TY - JOUR
T1 - Endoglin interacts with VEGFR2 to promote angiogenesis
AU - Tian, Hongyu
AU - Huang, Jennifer J.
AU - Golzio, Christelle
AU - Gao, Xia
AU - Hector-Greene, Melissa
AU - Katsanis, Elias Nicholas
AU - Blobe, Gerard C.
N1 - Funding Information:
The authors thank Dr. Elisabetta Dejana [Italian Foundation for Cancer Research (FIRC) Institute of Molecular Oncology, European Institute of Oncology, Milan, Italy] for providing mouse embryonic endothelial cells; Dr. Christopher D. Kontos (Duke University) for providing the VEGFR2 construct; Tracon Pharma, Inc. (San Diego, CA, USA) for providing TRC105 antibody; and Genentech, Inc. for providing bevacizumab and B20-4.1 antibodies. This work was supported, in part, by Susan G. Komen for the Cure Grants CCR15333124 (to H.T.) and SAC10002 (to G.C.B.), and an HHT Young Scholar Award (to H.T.). The authors declare no conflicts of interest.
PY - 2018/6
Y1 - 2018/6
N2 - Endoglin, a TGF-b coreceptor predominantly expressed in endothelial cells, plays an important role in vascular development and tumor-Associated angiogenesis. However, the mechanism by which endoglin regulates angiogenesis, especially during tip cell formation, remains largely unknown. In this study, we report that endoglin promotedVEGF-induced tip cell formation.Mechanistically, endoglin interactedwithVEGF receptor (VEGFR)-2 in a VEGF-dependent manner, which sustained VEGFR2 on the cell surface and prevented its degradation. Endoglin mutants deficient in the ability to interactwithVEGFR2 failedto sustainVEGFR2 on the cell surface and topromote VEGF-induced tip cell formation. Further, an endoglin-Targeting monoclonal antibody (mAb), TRC105, cooperated with aVEGF-A targeting mAb, bevacizumab, to inhibitVEGF signaling and tip cell formation in vitro and to inhibit tumor growth, metastasis, and tumor-Associated angiogenesis in a murine tumor model. This study demonstrate a novelmechanism bywhich endoglin initiates and regulatesVEGF-driven angiogenesiswhile providing a rationale for combining anti-VEGF and anti-endoglin therapy in patients with cancer.
AB - Endoglin, a TGF-b coreceptor predominantly expressed in endothelial cells, plays an important role in vascular development and tumor-Associated angiogenesis. However, the mechanism by which endoglin regulates angiogenesis, especially during tip cell formation, remains largely unknown. In this study, we report that endoglin promotedVEGF-induced tip cell formation.Mechanistically, endoglin interactedwithVEGF receptor (VEGFR)-2 in a VEGF-dependent manner, which sustained VEGFR2 on the cell surface and prevented its degradation. Endoglin mutants deficient in the ability to interactwithVEGFR2 failedto sustainVEGFR2 on the cell surface and topromote VEGF-induced tip cell formation. Further, an endoglin-Targeting monoclonal antibody (mAb), TRC105, cooperated with aVEGF-A targeting mAb, bevacizumab, to inhibitVEGF signaling and tip cell formation in vitro and to inhibit tumor growth, metastasis, and tumor-Associated angiogenesis in a murine tumor model. This study demonstrate a novelmechanism bywhich endoglin initiates and regulatesVEGF-driven angiogenesiswhile providing a rationale for combining anti-VEGF and anti-endoglin therapy in patients with cancer.
KW - Cancer
KW - Endothelial
KW - Signaling
KW - Sprouting
KW - VEGF
UR - http://www.scopus.com/inward/record.url?scp=85046096748&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85046096748&partnerID=8YFLogxK
U2 - 10.1096/fj.201700867RR
DO - 10.1096/fj.201700867RR
M3 - Article
C2 - 29401587
AN - SCOPUS:85046096748
SN - 0892-6638
VL - 32
SP - 2934
EP - 2949
JO - FASEB Journal
JF - FASEB Journal
IS - 6
ER -