Ovarian cancer cell-derived migration inhibitory factor enhances tumor growth, progression, and angiogenesis.
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-alpha, 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.
Hagemann
Thorsten
T
Queen Mary's Medical School, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, United Kingdom. t.hagemann@qmul.ac.uk
Robinson
Stephen C
SC
Thompson
Richard G
RG
Charles
Kellie
K
Kulbe
Hagen
H
Balkwill
Frances R
FR
D000818:Animals; D001201:Ascites / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000473:pathology; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000473:pathology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D008263:Macrophage Migration-Inhibitory Factors; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt