Dual-function synthetic peptide derived from BMP4 for highly efficient tumor targeting and antiangiogenesis.
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.
Department of Dental Regenerative Biotechnology, Dental Research Institute.
Suk Hyun
SH
Choi
Central Research Institute, Nano Intelligent Biomedical Engineering Corporation (NIBEC), School of Dentistry, Seoul National University, Seoul.
Jue Yeon
JY
Lee
Department of Dental Regenerative Biotechnology, Dental Research Institute.
Jin Sook
JS
Suh
Department in Microbiology, School of Biological Sciences, College of Natural Sciences, Chungbuk National University, Cheongju, South Korea.
Yoon Shin
YS
Park
Central Research Institute, Nano Intelligent Biomedical Engineering Corporation (NIBEC), School of Dentistry, Seoul National University, Seoul.
Chong Pyoung
CP
Chung
Department of Dental Regenerative Biotechnology, Dental Research Institute.
Yoon Jeong
YJ
Park
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006493:Heparin / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D034421:Sus scrofa; D014018:Tissue Distribution / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D055415:Bone Morphogenetic Protein 4; D010455:Peptides; D006493:Heparin; D020778:Matrix Metalloproteinase 2
HBP; HSPGs; antiangiogenesis; breast cancer xenograft; endothelial cells; heparan sulfate proteoglycans; heparin-binding peptide; tumor microenvironment
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