Abstract 2911: Leptin Notch VEGFR-2 axis influences cancer stromal cell behavior

Abstract

Abstract PURPOSE: Breast cancer cells induce changes in the stromal environment during malignancy. These changes promote growth, angiogenesis, invasion, and metastasis. The secretion of the adipokine, leptin, from adipose tissue has been shown to contribute to cell proliferation, migration and survival. We previously reported that leptin induces Notch, a pro-survival factor and contributor to the VEGF/VEGFR-2 pro-angiogenic system. We hypothesize that the leptin Notch axis induces activation of fibroblast cells and leads to endothelial cell proliferation, tubule formation, and survival. These effects could be related to leptin-induced Notch expression and VEGFR-2 transactivation, independent of VEGF. METHODS: Mouse Embryo Fibroblast cells (NIH/3T3), human umbilical vein endothelial cells (HUVEC) and porcine aorta endothelial cells (PAEC) were challenged with leptin (dose and time-response), and inhibitors of Notch (DAPT) and VEGFR-2 (SU5416 kinase inhibitor). Expression of Notch, VEGFR-2, Ob-R and phosphorylation of VEGFR-2 were determined. The impact of treatment on angiogenic features of endothelial cells was determined. To determine whether leptin-Notch axis activates fibroblast cells, leptin doses 0.6, 1.2, and 6.2 were used. RESULTS: Leptin induced phosphorylation of VEGFR-2 at intracellular site Y1175 and tubule formation in HUVEC. Leptin induced phosphorylation of VEGFR-2 at sites Y951, Y996, Y1059, and Y1175 in PAEC VEGFR2. Protein expression of Notch4 and Jagged1 was induced by leptin treatment in NIH/3t3 cells. CONCLUSION: Leptin secreted by fibroblast cells and/or adipose tissue may contribute to tumor angiogenesis by acting directly on stromal cells and inducing a VEGFR-2/Notch crosstalk. Novel therapies that target leptin signaling could be a new strategy for the prevention and treatment of breast cancer. These therapies could be more relevant for obese cancer patients with high circulating amounts of leptin. Citation Format: Viola Lanier, Merle Jeffers, Johannes Walterberger, Leonard Anderson, Ruben Gonzalez. Leptin Notch VEGFR-2 axis influences cancer stromal cell behavior. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2911. doi:10.1158/1538-7445.AM2015-2911