Marks Friedrich, Fürstenberger Gerhard, Müller-Decker Karin
Deutsches Krebsforschungszentrum, Research Program Cell and Tumor Biology, Heidelberg, Germany.
Recent Results Cancer Res. 2007;174:37-47. doi: 10.1007/978-3-540-37696-5_3.
Tumor promotion is an essential process in multistage cancer development providing the conditions for clonal expansion and genetic instability of preneoplastic and premalignant cells. It is caused by a continuous disturbance of cellular signal transduction that results in an overstimulation of metabolic pathways along which mediators of cell proliferation and inflammation as well as genotoxic by-products are generated. Among such pathways the oxidative metabolism of arachidonic acid has turned out to be of utmost importance in tumor promotion. The aberrant overexpression of cyclooxygenase-2, an inducible enzyme of prostanoid synthesis and lipid peroxidation, is a characteristic feature of more than two-thirds of all human neoplasias, and the specific inhibition of this enzyme has been found to have a substantial chemopreventive effect in both animal models and man. The prostaglandins produced by COX-2 promote tumor development by stimulating cell proliferation and angiogenesis and by suppressing programmed cell death and immune defense. In mice, a COX-2 transgene fused with the keratin 5 promoter, which is constitutively active in the basal (proliferative) compartment of stratified and simple epithelia, causes a preneoplastic and premalignant phenotype in several organs. Among these organs, skin, mammary gland, urinary bladder, and pancreas have been investigated in more detail. Histologically and biochemically, the COX-2-dependent alterations resemble an autopromoted state that--as shown for skin and urinary bladder--strongly sensitizes the tissue for carcinogenesis. In transgenic animals COX-2 expression is not restricted to keratin 5-positive cells but is seen also in adjacent keratin 5-negative cells. This spreading of the COX-2 signal indicates a paracrine mechanism of autoamplification. While cancer chemoprevention by COX-2 inhibition is a rapidly developing field, much less is known about other pathways of unsaturated fatty acid metabolism, although some of them may play a role in carcinogenesis rivaling that of prostaglandin formation. Here an urgent demand for systematic research exists.
肿瘤促进是多阶段癌症发展中的一个重要过程，为肿瘤前和癌前细胞的克隆扩增和基因不稳定提供条件。它是由细胞信号转导的持续紊乱引起的，这导致代谢途径的过度刺激，沿着这些途径产生细胞增殖和炎症介质以及遗传毒性副产物。在这些途径中，花生四烯酸的氧化代谢在肿瘤促进中已被证明至关重要。环氧化酶-2是前列腺素合成和脂质过氧化的诱导酶，其异常过表达是超过三分之二的人类肿瘤的特征，并且已发现在动物模型和人类中对该酶的特异性抑制具有显著的化学预防作用。COX-2产生的前列腺素通过刺激细胞增殖和血管生成以及抑制程序性细胞死亡和免疫防御来促进肿瘤发展。在小鼠中，与角蛋白5启动子融合的COX-2转基因在分层和单层上皮的基底（增殖）区室中持续活跃，在多个器官中引起肿瘤前和癌前表型。在这些器官中，皮肤、乳腺、膀胱和胰腺已被更详细地研究。在组织学和生物化学上，COX-2依赖性改变类似于自促进状态，如皮肤和膀胱所示，这种状态强烈使组织对致癌作用敏感。在转基因动物中，COX-2表达不仅限于角蛋白5阳性细胞，也见于相邻的角蛋白5阴性细胞。COX-2信号的这种扩散表明一种自放大的旁分泌机制。虽然通过抑制COX-2进行癌症化学预防是一个快速发展的领域，但对于不饱和脂肪酸代谢的其他途径了解较少，尽管其中一些途径可能在致癌作用中发挥与前列腺素形成相当的作用。这里存在对系统研究的迫切需求。
