title: Signal regulatory protein α is associated with tumor-polarized macrophages phenotype switch and plays a pivotal role in tumor progression.
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, PR China.
authors.forename: Yu-fei
authors.initials: YF
authors.lastname: Pan
authors.forename: Ye-xiong
authors.initials: YX
authors.lastname: Tan
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Chun
authors.initials: C
authors.lastname: Yang
authors.forename: Zhi-wen
authors.initials: ZW
authors.lastname: Ding
authors.forename: Li-wei
authors.initials: LW
authors.lastname: Dong
authors.forename: Hong-yang
authors.initials: HY
authors.lastname: Wang
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000187:drug effects / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000503:physiopathology*; D002465:Cell Movement / Q000502:physiology; D018920:Coculture Techniques; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology / Q000503:physiopathology*; D008264:Macrophages / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000943:Antigens, Differentiation; D016328:NF-kappa B; C501922:Sirpa protein, mouse; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; C501920:SIRPA protein, human; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt