长因子-α和uPA，以及 转化生长因子-α1，特别是在凋亡细胞中。移植物的移植 仅伴或不伴异型增生的转基因肝组织 裸鼠血管损伤能够产生由以下组成的肝癌细胞 小的二倍体细胞，表明启动的细胞是 在早期发育不良阶段，并可进展为肝细胞癌。它是 因此，很可能是发育不良的大肝细胞发生了凋亡， 这可能与转化生长因子-131的上调密切相关，并且 UPA，而其他细胞则进化为肝癌的前体细胞群。 由于c-myc、转化生长因子-α和异型增生同时存在 人类肝脏疾病前病变，我们的转基因小鼠系统出现 为研究人肝癌的发生机制提供一种合适的模型。

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.