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Angiogenesis, Metastasis, and the Cellular Microenvironment

Lipocalin 2 Antagonizes the Proangiogenic Action of Ras in Transformed Cells

Renal Division and Center for Study of the Tumor Microenvironment, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts

Requests for reprints: Vikas P. Sukhatme, Beth Israel Deaconess Medical, 330 Brookline Avenue, RW 563, Boston, MA 02215. E-mail: vsukhatm{at}bidmc.harvard.edu

Lipocalin 2 is an iron-binding secreted protein that converts embryonic kidney mesenchyme to epithelia. Previously, we reported that lipocalin 2 could revert 4T1-ras-transformed mesenchymal tumor cells to a more epithelial phenotype, increase E-cadherin expression, and suppress cell invasiveness in vitro and in vivo, indicating that lipocalin 2 is a metastasis suppressor. Here, we show that lipocalin 2 can suppress the ras-induced expression of vascular endothelial growth factor in 4T1 cells via down-regulation of ras mitogen-activated protein kinase and ras phosphatidylinositol-3-kinase signaling. In addition, the expression of thrombospondin-1 (an antiangiogenic molecule) was increased in tumors formed by 4T1-ras cells into which lipocalin 2 was stably introduced. Tumor angiogenesis, assessed via an intradermal tumor angiogenesis assay, was also suppressed by lipocalin 2. We also show that caveolin-1 is a critical mediator of this activity. These data provide new insights into the action of lipocalin 2 and raise the possibility that the administration of lipocalin 2 may be useful for inhibiting tumor angiogenesis, in addition to suppressing tumor metastasis, in cancers which show ras activation. (Mol Cancer Res 2006;4(11):821–9)

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