Host Pigment Epithelium-Derived Factor (PEDF) Prevents Progression of Uveal Melanoma Metastasis in the Liver

摘要

Uveal melanoma (UM) has a 30% five-year mortality rate, primarily due to liver metastasis. Both angiogenesis and stromagenesis are important mechanisms for the progression of liver metastasis. Pigment epithelium-derived factor (PEDF), an anti-angiogenic and anti-stromagenic protein, is produced by hepatocytes. Exogenous PEDF suppresses metastasis progression; however, the effects of host-produced PEDF on metastasis progression are unknown. We hypothesize that host PEDF inhibits liver metastasis progression through a mechanism involving angiogenesis and stromagenesis. Mouse melanoma cells were injected into the posterior ocular compartment of PEDF-null mice and control mice. After one month, the number, size, and mean vascular density (MVD) of liver metastases were determined. The stromal component of hepatic stellate cells (HSCs) and the type III collagen they produce was evaluated by immunohistochemistry. Host PEDF inhibited the total area of liver metastasis and the frequency of macrometastases (diameter >200μm) but did not affect the total number of metastases. Mice expressing PEDF exhibited significantly lower MVD and less type III collagen production in metastases. An increase in activated HSCs was seen in the absence of PEDF, but this result was not statistically significant. In conclusion, host PEDF inhibits the progression of hepatic metastases in a mouse model of UM, and loss of PEDF is accompanied by an increase in tumor blood vessel density and type III collagen.