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John Lattier, Hua Yang, Susan Crawford, Hans Grossniklaus; Host Pigment Epithelium-Derived Factor (PEDF) Prevents Progression of Uveal Melanoma Metastasis in the Liver and Inhibits Formation of Blood Vessels in the Metastatic Microenvironment. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4206.
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The most common form of eye cancer in adults, uveal melanoma has a 5-year mortality rate of 30% primarily due to liver metastasis. Angiogenesis is required for the progression of liver metastasis, thus our lab is focusing on factors that may prevent angiogenesis in the metastasis microenvironment. Pigment epithelium-derived factor (PEDF), a potent anti-angiogenic protein, is produced by liver hepatocytes. Our aim is to analyze the effect of host PEDF on the size, frequency, and mean vascular density of liver metastases in a mouse model of uveal melanoma. We hypothesize that PEDF inhibits the progression of liver metastasis through a mechanism involving angiogenesis.
Transgenic mice lacking one or both copies of PEDF were injected in the posterior compartment of the eye with B16LS9 mouse melanoma cells and monitored for one month while melanoma metastasized to their livers, alongside control C57BL/6 mice. Afterwards, livers were sectioned, stained, and analyzed for metastasis size and frequency, and mean vascular density. All data are reported as n=5.
PEDF-/- mice exhibited a 34.6x increase in metastasis area over PEDF+/+ controls, and PEDF+/- mice showed a 7.1x increase, both significantly greater than wild-type. However, there was no difference in the frequency of metastasis. The number of macrometastases (diameter>200μm) was significantly greater in PEDF-/- mice, with 6 per liver section, while PEDF+/- averaged 2 macrometastases per liver section, and PEDF+/+ averaged 0. The mean vascular density (MVD) was 20.8x greater in PEDF-/- metastases versus controls, while the MVD in PEDF+/- metastases was 7.3x greater than controls. In conclusion, PEDF inhibits the growth, but not frequency, of metastases in a mouse model of uveal melanoma while suppressing the formation of blood vessels, thus preventing the progression to macrometasases.
PEDF is an anti-angiogenic protein secreted by hepatocytes. In our mouse model, the host lacks the ability to synthesize PEDF. Blood vessels rapidly form within the metastases, and the metastases grow much larger. These experiments suggest that host PEDF may be a candidate for therapeutic development for patients with aggressive uveal melanoma due to its ability to inhibit metastasis growth.
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