A new view of the roles of blood flow dynamics and Kupffer cell in intra-hepatic metastasis of hepatocellular carcinoma

Abstract

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.