Introduction: α1-acid glycoprotein (AGP) is one of acute phage protein like CRP. It is known that plasma AGP concentration of several cancer patients is higher than that of healthy persons and tumor-associated macrophages (TAMs) of M2 phenotype in tumor tissues are associated with a poor clinical prognosis. it is recently reported that AGP up-regulates CD163, a M2 phenotype marker, in THP-1 macropahges. These facts suggest possibility that AGP is involved in tumor progression in cancer patients via inducing M2 phenotype in macrophages. Therefore, we try to examine the effect of AGP on macrophage activation and tumor development.
Methods: Firstly, the effect of AGP on STAT3 activation in human monocyte-derived macrophages (HMDMs) and tumor cells (ES-2, SBC-3 and HepG2 cells) were measured. Then, the effects of AGP-stimulated macrophage culture medium (AGP-MCM) on STAT3 activation and proliferation in tumor cells were examined. Finally, tumor cells were treated with three candidate factors secreted from AGP-stimulated macrophages, IL-6, GROα and CXCL8, followed by determination of the STAT3 activation and cell proliferation.
Results: AGP significantly induced activation of STAT3, a transcriptional factor relating to M2 differentiation, in HMDMs, whereas AGP had no effect on STAT3 activation in tumor cells, thus suggesting that AGP is a potential factor for M2 polarization. AGP-MCM significantly activated STAT3 and cell proliferation in tumor cells, thus indicating that AGP has the indirect effect on STAT3 activation and tumor proliferation. IL-6, GROα and CXCL8 were identified as the candidate factors contained in AGP-MCM which induce STAT3 activation and cell proliferation in tumor cells. Among those candidate factors, IL-6 induced both STAT3 activation and cell proliferation in all tumor cells.
Conclusion: it is possibility that AGP is involved in tumor progression in cancer patients with high blood AGP level via indirect effect against macrophage in tumor microenvironment.