Zhao-Jun Liu, Yurong Tan, Hongwei Shao, Yan Li, Omaida C. Velazquez
Surgery, University Miami, Miami, FL.
OBJECTIVES: Wnt-induced secreted protein-1 (WISP-1/CCN4) is involved in regulating cell proliferation, survival/apoptosis, migration and tumor growth. We previously observed that tumor stroma-produced WISP-1/CCN4 plays a critical role in melanoma growth and tumor angiogenesis. We sought to determine the biologic effect of WISP-1/CCN4 on endothelial cell biology and angiogenesis.
METHODS: The effects of WISP-1/CCN4 on cell growth and migration of human endothelial cells (EC) were examined by MTT and transwell-migration assay. Two- and three-dimensional (2-D and 3-D) angiogenesis models were used to study the role of WISP-1/CCN4 in vascular network formation of EC. Melanoma xenograft murine model was employed to examine the biological effect of WISP-1/CCN4 on tumor angiogenesis and growth. Human melanoma cells transduced with WISP-1/lentivirus or GFP/lentivirus were xenografted on skin of SCID mice (n=6/group). Expression of exogenous WISP-1/CCN4 in transduced melanoma cells was validated by Western blot. Tumor angiogenesis was assessed by mouse whole-body Dil-perfusion and tumor tissue confocal microscopy. Tumor size was measured to determine tumor growth.
RESULTS: WISP-1/CCN4 inhibited cell growth and migration of EC in vitro. Vascular network formation of EC in 2-D and 3-D angiogenesis models was suppressed considerably (p< 0.01) by supplementation of γhWISP-1 (100 ng/ml) in both Matrigel (2-D) and type I collagen gel (3-D). Elevated expression of WISP-1 in tumor tissue significantly antagonized tumor angiogenesis and retarded tumor growth in vivo.
CONCLUSIONS: Our results revealed a novel role of WISP-1/CCN4 in negatively regulating endothelial cell biology and angiogenesis, implicating that WISP-1/CCN4 may serve as a novel target for cancer therapeutic intervention.
AUTHOR DISCLOSURES: Y. Li: Nothing to disclose; Z. Liu: Nothing to disclose; H. Shao: Nothing to disclose; Y. Tan: Nothing to disclose; O. C. Velazquez: Nothing to disclose.
Posted April 2013