Peehl D M, Wong S T, Sellers R G, Jin S, Rhim J S
Department of Urology, Stanford University School of Medicine, CA 94305-5118, USA.
Carcinogenesis. 1997 Aug;18(8):1643-50. doi: 10.1093/carcin/18.8.1643.
Growth factor-independent proliferation and loss of response to differentiation factors are believed to be critical elements in carcinogenesis. We have developed an in vitro model of human prostatic carcinogenesis by the introduction of SV40 DNA into normal prostatic epithelial cells to create a transformed, immortal cell line, pRNS-1-1. This non-tumorigenic cell line responded similarly to normal prostatic epithelial cells to most growth- and differentiation-regulatory factors, with the notable exception of loss of response to the inhibitory factor 1,25-dihydroxyvitamin D3. In this study, we describe the introduction of the ras oncogene into pRNS-1-1 cells to create a tumorigenic cell line, pRNS-1-1/ras. In addition to an attenuated response to 1,25-dihydroxyvitamin D3, these cells also became unresponsive to retinoic acid and gained the ability to undergo clonal proliferation in the absence of epidermal growth factor (EGF). EGF-independent growth could not be linked to the production of autocrine transforming growth factor-alpha, but instead was likely due to sustained signaling by the ras oncogene, bypassing ligand-activation of the EGF receptor. Ligand-independent proliferation, coupled with the loss of response to the growth-inhibitory and differentiation agent retinoic acid, may be important elements in the conversion of human prostatic epithelial cells to tumorigenicity.
不依赖生长因子的增殖以及对分化因子反应的丧失被认为是致癌过程中的关键因素。我们通过将SV40 DNA导入正常前列腺上皮细胞，建立了一种人前列腺癌发生的体外模型，从而创建了一种转化的永生细胞系pRNS-1-1。这种非致瘤性细胞系对大多数生长和分化调节因子的反应与正常前列腺上皮细胞相似，但对抑制因子1,25 - 二羟基维生素D3失去反应是个明显的例外。在本研究中，我们描述了将ras癌基因导入pRNS-1-1细胞以创建致瘤性细胞系pRNS-1-1/ras的过程。除了对1,25 - 二羟基维生素D3的反应减弱外，这些细胞对视黄酸也变得无反应，并获得了在无表皮生长因子（EGF）的情况下进行克隆增殖的能力。不依赖EGF的生长与自分泌转化生长因子-α的产生无关，而是可能由于ras癌基因的持续信号传导，绕过了EGF受体的配体激活。不依赖配体的增殖，以及对生长抑制和分化剂视黄酸反应的丧失，可能是人类前列腺上皮细胞转化为致瘤性的重要因素。
