Maraviroc，CCR5受体拮抗剂，防止肝癌小鼠模型的发展

StephenW

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0053992
Maraviroc, a CCR5 Antagonist, Prevents Development of Hepatocellular Carcinoma in a Mouse Model
Laura Ochoa-Callejero,Laura Pérez-Martínez,Susana Rubio-Mediavilla,José A. teo,Alfredo Martínez ,José R. Blanco

Abstract

Chronic liver disease may result in a sequential progression through fibrosis, cirrhosis and lead, eventually, to hepatocellular carcinoma (HCC). Hepatic stellate cells (HSC) seem to be responsible for the fibrogenic response through the activation of an autocrine loop involving the chemokine receptor, CCR5. However, the role of CCR5 in HCC remains poorly understood. Since this receptor is also one of the main ports of entry for the human immunodeficiency virus (HIV), several CCR5 inhibitors are being used in the clinic to reduce viral load. We used one of these inhibitors, maraviroc (MVC), in a mouse model of diet-induced HCC to investigate whether this intervention would reduce disease progression. Animals treated with MVC on top of a normal control diet did not present any evidence of toxicity or any morphological change when compared with non-treated mice. Animals treated with MVC presented higher survival, less liver fibrosis, lower levels of liver injury markers and chemokines, less apoptosis, lower proliferation index, and lower tumor burden than their counterparts receiving only the hepatotoxic diet. In addition, MVC inhibits HSC activation markers such as phosphorylation of p38 and ERK, and increases hepatocyte survival. This study suggests that MVC, a well tolerated and clinically characterized drug, may be used as a preventative treatment for HCC. Clinical studies are needed to demonstrate the efficacy of this drug, or other CCR5 inhibitors, in patients with high risk of developing HCC.

StephenW

摘要

通过肝纤维化，肝硬化和铅的慢性肝病，可能会导致在一个连续的发展，最终，肝细胞癌（HCC）。肝星状细胞（HSC）似乎是负责的纤维化反应，通过激活的自分泌环的趋化因子受体CCR5。然而，在肝癌组织中CCR5的作用仍知之甚少。由于这种受体是人类免疫缺陷病毒（HIV）的主要入境口岸之一，CCR5抑制剂在临床上使用，以减少病毒载量。我们使用这些抑制剂maraviroc（MVC），在饮食诱导的肝癌小鼠模型的研究，这种干预是否会减少疾病进展。 MVC的正常控制饮食治疗的动物没有提出任何证据的毒性或任何形态的变化与非治疗组小鼠相比。治疗MVC的动物提出了更高的生存，肝纤维化，肝损伤标记物及趋化因子的水平较低，较少的细胞凋亡，细胞增殖指数较低，降低肿瘤负荷比他们的同行，只接受肝毒性的饮食。此外，MVC抑制HSC活化标志物如p38和ERK的磷酸化，并增加肝细胞的生存。这项研究表明，MVC，很好的耐受性和临床特征的药物，可以用来作为一种预防性治疗肝癌。临床的研究来证明这种药物的疗效，或其他CCR5抑制剂，在高风险的发展为HCC的患者

StephenW

[extract, fibrosis and HCC]

Regardless of etiology, chronic liver disease generally involves a process of progressive destruction and regeneration of the liver parenchyma, leading to fibrosis and cirrhosis. At early stages most patients are asymptomatic and can easily go undiagnosed and untreated for decades [8]. This chronic liver injury is characterized, at the molecular level, for the rapid turnover and excessive accumulation of extracellular matrix proteins which replace the functional parenchyma by fibrotic tissue [9]. Hepatic stellate cells (HSC) are the main source of the fibrotic tissue and, upon chronic damage, they secrete numerous inflammatory mediators including chemokines CCL3, CCL4, and CCL5, among others [10], [11]. Simultaneously, HSC express several chemokine receptors such as CXCR3, CCR1, CCR3, CCR5, and CCR7 [12], [13]. Moreover, HSC express the other HIV co-receptor, CXCR4. Binding of this receptor by its endogenous ligand, CXCL12, also has pro-fibrogenic effects on HSC [14]. It seems that the paracrine and autocrine activation of these receptors promotes the fibrogenic response [15], which is characterized by increased collagen synthesis, impaired collagen degradation, and secretion of further inflammatory mediators [16]. The progressive fibrosis and persistent liver inflammation would eventually lead to HCC [17].

[摘录，纤维化和肝癌]

无论病因，慢性肝病一般涉及到一个过程的渐进破坏和再生的肝实质，导致肝纤维化和肝硬化。在早期阶段，大多数病人是无症状的，几十年来[8]，可以很容易地去确诊和治疗。这种慢性肝损伤的特点，在分子水平，细胞外基质蛋白取代的功能实质的纤维化组织[9]的快速周转和过度积累。肝星状细胞（HSC）的主要来源的纤维组织，慢性损伤时，它们会分泌大量的炎症介质，其中包括CCL3，CCL4，CCL5趋化因子[10]，[11]。同时，HSC表达几个如趋化因子受体CXCR3，CCR1，CCR3，CCR5，和CCR7[12]，[13]。此外，HSC表示，CXCR4 HIV共受体。其内源性配体，CXCL12，这种受体的结合也有亲纤维化HSC[14]上的影响。它似乎激活这些受体的旁分泌和自分泌促进纤维化反应[15]，[16]其特征在于通过增加胶原蛋白的合成，受损的胶原降解，和进一步的炎症介质的分泌。进行性纤维化和持续的肝脏炎症，最终导致HCC [17]。