Peptides derived from type IV collagen, CXC chemokines, and thrombospondin-1 domain-containing proteins inhibit neovascularization and suppress tumor growth in MDA-MB-231 breast cancer xenografts.
Angiogenesis or neovascularization, the process of new blood vessel formation from preexisting microvasculature, involves interactions among several cell types including parenchymal, endothelial cells, and immune cells. The formation of new vessels is tightly regulated by a balance between endogenous proangiogenic and antiangiogenic factors to maintain homeostasis in tissue; tumor progression and metastasis in breast cancer have been shown to be angiogenesis-dependent. We previously introduced a systematic methodology to identify putative endogenous antiangiogenic peptides and validated these predictions in vitro in human umbilical vein endothelial cell proliferation and migration assays. These peptides are derived from several protein families including type IV collagen, CXC chemokines, and thrombospondin-1 domain-containing proteins. On the basis of the results from the in vitro screening, we have evaluated the ability of one peptide selected from each family named pentastatin-1, chemokinostatin-1, and properdistatin, respectively, to suppress angiogenesis in an MDA-MB-231 human breast cancer orthotopic xenograft model in severe combined immunodeficient mice. Peptides were administered intraperitoneally once per day. We have demonstrated significant suppression of tumor growth in vivo and subsequent reductions in microvascular density, indicating the potential of these peptides as therapeutic agents for breast cancer.
Koskimaki
Jacob E
JE
Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Karagiannis
Emmanouil D
ED
Rosca
Elena V
EV
Vesuna
Farhad
F
Winnard
Paul T
PT
Raman
Venu
V
Bhujwalla
Zaver M
ZM
Popel
Aleksander S
AS
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019743:Chemokines, CXC / Q000737:chemistry; D024141:Collagen Type IV / Q000737:chemistry; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000517:prevention & control*; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D019699:Thrombospondins / Q000737:chemistry; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D019743:Chemokines, CXC; D024141:Collagen Type IV; D009842:Oligopeptides; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019699:Thrombospondins