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Research Articles

Ovarian cancer cell–derived migration inhibitory factor enhances tumor growth, progression, and angiogenesis

Centre for Translational Oncology, Institute of Cancer and Cancer Research United Kingdom Clinical Cancer Centre, Barts and The London, Queen Mary's Medical School, London, United Kingdom

Requests for reprints: Thorsten Hagemann, Centre for Translational Oncology, Institute of Cancer and Cancer Research United Kingdom Clinical Cancer Centre, Barts and The London, Queen Mary's Medical School, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, United Kingdom. Phone: 44-20-78826108; Fax: 44-20-78826110. E-mail: t.hagemann{at}qmul.ac.uk

Abstract

In view of our previous findings that tumor cell–derived macrophage migration inhibitory factor (MIF) increased macrophage-mediated ovarian cancer cell invasiveness in vitro, we investigated the wider significance of ovarian cancer cell–derived MIF for tumor growth, metastasis, and angiogenesis. We found that MIF is expressed in borderline and malignant ovarian tumors, and active MIF is found in malignant ascitic fluid. We next investigated the expression and function of MIF in a syngeneic ovarian cancer model. Stable knockdown of MIF in the murine ovarian cancer cell line ID8 decreased in vivo tumor burden and overall survival. Tumors arising from MIF knockdown cells had decreased proliferation and significantly increased apoptosis. This was associated with an increased phosphorylation of p53 and reduced Akt phosphorylation. MIF knockdown led to a changed cytokine profile in the ascitic microenvironment; tumor necrosis factor-, interleukin-6 (IL-6), and IL-10 expression were all significantly decreased. Accompanying this decrease in cytokine expression was a significant decrease in macrophage infiltration into ascites. Additionally, MIF knockdown reduced the expression of proangiogenic cytokines vascular endothelial growth factor and keratinocyte chemoattractant (KC) and reduced the amount of endothelial cells in the malignant ascites. We conclude that autocrine production of MIF by ovarian cancer cells stimulates other cytokines, chemokines, and angiogenic factors that may promote colonization of the peritoneum and neovascularization of tumor deposits. [Mol Cancer Ther 2007;6(7):1993–2002]

Grant support: T. Hagemann was supported by Marie-Curie Intra-European Fellowship, Cancer Research United Kingdom and Cancer Research Committee of St. Bartholomew's Hospital. S. Robinson was supported by Cancer Research United Kingdom. K. Charles was supported by Centocor Inc. H. Kulbe was supported by Cancer Research United Kingdom. F. Balkwill is funded by the Higher Education Funding Council for England.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: T. Hagemann and S.C. Robinson contributed equally to this work.

¹ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

² N.F. Li, personal communication.

³ R. Payne, personal communication.

Received 2/21/07; revised 4/13/07; accepted 5/25/07.