Inhibition of Lymphangiogenesis and Angiogenesis in Breast Tumor Xenografts and Lymph Nodes by a Peptide Derived from Transmembrane Protein 45A

Abstract

Angiogenesis, the formation of new blood vessels from preexisting blood vessels, is a process that supports tumor growth and metastatic dissemination. Lymphangiogenesis also facilitates metastasis by increasing dissemination through the lymphatic vessels (LVs). Even after treatment with antiangiogenic agents, breast cancer patients are vulnerable to LV-mediated metastasis. We report that a 14-amino acid peptide derived from transmembrane protein 45A shows multimodal inhibition of lymphangiogenesis and angiogenesis in breast cancer. The peptide blocks lymphangiogenic and angiogenic phenotypes of lymphatic and blood endothelial cells induced by tumor-conditioned media prepared from MDA-MB-231 breast cancer cells. The peptide delays growth of MDA-MB-231 tumor xenografts and normalizes tumor-conditioned lymph nodes (LNs). These studies demonstrate the antilymphangiogenic and antiangiogenic potential of the peptide against primary tumors and premetastatic, tumor-conditioned regional LNs. Mechanistically, the peptide blocks vascular endothelial growth factor receptors 2 and 3 (VEGFR2/3) and downstream proteins by binding to neuropilin 1/2 (NRP1/2) and inhibiting VEGFR2/3 and NRP1/2 complex formation in the presence of VEGFA/C.