Secreted Anterior Gradient-2 Is A Potential Tumor-Microenvironment-Related Therapeutic Target

The secreted anterior gradient-2 (AGR2) orthologs in amphibians are critical signaling proteins in anterior specification and limb regeneration. It is also overexpressed in diverse human cancers especially adenocarcinomas. Although tumor-related functions of intracellular AGR2 have been intensively investigated and several AGR2-related signaling pathways have been identified, the full scope of secreted AGR2 functions, especially the exact mechanism of actions, remain insufficiently explored. Here we report that AGR2 induction after SKOV3 xenograft inoculation is tumor microenvironment (TME) dependent. This phenomenon can be mimic in vitro through serum deprivation but not hypoxia treatment. In addition, the secreted AGR2 may in turn influence the development of TME. It scatters the tumor cells and guides the nearby vascular endothelial cells and fibroblasts toward the source of AGR2 through various degrees of crosstalk with VEGF and bFGF pathways. Blocking the AGR2 inhibits the tumor growth and decreases the blood vessel density in SKOV3 xenograft model. Our results show that exogenous AGR2 binds specifically with VEGF and bFGF, and promotes their dimerization. This binding enhances the phosphorylation signals, such as ERK phosphorylation, induced by VEGF and bFGF, and promotes the VEGF- and bFGF- dependent angiogenesis. We also find that heparin may reverse the binding between bFGF and AGR2, indicating that dimerized bFGF that promoted by AGR2 would be released when it is close to the cell surface where heparin sulfate is abundant. Taken together, the present results suggest that tumor-secreted AGR2 may activate the specific growth factors surrounding the tumor cells to promote the angiogenesis and tumor growth, and also act as a short-range chemoattractant to guide surrounding vascular endothelial cells and fibroblasts toward tumor cells in building the TME. This mechanism of action directly links the secreted AGR2 with the cell signaling networks well-known in building TME. This may help to further explain how tumor cells interact with and attract nearby fibroblasts and blood vessel cells to form their microenvironment and support their growth, suggesting a potential anti-TME target. Citation Format: Hao Guo, Qi Zhu, Zhenghua Wu, Hitesh B. Mangukiya, Xiaoyan Yu, Dawei Li. Secreted anterior gradient-2 is a potential tumor-microenvironment-related therapeutic target. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 751.