Borbath I, Stärkel P
Laboratoire de gastro-entérologie, Faculté de médecine, Université catholique de Louvain, Brussels, Belgium.
Acta Gastroenterol Belg. 2011 Mar;74(1):34-44.
In the present work, we have evaluated the possibility of preventing liver carcinogenesis in rats at two stages of development. In the first series of experiments, we induced foci of altered hepatocytes, (FAH) which represent the first events in rodent liver carcinogenesis, using the chemical mutagens diethylnitrosamine (DEN) and acetylaminofluorene (AAF). In the second part of the work, we used repeated weekly injections of DEN only that gave rise to significant fibrosis at 11 weeks and the development of malignant tumours at 16 weeks. We chose to assess the chemopreventive effect of three different drugs: pioglitazone, lanreotide and S-trans-trans-farnesylthiosalicylic acid (FTS). Pioglitazone (PGZ) is an agonist of peroxisome proliferator-activated receptor gamma (PPARg), itself a member of the nuclear receptor superfamily, responsible for the modulation of a number of metabolic pathways, including cell differentiation, metabolism of lipids and inflammation. Lanreotide (LAN) is a somatostatin analogue that has an inhibitory effect on the release of several hormones, such as growth hormone and serotonine. FTS is a specific antagonist of the protoocogene Ras, tested here based on the rationale that Ras is activated in many hepatocellular carcinomas (HCC). We showed that both PGZ and LAN were efficient in the first, pre-neoplastic model, by reducing the size of FAH, decreasing proliferation specifically in FAH by interacting with proteins of the cell cycle. We could also demonstrate that LAN increased apoptosis. In the second model, LAN was able to diminish the number of established HCC by decreasing proliferation, in parallel with an anti-fibrotic action. Furthermore, enhanced apoptosis and antiangiogenic effects were observed when LAN was given from the start of the carcinogenic induction by DEN. The cellular mechanisms leading to its effects warrant further investigations. FTS also strongly inhibited the appearance of FAH and HCC in the second model, through a complete inhibition of Ras activation and the induction of pro-apoptotic pathways. On the contrary, PGZ did not prevent the appearance of neoplastic lesions. For these reasons, we did not analyse further its mechanism of action in the second model. Altogether, the results we obtained demonstrate an activity of both LAN and FTS, at the early onset of liver carcinogenesis, and later on when advanced fibrosis, cirrhosis and HCC are induced. These anti-tumoural effects could be complementary and will be tested in combination in the future.
在本研究中，我们评估了在大鼠发育的两个阶段预防肝癌发生的可能性。在第一系列实验中，我们使用化学诱变剂二乙基亚硝胺（DEN）和乙酰氨基芴（AAF）诱导了肝细胞灶性改变（FAH），这是啮齿动物肝癌发生的起始事件。在研究的第二部分，我们仅每周重复注射DEN，11周时可导致显著纤维化，16周时可引发恶性肿瘤。我们选择评估三种不同药物的化学预防效果：吡格列酮、兰瑞肽和S-反式-反式-法尼基硫代水杨酸（FTS）。吡格列酮（PGZ）是过氧化物酶体增殖物激活受体γ（PPARγ）的激动剂，PPARγ本身是核受体超家族的一员，负责调节多种代谢途径，包括细胞分化、脂质代谢和炎症反应。兰瑞肽（LAN）是一种生长抑素类似物，对多种激素的释放具有抑制作用，如生长激素和血清素。FTS是原癌基因Ras的特异性拮抗剂，基于Ras在许多肝细胞癌（HCC）中被激活的原理在此进行测试。我们发现，在第一个癌前模型中，PGZ和LAN均有效，通过减小FAH的大小，与细胞周期蛋白相互作用特异性降低FAH中的增殖。我们还能证明LAN可增加细胞凋亡。在第二个模型中，LAN能够通过降低增殖减少已形成的HCC数量，同时具有抗纤维化作用。此外，从DEN致癌诱导开始就给予LAN时，可观察到细胞凋亡增强和抗血管生成作用。导致其作用的细胞机制值得进一步研究。FTS在第二个模型中也通过完全抑制Ras激活和诱导促凋亡途径强烈抑制了FAH和HCC的出现。相反，PGZ未能预防肿瘤性病变的出现。因此，我们没有进一步分析其在第二个模型中的作用机制。总之，我们获得的结果表明，LAN和FTS在肝癌发生的早期以及后期诱导严重纤维化、肝硬化和HCC时均具有活性。这些抗肿瘤作用可能具有互补性，未来将进行联合测试。
