PUBLICATION
Endoglin targeting inhibits tumor angiogenesis and metastatic spread in breast cancer
- Authors
- Paauwe, M., Heijkants, R.C., Oudt, C.H., van Pelt, G.W., Cui, C., Theuer, C.P., Hardwick, J.C., Sier, C.F., Hawinkels, L.J.
- ID
- ZDB-PUB-160126-11
- Date
- 2016
- Source
- Oncogene 35(31): 4069-79 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Antibodies, Monoclonal/therapeutic use
- Breast Neoplasms/blood supply*
- Breast Neoplasms/pathology
- Endoglin/antagonists & inhibitors*
- Female
- Humans
- Indoles/therapeutic use
- Neoplasm Metastasis/prevention & control*
- Neovascularization, Pathologic/prevention & control*
- Pyrroles/therapeutic use
- Smad1 Protein/metabolism
- Vascular Endothelial Growth Factor A/antagonists & inhibitors
- Vascular Endothelial Growth Factor A/physiology
- Zebrafish
- PubMed
- 26804178 Full text @ Oncogene
Citation
Paauwe, M., Heijkants, R.C., Oudt, C.H., van Pelt, G.W., Cui, C., Theuer, C.P., Hardwick, J.C., Sier, C.F., Hawinkels, L.J. (2016) Endoglin targeting inhibits tumor angiogenesis and metastatic spread in breast cancer. Oncogene. 35(31):4069-79.
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.Oncogene advance online publication, 25 January 2016; doi:10.1038/onc.2015.509.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping