Linda Metheny-Barlow Lab

Metheny-Barlow Lab


Linda Metheny-Barlow Lab

The induction of tumor vasculature, known as the “angiogenic switch”, is a key rate-limiting step in tumor progression and the resulting acquisition of a tumor blood supply typically correlates with poor prognosis in breast cancer.  Thus, targeting angiogenesis may be an effective therapeutic strategy, as underscored by the recent clinical success of anti-VEGF therapies.  Despite these promising results, there remains a need to increase the strategies used for anti-angiogenic modalities, with the hopes of circumventing pro-angiogenic signaling redundancies and improving the efficacy of treatments for breast and other tumors. 

My work involves the study of factors that control the proliferation of the endothelium and the identification of strategies to therapeutically inhibit pathological angiogenesis.  In a normal mature vessel, the endothelium is supported by mural cells (smooth muscle cells or pericytes) that function, in part, to maintain quiescence of the vessel; this mural cell-mediated inhibition of endothelial proliferation is thought to require close physical and functional contact between the two cell types.  In contrast, the proliferative vessels characteristic of tumors frequently lack this close physical mural cell support and can therefore respond to angiogenic signals.  Overexpression of Angiopoietin-1 (Ang-1) restores mural cell support to breast tumor vessels, thereby inhibiting angiogenesis and preventing tumor growth.  One ongoing project will examine the mechanism(s) by which Ang-1 influences paracrine interactions between breast cancer cells, mural cells, and endothelial cells to prevent angiogenic activation and identify strategies to enhance mural cell support to tumor vessels.  Importantly, this restoration of mural cell support to tumor vessels may also serve to inhibit metastasis and enhance the efficacy of standard chemotherapy and radiation therapy.  We have further identified that a molecule termed Vascular Endothelial Growth Inhibitor (VEGI) is upregulated in endothelial cells that are growth arrested by functional mural cell contact.  Recombinant VEGI protein has been shown to potently inhibit angiogenic responses in vitro and invivo.  A second project focuses on elucidation of the signal transduction pathways utilized by VEGI to induce or maintain endothelial cells in a quiescent state and thereby inhibit angiogenesis.  


Last Updated: 01-06-2015
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