title: Endoglin targeting inhibits tumor angiogenesis and metastatic spread in breast cancer.
abstract: Endoglin, a transforming growth factor-β co-receptor, is highly expressed on angiogenic endothelial cells in solid tumors. Therefore, targeting endoglin is currently being explored in clinical trials for anti-angiogenic therapy. In this project, the redundancy between endoglin and vascular endothelial growth factor (VEGF) signaling in angiogenesis and the effects of targeting both pathways on breast cancer metastasis were explored. In patient samples, increased endoglin signaling after VEGF inhibition was observed. In vitro TRC105, an endoglin-neutralizing antibody, increased VEGF signaling in endothelial cells. Moreover, combined targeting of the endoglin and VEGF pathway, with the VEGF receptor kinase inhibitor SU5416, increased antiangiogenic effects in vitro and in a zebrafish angiogenesis model. Next, in a mouse model for invasive lobular breast cancer, the effects of TRC105 and SU5416 on tumor growth and metastasis were explored. Although TRC105 and SU5416 decreased tumor vascular density, tumor volume was unaffected. Strikingly, in mice treated with TRC105, or TRC105 and SU5416 combined, a strong inhibition in the number of metastases was seen. Moreover, upon resection of the primary tumor, strong inhibition of metastatic spread by TRC105 was observed in an adjuvant setting. To confirm these data, we assessed the effects of endoglin-Fc (an endoglin ligand trap) on metastasis formation. Similar to treatment with TRC105 in the resection model, endoglin-Fc-expressing tumors showed strong inhibition of distant metastases. These results show, for the first time, that targeting endoglin, either with neutralizing antibodies or a ligand trap, strongly inhibits metastatic spread of breast cancer in vivo.
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Paauwe
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: R C
authors.initials: RC
authors.lastname: Heijkants
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: C H
authors.initials: CH
authors.lastname: Oudt
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: G W
authors.initials: GW
authors.lastname: van Pelt
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Cui
authors.affiliation: Tracon Pharmaceuticals, San Diego, CA, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Theuer
authors.affiliation: Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: J C H
authors.initials: JC
authors.lastname: Hardwick
authors.affiliation: Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: C F M
authors.initials: CF
authors.lastname: Sier
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: L J A C
authors.initials: LJ
authors.lastname: Hawinkels
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000098:blood supply* / Q000473:pathology; D000071063:Endoglin / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011758:Pyrroles / Q000627:therapeutic use; D051898:Smad1 Protein / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000502:physiology; D015027:Zebrafish
chemical_list: D000911:Antibodies, Monoclonal; D000071063:Endoglin; D007211:Indoles; D011758:Pyrroles; D051898:Smad1 Protein; D042461:Vascular Endothelial Growth Factor A; C116890:Semaxinib; C579557:carotuximab