Impact of cirrhosis on the development of experimental hepatic metastases by B16F1 melanoma cells in C57BL/6 mice

Abstract

Metastases rarely occur in human livers with cirrhosis in clinical studies. We postulated that this phenomenon would also occur in experimental cirrhosis. Cirrhosis was established in C57BL/6 mice by carbon tetrachloride (CCl 4 ) gastrogavage. B16F1 melanoma cells were injected into the mesenteric vein to induce hepatic metastases. Contrary to our postulate, there was greater than 4-fold increase in metastasis in animals with cirrhosis compared to controls. Intravital videomicroscopy showed that the hepatic sinusoids were narrower and more tumor cells were retained in the terminal portal vein ( T he liver is a common site of metastatic tumor growth. Interestingly, the liver with cirrhosis has been reported to inhibit metastasis. 1 In clinical studies, colorectal cancers rarely metastasize to livers with cirrhosis. 2,3 Autopsy studies have shown that the rate of metastasis to such livers is lower than that to normal livers. 4,5 However, the mechanisms responsible for this result are not clear. Vanbockrijck and Kloppel suggested that the lower incidence of metastasis is due to a shorter life expectancy of patients with cirrhosis. 6 Seymour and Charnley considered that venovenous shunting in cirrhosis may prevent tumor cells from reaching the liver, and that changes in the architecture of cirrhotic sinusoids may reduce metastasis. 5 The activation of Kupffer cells in cirrhosis may also inhibit the formation of hepatic metastases. 7 Based on previous studies, the fate of metastatic cells in the liver is determined by the expression of hepatic microvasculature adhesion molecules and the release of endothelial-derived nitric oxide (NO). Specifically, the expression of inducible vascular adhesion molecules can cause tumor cell arrest in terminal portal vein (TPV) and increase metastasis. 8 Alternatively, tumor cell arrest in hepatic sinusoids can induce endothelial and hepatic NO release, causing tumor cell apoptosis and inhibiting metastasis. 9,10 We predicted these mechanisms would apply in a cirrhotic model. To examine this possibility, we established cirrhosis in C57BL/6 mice, using carbon tetrachloride (CCl 4 ) gastrogavage. Liver metastasis was induced by injecting B16F1 melanoma cells into the portal venous system. Surprisingly, we found a significant increase in metastasis of B16F1 melanoma cells in animals with cirrhosis. Our studies demonstrated that alterations

Discoidin domain receptor 2 deficiency predisposes hepatic tissue to colon carcinoma metastasis

“…TGFβ is the most important growth factor involved in liver fibrosis,31 but at the same time, it is a strong immune suppressor,24 a proangiogenic factor32 and promotes metastasis of colorectal cancer cells, thereby acting as an oncogene 36. It has been reported that carbon tetrachloride (CCl 4 )-induced hepatic cirrhosis increased hepatic metastasis 37. Therefore, overexpression of TGFβ may account for growth-stimulating properties of tumour-activated DDR2 −/− HSCs on colorectal cancer cells.…”

The innate immune receptor Dectin-2 mediates the phagocytosis of cancer cells by Kupffer cells for the suppression of liver metastasis

“…We first examined the contribution of Dectin-2 to antitumor immunity by evaluating wild-type (WT) and Dectin-2-deficient (Dectin-2 KO) mice for subcutaneous tumor growth, lung metastasis, and liver metastasis of colon carcinoma cell line SL4, Lewis lung carcinoma cell line 3LL, and melanoma cell line B16F1 and B16F10, all of which have been demonstrated to undergo metastasis in mice (15)(16)(17)(18). We found that Dectin-2 KO mice showed more metastatic nodules in the liver compared with WT mice at 14 d after the intrasplenic inoculation with SL4, B16F1, or B16F10 cells, but not after inoculation with 3LL cells (Fig.…”

The Liver Prometastatic Reaction of Cancer Patients: Implications for Microenvironment-Dependent Colon Cancer Gene Regulation

“…Consistent with these findings, more mitotic and Ki-67-expressing cancer cells were detected in the cirrhotic livers. Taken together the results suggest that microenvironmental changes in the architecture, adhesion molecule expression and NO production levels may cause more cancer cells to arrest, survive and proliferate in the microvasculature of livers with cirrhosis [79].…”

“…Moreover, recent observations argue against the antimetastatic effects of cirrhosis. For example, using intravital videomicroscopy Qi et al [79] showed that the hepatic sinusoids were narrower in cirrhotic livers and more cancer cells were retained in terminal portal veins. This was also consistent with the increased expression of vascular adhesion molecules by sinusoids of cirrhotic livers.…”