Extracellular AGR2 activates neighboring fibroblasts through endocytosis and direct binding to β-catenin that requires AGR2 dimerization and adhesion domains

Construction and stable gene expression of AGR2xPD1 bi-specific antibody that enhances attachment between T-Cells and lung tumor cells, suppress tumor cell migration and promoting CD8 expression in cytotoxic T-cells

“…Extracellular or secreted AGR2 influences fibroblast organization, elongation, and migration; besides, it has also been revealed that AGR2 secreted by cancer cells is taken up by surrounding fibroblasts. Murine antibody 18A4 developed in our lab significantly inhibits the uptake and activation of AGR2 ( Merugu et al 2021a ). 18A4 was humanized (18A4HU I) to overcome the immunogenicity by CDR grafting technique and de-immunization analysis.…”

“…AGR2 usually resides within ER for its proteostasis and protein folding functions; it also localizes in other cellular compartments, plasma membrane, cytoplasm, and extracellular environment ( Fessart et al, 2021 , Moidu et al, 2020 ). We have reported the role of extracellular AGR2 as paracrine signaling in tumor microenvironment (TME) development ( Mangukiya et al, 2019 , Merugu et al, 2021 ). AGR2 overexpression leads to enhanced cancer cell proliferation, metastasis, and survival, promoting tumor progression and drug resistance ( Li et al, 2015 , Pohler et al, 2004 ).…”

The anterior gradient homologue 2 (AGR2) co-localises with the glucose-regulated protein 78 (GRP78) in cancer stem cells, and is critical for the survival and drug resistance of recurrent glioblastoma: in situ and in vitro analyses

“…AGR2 overexpression has been linked to higher ER stress [ 69 , 70 ], possibly via several modulators [ 17 , 32 ]. Surprisingly, AGR2 was detected in the nucleus in both cell lines, a unique feature that was not seen in situ, suggesting that AGR2 behaviour is likely to be responsive to the tumour microenvironment [ 71 , 72 ].…”

AGR2: a secreted protein worthy of attention in diagnosis and treatment of breast cancer

“…Similarly, extracellular AGR2 can also directly promote the dimerization of VEGF and FGF2 and increase the concentration of active VEGF and FGF2 in the local environment of tumor, thus leading to the migration and aggregation of vascular endothelial cells and fibroblasts to the surrounding of tumor cells, and promoting angiogenesis, providing favorable conditions for the formation of tumor microenvironment ( 41 ). Meanwhile, AGR2 can be internalized into fibroblasts and cancer cells through endocytosis, then it will interact with β-catenin, resulting in β-catenin accumulation in the nucleus and regulating fibroblasts around tumor cells to affect tumor microenvironment (TME) ( 64 , 65 ). Extracellular AGR2 and ER-α can interact to induce the expression of IGF-1, thereby promoting the proliferation, migration and epithelial-mesenchymal transition process in breast cancer cells and enhancing drug resistance ( 48 ).…”