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Hua Yang, Qing Zhang, Hans E. Grossniklaus; Angiogenic Homeostasis Maintains Mouse Ocular Micrometastasis Melanoma Dormancy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1460.
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© ARVO (1962-2015); The Authors (2016-present)
Approximately 50% of patients with uveal melanoma will develop metastases within 15 years after treatment of the primary ocular tumor. Hepatic micrometastatic emergence from dormancy leads to tumor progression and mortality. Thus, understanding how metastatic uveal melanoma cells become and remain dormant, may lead to new strategies to prevent emergence from dormancy. The purpose of this study is to investigate whether host hepatic angiogenic homeostasis affect the status of metastasis from ocular melanoma.
B16LS9 cells were inoculated into the posterior ocular compartments of PEDF null mice and gene background control C57BL6 mice. At the 5th or 7th day after inoculation, the inoculated eye was histologically examined for presence of melanoma. At the 5th or 28th day, the mice were sacrificed and the sizes of the hepatic micrometastases were measured with Image J. Immunohistochemical staining for Ki67 and CD31 were performed on the hepatic sections. Blood samples were collected at the day before inoculation, 5th day and 21st day after inoculation. PEDF and VEGF protein levels were determined by ELISA.
There were statistical significant differences in the size of hepatic metastasis at the 5th day between PEDF null mice and C57BL6 (p=0.020), and in the size of hepatic metastasis at the 5th day and 28th day in PEDF knockout mice (p=0.042), but no difference in C57BL6 controls (p=0.425). There were no metastases greater than 200 µm in diameter in C57BL6 mice, whereas there were in PEDF null mice at the 5th day and 28th days after inoculation. Expression of Ki67 and CD31 in hepatic metastasis of PEDF null mice was greater than C57BL/6 mice. Sera VEGF levels were increased at 5 day and 3 weeks, comparing with before inoculation. In PEDF null mice, sera PEDF was not detected at any time point, but was persistently elevated thus maintaining a PEDF/VEGF ratio in C57BL6 control mice.
Homeostasis of PEDF and VEGF maintains the inhibition of angiogenesis in hepatic micrometastases and is an important mechanism of tumor dormancy. Disruption of this angiogenesis balance plays a key role in metastatic progression in our ocular melanoma mouse model. This understanding may provide a new strategy to prolong survival time for the patients after successful primary ocular melanoma therapy.
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