Angiogenesis modulated by CD93 and its natural ligands IGFBP7 and MMRN2: a new target to facilitate solid tumor therapy by vasculature normalization

Abstract

The tumor vasculature was different from the normal vasculature in both function and morphology, which caused hypoxia in the tumor microenvironment (TME). Previous anti-angiogenesis therapy had led to a modest improvement in cancer immunotherapy. However, antiangiogenic therapy only benefitted a few patients and caused many side effects. Therefore, there was still a need to develop a new approach to affect tumor vasculature formation. The CD93 receptor expressed on the surface of vascular endothelial cells (ECs) and its natural ligands, MMRN2 and IGFBP7, were now considered potential targets in the antiangiogenic treatment because recent studies had reported that anti-CD93 could normalize the tumor vasculature without impacting normal blood vessels. Here, we reviewed recent studies on the role of CD93, IGFBP7, and MMRN2 in angiogenesis. We focused on revealing the interaction between IGFBP7-CD93 and MMRN2-CD93 and the signaling cascaded impacted by CD93, IGFBP7, and MMRN2 during the angiogenesis process. We also reviewed retrospective studies on CD93, IGFBP7, and MMRN2 expression and their relationship with clinical factors. In conclusion, CD93 was a promising target for normalizing the tumor vasculature.

Keywords: CD93; IGFBP7; Immune therapy; MMRN2; Vasculature normalization.

Fig. 1

Effects of CD93, IGFBP7, and MMRN2 on the vasculature were listed in the figure Alt Text: The figure is divided into two small figures, quiescent vasculature, and tumor-related vasculature, and lists the roles of related molecules in shape similar to a dandelion

Fig. 2

The signal molecules modulated by IGFBP7 and MMRN2. The red icons represent the signal molecule regulated by MMRN2, and the purple icons represent the signaling molecules regulated by IGFBP7. 1). IGFBP7 promoted TGF-1R and AKT phosphorylation and activated the p38MAPK pathway, upregulating p53, p27Kip1, and p21Cip1. 2). IGFBP7 inhibited AKT and MPK3 activity, MEK and ERK1/2 phosphorylation, and COX-2 and VEGF mRNA expression. IGFBP7 interrupts the IGF1R-IGF1/2 interaction and, in turn, inhibited the downstream PI3K-AKT pathway. 3) TGF-β1 induced by TGF-β1/ALK5/Smad-2 and VEGF induced IGFBP7 expression. MKP3 could inhibit IGFBP7 expression. IGFBP7 transcriptional activation required Smarcb1 participation, while Smarcb1 inhibited AKT activation. 4) MMRN2 inhibited p38 activation and Src, VEGFR2, and VE-cadherin phosphorylation. 5) MMRN2 downregulated VEGFR1, VEGFR2, Tie2, MLC2, Apelin, and Ang-2. 6) MMRN2 upregulated VE-cadherin, β-catenin, ZO-1, and JAM-A, MMRN2 upregulated some cytokines, such as Ang2, PDGF, and HB-EGF, and 7) VEGFF-A could downregulate MMRN2. Alt Text: There is a connected cell in the figure in which the intrinsic pathways involved in the relevant molecules are marked

Fig. 3

The signal pathway mediated by CD93 in ECs. (1) Integrin participated in the activation of Src and FAK, and CD93 ensured FAK activation. (2) Cell adhesion on laminin caused DG phosphorylation, phosphorylated DG recruits Src, integrin-induced Scr activation, and activated Src was induced to phosphorylate the CD93 cytoplasmic domain. Phosphorylated CD93 recruits and phosphorylated Cb1, phosphorylated the Cb1 receptor, and interacted with Crk, which interacted with DOCK180 and regulated downstream Rho GTPases, including Rac1, Cdc42, and RhoA. (3) The cytoplasmic region of CD93 interacted with moesin and F-actin. (4) Dystroglycan interacted with dystrophin, and dystrophin interacted with F-actin. (5) The small GTPase Rab5c participated in cycling CD93 to the surface of ECs, and CD93, MMRN2, and β1 integrin form a complex in the Rab5c endosomal compartment Alt Text: There are two connected cells in the figure, the left side depicts the intrinsic signaling pathway, and the right side depicts the changes in the related protein backbone and the transport of molecules