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Endoglin targeting inhibits tumor angiogenesis and metastatic spread in breast cancer
M Paauwe1,2, R C Heijkants1, C H Oudt1
1Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
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.
Insights
Targeting endoglin, a protein on tumor blood vessels, with antibodies or traps significantly reduced breast cancer metastasis in mice. This approach shows promise for inhibiting cancer spread, even after primary tumor removal.
Area of Science:
- Oncology
- Cancer Biology
- Angiogenesis Research
Background:
- Endoglin is highly expressed on tumor endothelial cells and is a target for anti-angiogenic therapy.
- VEGF signaling is crucial for angiogenesis, and its inhibition can lead to compensatory increases in endoglin signaling.
- The interplay between endoglin and VEGF signaling in breast cancer metastasis is not fully understood.
Purpose of the Study:
- To investigate the functional redundancy between endoglin and VEGF signaling in angiogenesis.
- To evaluate the efficacy of targeting both endoglin and VEGF pathways on breast cancer metastasis.
- To explore the anti-metastatic potential of endoglin inhibition using neutralizing antibodies and ligand traps.
Main Methods:
- In vitro studies using endothelial cells and a zebrafish angiogenesis model.
- In vivo experiments using a mouse model of invasive lobular breast cancer.
- Treatment with TRC105 (endoglin-neutralizing antibody) and SU5416 (VEGF receptor kinase inhibitor).
- Assessment of tumor growth, vascular density, and metastasis formation.
- Evaluation of endoglin-Fc (ligand trap) in a tumor resection model.
Main Results:
- Combined targeting of endoglin and VEGF pathways enhanced anti-angiogenic effects in vitro and in zebrafish.
- TRC105 and SU5416 reduced tumor vascular density but did not affect primary tumor volume in mice.
- Treatment with TRC105, alone or combined with SU5416, significantly inhibited breast cancer metastasis.
- Adjuvant treatment with TRC105 post-tumor resection strongly inhibited metastatic spread.
- Endoglin-Fc expression in tumors also led to significant inhibition of distant metastases.
Conclusions:
- Targeting endoglin, via neutralizing antibodies or ligand traps, is a potent strategy to inhibit breast cancer metastasis.
- Endoglin signaling plays a critical role in promoting metastatic spread, independent of primary tumor growth.
- Combined inhibition of endoglin and VEGF pathways demonstrates synergistic anti-angiogenic effects.
- Endoglin-targeted therapies hold significant promise for preventing or treating metastatic breast cancer.
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