Moses H L, Arteaga C L, Alexandrow M G, Dagnino L, Kawabata M, Pierce D F, Serra R
Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, TN 37232-2175, USA.
Princess Takamatsu Symp. 1994;24:250-63.
The beta-type transforming growth factors (TGF beta) are potent inhibitors of cell proliferation. The mechanisms of TGF beta growth inhibition have been investigated. In skin keratinocytes, TGF beta 1 rapidly suppresses c-myc expression at the level of transcriptional initiation, and expression of c-myc was shown to be necessary for proliferation of these cells. Overexpression of c-myc, using an inducible construct, blocks growth inhibition by TGF beta 1. In 11.5 day p.c. lung bud organ cultures, TGF beta 1 inhibits tracheobronchial epithelial development, including branching morphogenesis. At this stage of development, the tracheobronchial epithelia express N-myc, but not c-myc, TGF beta 1 was shown to markedly inhibit N-myc expression in epithelia of the lung bud organ cultures. N-myc gene knockout experiments by others have shown that N-myc is required for branching morphogenesis of the tracheobronchial tree. The data indicate that suppression of expression of either N-myc or c-myc may play a role in TGF beta growth inhibition. To study the role of TGF beta 1 in normal mammary development and in mammary neoplasia, we have constructed three transgenic mouse lines that express a simian TGF beta 1S223/225 mutated to produce a constitutively active product under the control of the MMTV enhancer/promoter. Expression of the transgene was associated with marked suppression of the normal pattern of mammary ductal tree development in female transgenics from all three lines. However, during pregnancy, alveolar outgrowths developed from the hypoplastic ductal tree, and lactation occurred. Unlike many other transgenic mouse models in which expression of TGF alpha or oncogenes under control of the MMTV promoter leads to mammary epithelial hyperplasia and increased tumor formation, the MMTV-TGF beta 1 transgene causes conditional hypoplasia of the mammary ductal tree. No spontaneous tumors have been detected in the MMTV-TGF beta 1 transgenic animals, indicating that overexpression of TGF beta 1 in mammary epithelia does not enhance, and may actually suppress, early stages of carcinoma development. Other studies have shown that overexpression of TGF beta 1 in carcinoma cells enhances tumorigenicity and metastatic spread. We propose that TGF beta has a bifunctional role in carcinogenesis, retarding carcinoma development but enhancing progression once neoplastic transformation has occurred and the growth inhibitory response to TGF beta has been lost.
β型转化生长因子（TGF-β）是细胞增殖的强效抑制剂。人们对TGF-β抑制生长的机制进行了研究。在皮肤角质形成细胞中，TGF-β1在转录起始水平迅速抑制c-myc的表达，而c-myc的表达被证明是这些细胞增殖所必需的。使用可诱导构建体过表达c-myc可阻断TGF-β1对生长的抑制作用。在妊娠11.5天时的肺芽器官培养物中，TGF-β1抑制气管支气管上皮发育，包括分支形态发生。在这个发育阶段，气管支气管上皮表达N-myc，但不表达c-myc，TGF-β1被证明可显著抑制肺芽器官培养物上皮中N-myc的表达。其他人进行的N-myc基因敲除实验表明，N-myc是气管支气管树分支形态发生所必需的。这些数据表明，抑制N-myc或c-myc的表达可能在TGF-β抑制生长中起作用。为了研究TGF-β1在正常乳腺发育和乳腺肿瘤形成中的作用，我们构建了三种转基因小鼠品系，它们在MMTV增强子/启动子的控制下表达一种发生S223/225突变的猿猴TGF-β1，以产生一种组成型活性产物。转基因的表达与所有三个品系的雌性转基因小鼠乳腺导管树正常发育模式的显著抑制相关。然而，在怀孕期间，从发育不全的导管树长出了肺泡，并且发生了泌乳。与许多其他在MMTV启动子控制下表达TGF-α或癌基因导致乳腺上皮增生和肿瘤形成增加的转基因小鼠模型不同，MMTV-TGF-β1转基因导致乳腺导管树的条件性发育不全。在MMTV-TGF-β1转基因动物中未检测到自发肿瘤，这表明乳腺上皮中TGF-β1的过表达不会增强，实际上可能会抑制癌发展的早期阶段。其他研究表明，癌细胞中TGF-β1的过表达会增强肿瘤发生能力和转移扩散。我们提出，TGF-β在致癌过程中具有双功能作用，它会延缓癌发展，但一旦发生肿瘤转化且对TGF-β的生长抑制反应丧失，它会增强进展。
