Dual-function synthetic peptide derived from BMP4 for highly efficient tumor targeting and antiangiogenesis

Abstract

Angiogenesis plays a critical role in the growth and metastasis of cancer, and growth factors released from cancer promote blood-vessel formation in the tumor microenvironment. The angiogenesis is accelerated via interactions of growth factors with the high-affinity receptors on cancer cells. In particular, heparan sulfate proteoglycans (HSPGs) on the surface of cancer cells have been shown to be important in many aspects of determining a tumor’s phenotype and development. Specifically, the regulation of the interactions between HSPGs and growth factors results in changes in tumor progression. A peptide with heparin-binding (HBP) activity has been developed and synthesized to inhibit tumor growth via the prevention of angiogenesis. We hypothesized that HBP could inhibit the interaction of growth factors and HSPGs on the surface of cancer cells, decrease paracrine signaling in endothelial cells (ECs), and finally decrease angiogenesis in the tumor microenvironment. In this study, we found that HBP had antiangiogenic effects in vitro and in vivo. The conditioned media obtained from a breast cancer cell line treated with HBP were used to culture human umbilical vein ECs (HUVECs) to evaluate the antiangiogenic effect of HBP on ECs. HBP effectively inhibited the migration, invasion, and tube formation of HUVECs in vitro. In addition, the expressions of angiogenesis-mediating factors, including ERK, FAK, and Akt, were considerably decreased. HBP also decreased the levels of invasive factors, including MMP2 and MMP9, secreted by the HUVECs. We demonstrated significant suppression of tumor growth in a breast cancer xenograft model and enhanced distribution of HBP at the site of tumors. Taken together, our results show that HBP has antiangiogenic effects on ECs, and suggest that it may serve as a potential antitumor agent through control of the tumor microenvironment.

Keywords:

• heparin-binding peptide
• HBP
• antiangiogenesis
• heparan sulfate proteoglycans
• HSPGs
• endothelial cells
• breast cancer xenograft
• tumor microenvironment

Acknowledgments

This study was supported by a National Research Foundation of Korea Grant, through the Oromaxillofacial Dysfunction Research Center for the Elderly (2012000912) at Seoul National University, and in part by the Bio and Medical Technology Development Program of the National Research Foundation (NRF), funded by the Ministry of Science, ICT, and Future Planning (2014M3A9E3064430, 2012M3 A9C6049727).

Disclosure

The authors report no conflicts of interest in this work.