CD146 is an endothelial cell adhesion molecule. Due to its over-expression in fast proliferating tumors, it was initially identified as a melanoma tumor marker. However, recent evidence shows that CD146 has a multitude of other functions, which encompasses a wide variety of physiological processes such as development, signal transduction, cell migration and differentiation of mesenchymal stem cells, angiogenesis and immune response. Our research group has a longstanding interest in the study of CD146 molecule, particularly focusing on the exploration of new and potential mechanisms.

CD146 and Tumor Angiogenesis

Angiogenesis induced by tumor secreted vascular endothelial growth factor are essential in tumor growth and migration process. In 2003, we used AA98 specific monoclonal antibodies targeting tumor blood vessels; CD146 was confirmed for the first time as a new target for anti-angiogenic drugs (Blood, 2003).

In 2006, our study indicated that inhibition of NF-κB by monoclonal antibody AA98 played a crucial role in the inhibition of endothelial cell migration, as well as angiogenesis and tumor suppression (Mol Cancer Ther, 2006). Subsequently, we discovered that CD146 siRNA which specifically inhibited the expression of CD146 on mRNA and protein level hindered the regeneration, adhesion and migration ability of HUVEC cells (Cell Research, 2006).

Our group in 2007 constructed and expressed a single chain antibody fragment containing three domains of AA98, which demonstrated antiangiogenic properties (Anticancer Research, 2007). In the same year, we provided evidence of CD146 dimerization and its affect on tumor microenvironment, hinting that CD146 dimerization may be correlated to tumor malignancy (Biochimica et Biophysica Acta, 2007).

Our paper published in 2009 suggests CD146 is a membrane receptor for mediating tumor angiogenesis (Int. J. Biochem. Cell Biol, 2009), which in 2012 we found that it was co-receptor of VEGFR-2 (Blood, 2012).

In 2013, we proceeded to use miRNA-imaging methods to identify a new angiogenesis-related miRNA, additionally we expect miR-329 to be a potential therapeutic tool for the treatment of neovascularization diseases (Molecular & Cellular Biology, 2013).

In 2014 we discovered that CD146 knockout mice limited the ability of VEGF-induced VEGFR-2 phosphorylation and AKT/p38 MAPKs/NF-κB activation of endothelial cells, which revealed the potential cause of limited tumor angiogenesis in CD146 knockout mice (Protein & Cell, 2014).

In 2015, our data uncover CD146 as a previously unknown receptor for netrin-1 and also reveal a functional ligand for CD146 in angiogenesis, demonstrating the involvement of netrin-CD146 signaling in angiogenesis during vertebrate development (Cell Research, 2015).

In 2016, our findings provide evidence that CD146 functions as a suppressor of tumorigenesis and cancer stemness in CRC through inactivating the canonical wnt/β-catenin cascade (Oncotarget, 2016).

Figure 1.  vascular endothelial growth factor receptor 2 (VEGFR2) signaling pathway

CD146 and Various Diseases

In 2004, our group found that preeclampsia is caused by the inability of the intermediate trophoblast to express melanoma cell adhesion molecule (MCAM/CD146), hinting that CD146 is an influential factor in trophoblast invasion (Laboratory Investigation, 2004).

In 2009, we discovered that CD146 interaction with moesin protein can promote the migration of melanoma cells (生物物理学报，2009). In the same year, we found that patients with systemic vasculitis had elevated level of soluble and neutrophil CD146, which were associated with remission after therapy (Laboratory Medicine, 2009).

In 2011, we found the association of CD146 expression with MVD and its correlation with progression in breast carcinoma indicating that CD146 could be a new drug target in the treatment of breast cancer (Pathology Research and Practice, 2011). In the same year, our research on CD146 provided mechanism foundation for the human melanoma cell migration (Oncogene, 2011).

In the 2012 paper, we observed CD146 over-expression had significant correlation with high tumor grade, poor prognosis and triple negative breast cancer (PNAS, 2012).

In the following year, we confirmed that CD146 is a marker in the diagnosis of cervical cancer and endometrial carcinoma (Oncology Letters, 2013). In 2013, our research in cerebrospinal fluid led to the finding that CD146 levels correlated with multiple sclerosis (Neuroscience, 2013). In addition, in 2013 our study showed endothelial CD146 played a positive role in the extravasation of T cells in encephalitis (Scientific Reports, 2013).

In 2014, our lab showed that the over-expression of CD146 had positive influence in the enteritis disease inflammatory response, further giving evidence to the colitis-related colorectal carcinogenesis (American Journal of Pathology, 2014). In another research the same year, we revealed the complex signaling network of CD146-mediated epithelial-mesenchymal transition, providing pivotal evidence for the internal mechanism of the relationship between CD146 and TNBC (Journal of Proteomics, 2014).

Figure 2.  Effect of CD146 on the transformation of chronic inflammation to cancer in endothelial cells

CD146 and Physiological Development

Our 2004 research indicated that CD146 was a key molecule in the ability of cell infiltration, which provided molecular mechanism for the further study of embryo implantation and tumor invasion (生物化学与生物物理进展，2004).

In 2008, our data presented direct evidence for the role of CD146 in mediating embryonic attachment and trophoblastic invasion, and provided new insight into the molecular mechanism underlying unexplained pregnancy loss and recurrent miscarriage (J. Cell. Physiol, 2008).

In 2013, we observed lower body weight and less food intake in nervous system CD146 knockout mice (CD146ns-ko). Further experiments showed CD146ns-ko mice displayed significantly reduced physical activity, while spatial learning and memory abilities were also significantly impaired (PLOS ONE, 2013). In the same year, our experimental results showed that the CD146 as a functional receptor of Wnt5a regulates cell migration and expansion which closes the traditional Wnt signal (NATURE COMMUNICATIONS, 2013).

Fig 3.  Schematic diagram of the interaction between cell membrane receptor CD146 and Wnt5a