Host pigment epithelium-derived factor (PEDF) prevents progression of liver metastasis in a mouse model of uveal melanoma

• Type of Material: Article
• Authors: John M. Lattier, Emory University; Hua Yang, Emory University; Susan Crawford, University of St. Louis; Hans Grossniklaus, Emory University
• Language: English
• Date: 2013-12-01
• Publisher: Springer (part of Springer Nature): Springer Open Choice Hybrid Journals
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Springer Science+Business Media Dordrecht.
• Final Published Version (URL): http://dx.doi.org/10.1007/s10585-013-9596-3
• Title of Journal or Parent Work: Clinical and Experimental Metastasis
• ISSN: 0262-0898
• Volume: 30
• Issue: 8
• Start Page: 969
• End Page: 976
• Grant/Funding Information: Supported in part by NIH R01 CA17006 (HEG), P3006360 (HEG), unrestricted departmental grant from Research to Prevent Blindness, Inc, New York, NY
• Keywords: IDENTIFICATION; Uveal melanoma; TUMOR-ASSOCIATED MACROPHAGES; Angiogenesis; OCULAR MELANOMA; DEPENDENT PROBE AMPLIFICATION; EXPRESSION; PEDF; HEPATIC STELLATE CELLS; Oncology; MICROMETASTASES; Stromagenesis; Metastasis; RECEPTOR; SURVIVAL; Science & Technology; Life Sciences & Biomedicine; GROWTH-FACTOR VEGF
• Research Categories: Health Sciences, Pathology; Health Sciences, Oncology

Abstract

Uveal melanoma (UM) has a 30 % 5-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 1 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 >200 μm) 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.