A new view of the roles of blood flow dynamics and Kupffer cell in intra-hepatic metastasis of hepatocellular carcinoma
A new view of the roles of blood flow dynamics and Kupffer cell in intra-hepatic metastasis of hepatocellular carcinoma
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DOI：
10.1016/j.mehy.2011.03.033
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发表时间：
2011-07-01
影响因子：
4.7
通讯作者：
Dong, Jiahong
中科院分区：
文献类型：
--
作者：
Liu, Qiaofei;Zhang, Aiqun;Dong, Jiahong
病毒性肝癌是一种以早期肝内转移为特征的恶性肿瘤。单纯性原发性肝癌无肝硬化（SPLC）肝外转移（EHM）率高。以往对肝癌转移机制的研究主要集中在癌细胞的生物学行为上，而忽视了肿瘤微环境，尤其是血流动力学和枯否细胞。SPLC肝小叶损伤较少，而肝小叶损伤较少。VCPLC的特征是明显的肝纤维化，导致各种血流障碍，如中央小叶静脉阻塞、肝动脉-门静脉瘘（HAPVF）、门静脉逆流（PVC）。传统上认为肝脏Kupffer细胞是抵抗肝癌和转移性病变的强大防御细胞，但近年来的研究表明，在长期缺血缺氧应激下，Kupffer细胞可分泌多种促炎介质，促进肝纤维化甚至癌变。肿瘤相关巨噬细胞（tumor associated macrophages，TAMs）是一类存在于肿瘤局部缺血区的巨噬细胞，可促进肿瘤的进展和转移。基于VCPLC和SPLC完全不同的转移途径和显著不同的肿瘤微环境，我们假设：（1）与非肝硬化肝脏中的正常库普弗细胞不同，VCPLC的库普弗细胞，一群生活在极度缺血缺氧的血窦中的占优势的肝脏驻留巨噬细胞，可能不起对抗癌细胞的战斗机作用，更糟糕的是，缺血缺氧状态可能刺激枯否细胞分泌细胞因子和趋化因子，如TAMs，促进肿瘤生长和转移：（2）血流障碍而非癌细胞的行为是决定不同转移偏好的主要力量。在VCPLC中，中央小叶静脉被肝硬化结节机械压缩，因此癌细胞不能走到肝外，而是肝动脉-门静脉瘘（HAPVF）和门静脉逆流（PVC）将癌细胞装载到肝内。在SPLC中，癌细胞可以直接在肝外流畅地穿过中央小叶静脉。总之，两种原发性肝癌血流动力学的差异是决定其转移途径选择的主要因素。在肝癌的发生、发展过程中，枯否细胞不应是肿瘤和转移灶的强大防御细胞，而应在长期缺血缺氧应激和肿瘤源性因子的作用下，被驯化为肿瘤相关抗原（TAM），在肿瘤的发生甚至转移中发挥重要作用，因此枯否细胞可能成为防治肝癌发生和转移的新靶点。皇冠版权所有（C）2011由爱思唯尔有限公司出版。保留所有权利。
Viral cirrhotic primary liver cancer (VCPLC) is characterized by intra-hepatic metastasis (IHM) at early stage. By contrast, simple primary liver cancer without cirrhosis (SPLC) has high extra-hepatic metastasis (EHM) rate. Historically, studies on mechanism of metastasis of PLC mainly focused on biological behaviors of cancer cells, however tumor microenvironment is always neglected, especially blood flow dynamics and Kupffer cells. In SPLC, few damages of hepatic lobules occur, to the contrary. VCPLC is characterized by obvious hepatic fibrosis which results in varieties of blood flow disturbances, such as central lobular vein obstruction, hepatic artery-portal vein fistula (HAPVF), and portal vein countercurrent (PVC). Traditionally, Kupffer cells in liver are regarded as powerful defenses against PLC and metastasis lesions in liver, however, recent studies show under long term ischemic-hypoxic stress, Kupffer cells can secrete varieties of pro-inflammatory mediators to promote fibrosis or even cancerogenesis. Tumor associated macrophages (TAMs) are a group of macrophages living in ischemic tumor lesions which can promote tumor progression and metastasis. Based on the totally different metastasis routes and significantly different tumor microenvironment of VCPLC and SPLC, we hypothesize: (1) unlike the normal Kupffer cells in non-cirrhosis liver, Kupffer cells of VCPLC, a group of dominant hepatic resident macrophages living in extremely cirrhotic ischemic-hypoxic sinusoids, might not act as fighters against cancer cells, what is worse, ischemic-hypoxic situation might incite Kupffer cells to secrete cytokines and chemokines, just like TAMs, to promote tumor growth and metastasis: (2) the blood flow disturbances, not the behaviors of cancer cells, are the main force to determine the different metastasis preferences. In VCPLC, central lobular vein is mechanically compressed by cirrhosis nodes, so cancer cells cannot go extra-hepatically, instead, the hepatic artery-portal vein fistula (HAPVF) and portal vein countercurrent (PVC) load cancer cells intra-hepatically. In SPLC, cancer cells can run directly extra-hepatically through central lobular vein fluently. In short, the different blood flow dynamics between these two PLC is the predominant factor to determine the preferences of metastasis route. In VCPLC, the Kupffer cells should not be the powerful defenses against tumor and metastasis lesions, instead, they should be tamed to be some TAMs by long term ischemic-hypoxic stress and tumor derived factors to play important roles in tumorigenesis or even metastasis, so Kupffer cells can be a new target for preventing hepatocancerogenesis and metastasis. Crown Copyright (C) 2011 Published by Elsevier Ltd. All rights reserved.