Anterior gradient 2 as a supervisory marker for tumor vessel normalization induced by anti-angiogenic treatment

Anti-angiogenic therapy provides transient tumor vascular normalization, which results in a window of opportunity for improvement of radio- or chemotherapy. Biomarkers indicating this window are required for rationalizing anti-angiogenesis. Anterior gradient 2 (AGR2), the majority of which is secreted from tumor cells, is an easily detected plasma protein. In the present study, it was demonstrated that AGR2 could be applied as a biomarker for the supervision of vascular normalization during anti-angiogenic treatment with gold nanoparticles (AuNPs). Nude mice inoculated with SW620 human colorectal cancer cells were treated with AuNPs. Vessel density, pericyte coverage, vessel permeability, tumor hypoxia, tumor growth and AGR2 secretion were detected following treatment with AuNPs at days 0, 4, 6, 9 and 14. Tumor volume and vessel density were reduced, whereas pericyte coverage was increased, and hypoxia and vessel permeability were improved between days 6-9; however, these improvements decreased by day 14, revealing a time frame for tumor vascular normalization, namely days 4-9, during treatment with AuNPs in mice. AGR2 levels in tumor tissues and plasma were significantly low at day 9, along with vascular normalization; therefore, AGR2 can be used as a potential marker for monitoring tumor vascular normalization during anti-angiogenic treatment.