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 (TPV) in cirrhotic livers. Immunohistochemistry demonstrated that the expression of vascular adhesion molecules was significantly increased in
cirrhosis. Using confocal microscopy and the fluorescent
nitric oxide (NO) probe
4,5-diaminofluorescein diacetate, a significantly lower level of NO release was detected in livers with
cirrhosis both in basal conditions and after
tumor cell arrest. Eight hours after mesenteric vein
tumor cell injection, the percentage of apoptotic
tumor cells in the sinusoids was 17% +/- 2% in livers with
cirrhosis and 30% +/- 5% in normal livers. More mitotic and Ki-67 labeled
tumor cells were seen in livers with
cirrhosis. In conclusion, the changes in architecture and adhesion molecule expression in livers with
cirrhosis may cause more
tumor cells to arrest in the TPV. Lower levels of NO production may reduce apoptosis of B16F1 cells in livers with
cirrhosis. As a result, these changes may promote the growth of
metastasis in this cirrhotic model.