Inhibition Of Tumor Angiogenesis And Melanoma Growth By Targeting Vascular E-selectin
Zhao-Jun Liu, MD*, Runxia Tian, MD*, Yan Li, MD*, Weijun An, MD*, Ying Zhuge, MD*, Alan S Livingstone, MD, Omaida C Velazquez, MD*
University of Miami, Miami, FL
Objectives: Aggressive human melanomas express CXCR4, the receptor for the chemokine, stromal cell-derived factor-1alpha (SDF-1α). The CXCR4-SDF-1α axis has been postulated to increase melanoma invasiveness. We discovered that SDF-1α specifically upregulates E-selectin on endothelial cells (EC), thus tethering circulating endothelial progenitor cells (EPC) and facilitating homing (Ann Surg. 2010). We investigate the hypothesis that siRNA-mediated E-selectin blockade inhibits melanoma angiogenesis and tumor growth.
Methods: Human melanoma cells overexpressing SDF-1α were xenografted on SCID mice. SDF-1α expression in cells was measured by ELISA. In vitro melanoma cell growth was examined by MTT. In vivo vascular E-selectin knock-down was achieved by administration of high-volume E-selectin siRNA (100pmol/180μl/week for 3 weeks) and inhibition was validated by immunostaining (N=6/group, E-Selectin siRNA vs control siRNA). Tumor angiogenesis was quantified (DiI-perfusion and LASER confocal microscopy). EPC homing to tumor vasculature was detected by immunostaining. Explanted in vivo tumor size and weight were measured.
Results: Primary melanoma cells expressed a range of SDF-1α basal levels. Additional enforced overexpression of SDF-1α (by Lenti-SDF-1α) increased melanoma cell growth both in vitro (P=0.001) and in vivo (P=0.023), enhanced EPC homing to tumor tissue (P=0.045), and increased tumor angiogenesis (P=0.03). Knocking-down vascular E-selectin significantly inhibited SDF-1α-induced EPC homing (P=0.04), tumor angiogenesis (P=0.045), and decreased melanoma growth in vivo (P=0.027).
Conclusions: Down-regulation of vascular E-selectin profoundly inhibits EPC homing, tumor angiogenesis and tumor growth in human melanoma animal model, potentially by suppression of E-selectin-mediated EPC-EC interactions/homing. These findings identify E-selectin as a novel target for inhibition of melanoma angiogenesis and tumor growth.
Back to 2011 Program