Faculty Collaboration Database

Pigment epithelium-derived factor stimulates tumor macrophage recruitment and is downregulated by the prostate tumor microenvironment. Neoplasia 2010 Apr;12(4):336-45

Date

04/03/2010

Pubmed ID

20360944

Pubmed Central ID

PMC2847741

DOI

10.1593/neo.92046

Scopus ID

2-s2.0-77951675551 (requires institutional sign-in at Scopus site)   41 Citations

Abstract

Pigment epithelium-derived factor (PEDF) is a potent inhibitor of angiogenesis but whether it has additional effects on the tumor microenvironment is largely unexplored. We show that overexpression of PEDF in orthotopic MatLyLu rat prostate tumors increased tumor macrophage recruitment. The fraction of macrophages expressing inducible nitric oxide synthase, a marker of cytotoxic M1 macrophages, was increased, suggesting that PEDF could enhance antitumor immunity. In addition, PEDF overexpression reduced vascular growth both in the tumor and in the surrounding normal tissue, slowed tumor growth, and decreased lymph node metastasis. Contrary, extratumoral lymphangiogenesis was increased. PEDF expression is, for reasons unknown, often decreased or lost during prostate tumor progression. When AT-1 rat prostate tumor cells, expressing high levels of PEDF messenger RNA (mRNA) and protein, were injected into the prostate, PEDF is markedly downregulated, suggesting that factors in the microenvironment suppressed its expression. One such factor could be macrophage-derived tumor necrosis factor alpha (TNFalpha). A fraction of the accumulating macrophages expressed TNFalpha, and TNFalpha treatment downregulated the expression of PEDF protein and mRNA in prostate AT-1 tumor cells in vitro and in the rat ventral prostate in vivo. PEDF apparently has multiple effects in prostate tumors: it suppresses angiogenesis and metastasis, but it also causes macrophage accumulation. Accumulating macrophages may inhibit tumor growth, but they may also suppress PEDF and enhance lymph angiogenesis and, in this way, eventually enhance tumor growth.

Author List

Halin S, Rudolfsson SH, Doll JA, Crawford SE, Wikström P, Bergh A

Author

Jennifer A. Doll PhD Assistant Professor in the Biomedical Sciences department at University of Wisconsin - Milwaukee

MESH terms used to index this publication - Major topics in bold

Animals
Carcinoma
Cell Movement
Cell Proliferation
Cytokines
Down-Regulation
Eye Proteins
Gene Expression Regulation, Neoplastic
Lymphatic Metastasis
Macrophages
Male
Neoplasm Transplantation
Neovascularization, Pathologic
Nerve Growth Factors
Prostatic Neoplasms
Rats
Serpins
Transfection
Tumor Necrosis Factor-alpha