Tumor-secreted anterior gradient-2 binds to VEGF and FGF2 and enhances their activities by promoting their homodimerization

Abstract

The importance of the tumor microenvironment in targeted anticancer therapies has been well recognized. Various protein factors participate in the cross-talk between tumor cells and non-malignant cells. Anterior gradient-2 (AGR2) is overexpressed in diverse human adenocarcinomas and it exists in both intracellular and extracellular spaces. Although intracellular AGR2 has been intensively investigated, the function of secreted AGR2, especially its exact mechanism of action is still poorly understood. Here we report that the secreted AGR2 promotes the angiogenesis and the invasion of vascular endothelial cells and fibroblasts by enhancing the activities of vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2). Further study indicated that AGR2 directly binds to these extracellular signaling molecules, and enhances their homodimerization. The extracellular AGR2 activity can be blocked to reduce angiogenesis and inhibit tumor growth in vitro and in vivo by a monoclonal antibody targeting the AGR2 self-dimerization region, and combined treatment with bevacizumab produced maximum inhibition effect. In conclusion, our investigation reveals a mechanism that directly links the secreted AGR2 with extracellular signaling networks, and we propose that the secreted AGR2 is a blockable molecular target, which acts as a chaperon-like enhancer to VEGF and FGF2.

Anterior gradient 2 is induced in cutaneous wound and promotes wound healing through its adhesion domain

“…Recent publication revealed that secreted AGR2 promotes endothelial cells and Fibro. migration to form tumor microenvironment [14]. This lead us to hypothesize that the possible role of AGR2 in wound-healing process is to promote the migration of various cell types for the wound-healing process.…”

The role of protein disulphide isomerase AGR2 in the tumour niche

“…eAGR2 interacts with Vascular endothelial growth factor A via its thioredoxin motif. Furthermore, eAGR2 has been shown to directly bind to VEGF and fibroblast growth factor 2, which are the major players in tumour angiogenesis, and enhances their activities [Guo et al., ]. This enhancement is dependent on both the AGR2 self‐dimerisation region and the two signalling pathways.…”

Modulating secreted components of tumor microenvironment: A masterstroke in tumor therapeutics

“…12,15 Another chaperon-like enhancer molecule anterior gradient-2 secreted from tumor cells has been shown to activate VEGF and fibroblast growth factor and suggested as a potential therapeutic target. 41 Other than exosomal miRNAs, secreted cytokines and extracellular peptides, tumor secreted metabolites have been seen as a new class of therapeutic targets and tumor biomarkers. 26,97,102,108 For an example, Salimian Rizi et al 102 reported that use of inhibitor of arginine, secreted metabolite in TME can serve as therapeutic by dismantling the metabolic crosstalk between developmental adipose stromal cells and endometrial and ovarian tumor cells.…”