Surgical Stress and Tumor Behavior: Impact of Ischemia-Reperfusion and Hepatic Resection on Tumor Progression (2007)

In this issue of Liver Transplantation, the article from the University of Hong Kong by Man et al.1 introduces potentially important concepts related to the mechanisms involved in tumor progression associated to surgical stress, specifically hepatic ischemia-reperfusion and major hepatic resection. This study attempted to determine the molecular mechanisms involved in enhanced tumor progression exhibited in the remnant liver following ischemia-reperfusion and major hepatic resection. To study the effects of ischemia-reperfusion and major hepatic resection, the expression of mitogenic/cell cycle–associated molecules (Rho-associated coil-containing protein kinase [ROCK], Cdc42, proliferating cell nuclear antigen [PCNA]), adhesion-associated molecule (FAK), and angiogenic factors (early growth response-1 [Egr-1]/VEGF) in tumor tissues and cells were evaluated. The data generated on the expression of these markers have provided evidence which indicates that hepatic surgical stress, such as ischemia-reperfusion and major hepatic resection, stimulate tumor cell invasion, migration, and metastasis. However, it is clear that further studies are needed to address the precise significance of the expression of these molecules in relation to tumor progression. The mechanisms of tumor progression are complex. Therefore, the results of the experiments reported in this study must be regarded as preliminary. Nevertheless, the findings in this study may help to elucidate the mechanisms involved and the nature of tumor progression; and, in addition, the findings suggest future therapeutic approaches. Much attention has been devoted to understanding the mechanisms of postischemic liver damage. In this context, oxidative stress-mediated cell/tissue damage must be considered. Oxidative stress during ischemia-reperfusion was first studied in the early 1980s.2-4 Since then, xanthine oxidase-/neutrophil-induced oxidative stress has been extensively studied as a major cause of organ damage after reperfusion.4, 5 In the 1990s, more attention has been paid to harmful cellular reactive oxygen species (ROS), and their origin. Cellular ROS of nonphagocytic cells are believed to originate in mitochondria6, 7 and/or membrane-associated Nox (nicotineamide adenine dinucleotide phosphate [NADPH]-oxidases) oxidase.8, 9 It has been established that redox-sensitive molecules play major roles in various pathophysiological processes,10-13 with the result that the concept of oxidative stress to cells and organs has undergone dramatic changes. In general, ROS from: 1) NADPH oxidase (neutrophils/phagocytes); 2) the mitochondrial respiratory complex14; and 3) Nox oxidase (nonphagocytic cells) can explain the mediation of oxidative stress during ischemia and after reperfusion. ROS from the first 2 of these sources are considered to be important in mediating cell damage (apoptosis or necrosis), and ROS from the third source may be responsible for redox-dependent signal transduction that leads to apoptosis and proliferation (Fig. 1). Schematic scheme illustrating the effects of hepatic ischemia-reperfusion and major hepatic resection on liver cell injury and proliferation. Cellular ROS activate some redox-dependent signals and may regulate certain cell functions.15 Rac1 small guanosine triphosphatase (GTPase) and the gp91 component of NADPH oxidase/Nox are essential for activation of oxidase10; the former is definitely responsible for the regulation of oxidase activity.16, 17 Rac1, if bound to guanosine triphosphate, activates Nox and mediates oxidative stress in cells; this process may lead to malignant transformation in some cells.8, 9, 18, 19 In general, tumor cells possess antiapoptotic/antioxidant properties, which appear to be unique characteristics that facilitate their survival.20-22 Potentially, tumor cells are more likely to survive ischemia-reperfusion–induced damage than normal liver cells (Fig. 2). When angiogenic EGR-1/VEGF and adhesion-associated FAK are upregulated in tumor tissue, and the microvascular environment is disrupted in peritumor liver tissue, as reported in this study by Man et al.,1 further invasion of the tumor and metastasizing of the tumor to remote organs will be facilitated. Putative mechanisms of tumor cell survival, progression, and metastasis after surgical stress to the liver (ischemia-reperfusion, major resection). ROS, reactive oxygen species. Liver regeneration after hepatic resection has also been extensively studied. In particular, the mechanisms underlying the initiation, maintenance, and termination of liver regeneration have been investigated in vivo using animal models.23-26 After hepatic resection, various molecules are induced and/or secreted that promote regeneration by various cells and organs, including the liver. In the liver, gut-derived factors, such as lipopolysaccharide, are upregulated after hepatic resection and are delivered to the liver via the portal venous system. These factors activate hepatic nonparenchymal cells (including Kupffer cells and stellate cells). Kupffer cells and stellate cells secrete interleukin-6/tumor necrosis factor-alpha and hepatocyte growth factor/tumor growth factor-beta, respectively, in response to hepatic resection. With regard to extrahepatic organs, the thyroid, pancreas, adrenal gland, and duodenum secrete triiodothronine, insulin, norepinephrine, and epidermal growth factor, respectively, and, in addition, platelets secrete serotonin23 (Fig. 1). It appears that the autonomic nervous system must be involved in liver regeneration though the exact mechanism is still unclear. There are many reports describing an inhibitory effect of vagotomy on liver regeneration.27, 28 In this context it may be relevant that acetylcholine (Ach) receptors have been reported on hepatocytes, Kupffer cells, and hepatic sinusoidal cells.29-31 Tumor progression may be influenced by humoral regulation, which may be mediated by hormones, growth factors, and cytokines. Some tumors, such as those arising in lung, breast, prostate, liver, colon, and rectum appear to be subject to humoral regulation of their growth. Hence these tumors may be suitable targets for cancer therapy with antihumoral regimens.32-40 Thus, proinflammatory cytokines induced by ischemia-reperfusion and hormones released from extrahepatic organs after hepatic resection may promote progression of liver tumors and metastasizing of these tumors. In conclusion, ischemia-reperfusion tends to disrupt normal liver tissue, including the microvasculature, and to create an environment that may promote tumor progression. Antiapoptotic/antioxidative tumor cells will be induced by direct oxidative mitogenic stimuli as well as by indirect proinflammatory cytokine stimuli. In addition, hepatic resection will induce tumor cells to become more aggressive by promoting production of cytokines by nonparenchymal liver cells and/or secretion of hormones by extrahepatic tissues (Figs. 1 and 2). The study by Man et al.1 may lead to an improved understanding of the steps of tumor progression in various surgical settings. We thank Ms. K. Kaga for her excellent illustrations.