Supported by grants from National Natural Science Foundation of China (81001075, 91229205), the Funds for Creative Research Groups of China (81221061), the State Key Project for Liver Cancer (2012ZX10002-009, 2013ZX10002-010) and the Key Project for Military (BWS11J036).
Signal regulatory protein α is associated with tumor-polarized macrophages phenotype switch and plays a pivotal role in tumor progression
Article first published online: 1 JUL 2013
Copyright © 2013 by the American Association for the Study of Liver Diseases
Volume 58, Issue 2, pages 680–691, August 2013
How to Cite
Pan, Y.-f., Tan, Y.-x., Wang, M., Zhang, J., Zhang, B., Yang, C., Ding, Z.-w., Dong, L.-w. and Wang, H.-y. (2013), Signal regulatory protein α is associated with tumor-polarized macrophages phenotype switch and plays a pivotal role in tumor progression. Hepatology, 58: 680–691. doi: 10.1002/hep.26391
Potential conflict of interest: Nothing to report.
These authors contributed equally to this work.
- Issue published online: 29 JUL 2013
- Article first published online: 1 JUL 2013
- Accepted manuscript online: 16 MAR 2013 02:14AM EST
- Manuscript Accepted: 9 MAR 2013
- Manuscript Received: 24 OCT 2012
- National Natural Science Foundation of China. Grant Number: 81001075, 81071681
- Funds for Creative Research Groups of China. Grant Number: 81221061
- State Key Project for Liver Cancer. Grant Number: 2012ZX10002-009
- Key Project for Military. Grant Number: BWS11J036
Macrophages (Mψ) are the major component of infiltrating leukocytes in tumors and exhibit distinct phenotypes according to the microenvironment. We have recently found that signal regulatory protein α (SIRPα), the inhibitory molecule expressed on myeloid cells, plays a critical role in controlling innate immune activation. Here, we identify that SIRPα is down-regulated on monocytes/Mψ isolated from peritumoral areas of hepatocellular carcinoma (HCC) samples, while its level is moderately recovered in intratumor Mψ. In vitro assays demonstrate that SIRPα expression is significantly reduced on Mψ when cocultured with hepatoma cells. This reduction is partly due to the soluble factors in the tumor microenvironment. Knockdown (KD) of SIRPα prolongs activation of nuclear factor kappa B (NF-κB) and PI3K-Akt pathways as Mψ encounter tumor cells, leading to an increased capacity of Mψ for migration, survival, and proinflammatory cytokine production. Enhanced Stat3 and impaired Stat1 phosphorylation are also observed in tumor-exposed SIRPα-KD Mψ. Adoptive transfer with SIRPα-KD Mψ accelerates mouse hepatoma cells growth in vivo by remolding the inflammatory microenvironment and promoting angiogenesis. SIRPα accomplishes this partly through its sequestration of the signal transducer Src homology 2-containing phosphotyrosine phosphatase (SHP2) from IκB kinase β (IKKβ) and PI3K regulatory subunit p85 (PI3Kp85). Conclusion: These findings suggest that SIRPα functions as an important modulator of tumor-polarized Mψ in hepatoma, and the reduction of SIRPα is a novel strategy used by tumor cells to benefit their behavior. Therefore, SIRPα could be utilized as a potential target for HCC therapy. (Hepatology 2013;58:680–691)