Oncostatin M Induction of Vascular Endothelial Growth Factor in Human Breast Cancer Cells Promotes Angiogenesis

Publication Date

4-2005

Type of Culminating Activity

Thesis

Degree Title

Master of Science in Biology

Department

Biology

Supervisory Committee Chair

Cheryl Jorcyk

Supervisory Committee Member

Julia Thom Oxford

Supervisory Committee Member

Troy Rohn

Abstract

Oncostatin M (OSM), a multifunctional cytokine belonging to the IL-6 family, is produced by many cell types including human T-Iymphocytes, neutrophils, macrophages and monocytes. OSM has been shown to inhibit the proliferation of breast and other tumor cell lines in vitro, and attention has been given to OSM as a potential cancer therapeutic. Recent studies, however, have shown that OSM may induce cell detachment and invasion in vitro, as well as induce vascular endothelial growth factor (VEGF) in endothelial and astroglioma cells. These results suggest that OSM may play a role in angiogenesis and tumor progression. In this paper we demonstrate that OSM induces VEGF by approximately 4-fold in several human breast cancer cell lines, including MDA- MB-231 and T47D, and that this induction is dose- and time-dependent. Additionally, we show that OSM-induced VEGF is mediated, in part, through STAT3 and HIF1α signaling pathways. Using inhibitors to STAT3 and HIF1α, we demonstrate a novel OSM up-regulation of HIF1α, a potent pro-angiogenic transcription factor, and provide new evidence that this system is also dependent upon STAT3 signaling. To determine the in vitro role of OSM-induced VEGF in neovascularization, we utilized conditioned media collected from both MDA-MB-231 and T47D cells. We show that OSM-treated breast cancer cell media increases tube formation as assayed by an increase in branch points; 57% with OSM-treated MDA-MB-231 and 33% with OSM-treated T47D cells. In addition, OSM-induced VEGF causes dramatic in vitro neovascularization, as measured by a 12-fold increase in Matrigel plug hemoglobin levels. These novel results show the first direct evidence that OSM-induced VEGF in human breast cancer cells occurs through activation of STAT3 and HIF1α, and has a potent pro-angiogenic effect on endothelial cells in vitro and in vivo. Taken together, these results suggest the importance of designing therapeutics to inhibit OSM-induced angiogenesis during breast cancer progression and subsequent metastasis.

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