A27
Targeting macrophage migration inhibitory factor in ovarian cancer prevents tumour angiogenesis and increases tumour cell apoptosis
Mónica Escórcio-Correia, Robin Soper, Thorsten Hagemann
Queen Mary's School of Medicine and Dentistry, Centre for Cancer and Inflammation, London, UK
Inflammation is key to the integrity and survival of multi-cellular organisms, but deregulation of this powerful component of the immune system is a characteristic of many chronic pathologies, including cancer. Cytokines appear to be crucial in generating a pro-inflammatory tumour-promoting milieu. Upstream of, or in a network with these mediators is another influential cytokine, macrophage migration inhibitory factor, MIF. In view of our previous findings that tumour cell derived MIF increased macrophage-mediated ovarian cancer cell invasiveness in vitro, we investigated the wider significance of ovarian cancer cell derived MIF for tumour growth, metastasis and angiogenesis.
MIF is expressed in malignant ovarian tumours, and active MIF is found in malignant ascitic fluid. Stable knock-down of MIF in the murine ovarian cancer cell line ID8 decreased in vivo tumour burden and overall survival. Tumours arising from MIF knock-down cells had decreased proliferation and significantly increased apoptosis. This was associated with increased phosphorylation of p53 and reduced Akt phosphorylation. MIF knockdown led to a changed cytokine profile in the ascitic microenvironment: TNF-α, 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 knock-down reduced the expression of pro-angiogenic cytokines VEGF and 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 tumour deposits.
