This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Culp, W. D. Articles by Garland, D. Search for Related Content PubMed PubMed Citation Articles by Culp, W. D. Articles by Garland, D.

---

Angiogenesis, Metastasis, and the Cellular Microenvironment

Interference of Macrophage Migration Inhibitory Factor Expression in a Mouse Melanoma Inhibits Tumor Establishment by Up-Regulating Thrombospondin-1

¹ National Eye Institute, NIH, Bethesda, Maryland and ² Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Hospital/Institute, Stockholm, Sweden

Requests for reprints: Donita Garland, Scheie Eye Institute, FM Kirby Center for Molecular Ophthalmology, University of Pennsylvania, 306 Stellar Chance Labs, 422 Curie Boulevard, Philadelphia, PA, 19104-6100. Phone: 215-573-4317; Fax: 215-573-8083. E-mail: garland1{at}mail.med.upenn.edu

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine with proinflammatory, proangiogenic, and protumorigenic properties. The molecular mechanisms underlying the role of MIF in tumorigenesis and angiogenesis are not well understood. To address these roles, an interfering MIF (iMIF) RNA was stably introduced into the B16-F10 mouse melanoma cell line, reducing MIF mRNA expression 1.6-fold and MIF protein expression 2.8-fold relative to control cells. When iMIF cells were subcutaneously injected into C57BL/6 mice, tumor establishment was significantly delayed and there was a marked absence of intratumoral vasculature in iMIF tumors relative to controls. A comparative gene expression analysis of iMIF and control melanoma cell lines revealed that thrombospondin-1 (TSP-1) mRNA expression was up-regulated 88-fold in the iMIF cells by real-time PCR. A 2-fold increase in TSP-1 protein levels was observed in iMIF cell culture supernatants. These results strongly suggest that the delayed tumor establishment and reduced vasculature in iMIF melanomas are linked to the up-regulation of the antiangiogenic TSP-1. They further define a novel function of MIF as a regulator of TSP-1 in a mouse melanoma model. (Mol Cancer Res 2007;5(12):1225–31)