Ischemia/reperfusion accelerates the outgrowth of hepatic micrometastases in a highly standardized murine model

Abstract

Mortality in colorectal cancer is associated with the development of liver metastases. Surgical removal of these tumors is the only hope for cure, but recurrence is common. During liver surgery, ischemia/reperfusion (I/R) often occurs as a result of hemorrhage or vascular clamping. Although the adverse effects of I/R on postoperative liver function are well documented, the influence of I/R on the outgrowth of residual micrometastases is unknown. We used a highly standardized mouse model of partial hepatic I/R to study the effects of I/R on the outgrowth of preestablished colorectal micrometastases. Five days following intrasplenic injection of C26 colon carcinoma cells, the vascular structures of the left lobe were clamped for 45 minutes under hemodynamically stable conditions. Tissue glutathione, plasma liver enzymes, hepatocellular necrosis, and tumor growth were assessed over time. I/R caused oxidative stress and early liver tissue damage. The outgrowth of micrometastases in occluded liver lobes was accelerated five-to sixfold compared with nonoccluded lobes and was associated with areas of necrotic liver tissue surrounded by inflammatory cells and apoptotic hepatocytes. Accelerated tumor growth and tissue necrosis were completely prevented by occluding blood flow intermittently. In contrast, ischemic preconditioning or treatment with the antioxidants ␣-tocopherol or ascorbic acid failed to protect against late tissue necrosis and tumor growth, although early hepatocellular damage was largely prevented by these methods. In conclusion, I/R is a strong stimulus of recurrent intrahepatic tumor growth. Measures to prevent I/R-induced late tissue necrosis cross-protect against this phenomenon. (HEPATOLOGY 2005;42:165-175.)

Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress

“…The first set of experiments were designed to evaluate whether I/R increased tumor growth in a model of circulating micrometastases. Colorectal liver metastases were induced in mice as previously described (7,8). In brief, 5×10 4 MC38 or MC38/Luc cells were injected through a 1 cm midline laparotomy into the spleen of 8-10 week old C57BL/6J WT mice or PAD4 −/− mice (19) using a 27ga.…”

Inferior survival in liver transplant recipients with hepatocellular carcinoma receiving donation after cardiac death liver allografts

“…IRI has been previously shown to stimulate the growth of micrometastases and increase the adhesion of tumor cells in nontransplant settings. 11,12 Murine animal models have shown that micrometastases are accelerated 5-to 6-fold in liver segments undergoing temporary vascular occlusion versus nonoccluded lobes. 12 In addition, others have suggested that IRI of a small liver remnant exacerbates liver tumor growth and metastasis through a marked activation of cell adhesion, invasion, and angiogenesis pathways.…”

“…11,12 Murine animal models have shown that micrometastases are accelerated 5-to 6-fold in liver segments undergoing temporary vascular occlusion versus nonoccluded lobes. 12 In addition, others have suggested that IRI of a small liver remnant exacerbates liver tumor growth and metastasis through a marked activation of cell adhesion, invasion, and angiogenesis pathways. 13 The surgical stress resulting from hepatic IRI not only makes the hepatic microenvironment favorable for tumor cell growth, migration, and invasion through the stimulation of an acute-phase inflammatory response and the disturbance of microcirculatory barrier function but also may promote local and distant metastases by directly activating cell migration and invasion pathways within the tumor cell itself.…”

Perinecrotic Hypoxia Contributes to Ischemia/Reperfusion-Accelerated Outgrowth of Colorectal Micrometastases

“…[13][14][15] Moreover, we have recently demonstrated that the outgrowth of pre-established micrometastases was strongly stimulated after I/R in a murine model. 16 The mechanisms that contribute to this phenomenon are unknown.…”