CD146 is a coreceptor for VEGFR-2 in tumor angiogenesis

Abstract

CD146 is a novel endothelial biomarker and plays an essential role in angiogenesis; however, its role in the molecular mechanism underlying angiogenesis remains poorly understood. In the present study, we show that CD146 interacts directly with VEGFR-2 on endothelial cells and at the molecular level and identify the structural basis of CD146 binding to VEGFR-2. In addition, we show that CD146 is required in VEGF-induced VEGFR-2 phosphorylation, AKT/p38 MAPKs/NF-κB activation, and thus promotion of endothelial cell migration and microvascular formation. Furthermore, we show that anti-CD146 AA98 or CD146 siRNA abrogates all VEGFR-2 activation induced by VEGF. An in vivo angiogenesis assay showed that VEGF-promoted microvascular formation was impaired in the endothelial conditional knockout of CD146 (CD146(EC-KO)). Our animal experiments demonstrated that anti-CD146 (AA98) and anti-VEGF (bevacizumab) have an additive inhibitory effect on xenografted human pancreatic and melanoma tumors. The results of the present study suggest that CD146 is a new coreceptor for VEGFR-2 and is therefore a promising target for blocking tumor-related angiogenesis.

Wnt5a uses CD146 as a receptor to regulate cell motility and convergent extension

“…Small interfering RNA (siRNA) targeting CD146, Dvl2, Dvl3, Ror2, Fz2, Fz3, Fz4, Fz5, Fz6, Fz7 and control siRNA were synthesized by Invitrogen (San Diego, CA, USA) using previously reported sequences as listed in Supplementary Table S1 (refs 23, 32,45,46).…”

“…The resultant supernatant was taken as the cytosol fraction and analysed by immunoblotting. Immunoblotting was performed as described previously with antibodies against FLAG, Myc, b-catenin, Dvl2, Dvl3 JNK, p-JNK and mouse anti-CD146 antibody AA1 or rabbit anti-CD146 antibody 32 .…”

“…Cell migration capacity was evaluated using the Transwell system 32 . In brief, 5,000 serum-starved cells in 100 ml of serum-free RPMI-1640 were added into the upper chamber and cultured with Wnt5a CM or control CM.…”

“…These results strongly suggest that CD146 is a negative regulator of canonical Wnt signalling at the b-catenin level. Although CD146 has been extensively studied in tumour metastasis, invasion and angiogenesis, its ligand is still under investigation 16,[32][33][34] . As a non-canonical Wnt ligand, Wnt5a has a critical role in regulating cell motility, cell polarity and CE during embryo gastrulation.…”

Different angiogenic potentials of mesenchymal stem cells derived from umbilical artery, umbilical vein and wharton’s jelly

“…In addition, the gain-of-function analysis of CD146 in zebrafish found that enforcing expression of CD146 induced sprouting angiogenesis [32]. Moreover, as a novel VEGFR-2 coreceptor, CD146 is required in the promotion of endothelial cell migration and microvascular formation [33].…”