title: Reductions in myeloid-derived suppressor cells and lung metastases using AZD4547 treatment of a metastatic murine breast tumor model.
abstract: BACKGROUND
  AZD4547, a small-molecule inhibitor targeting the tyrosine kinase of Fibroblast Growth Factor Receptors (FGFRs), is currently under phase II clinical study for human subjects having breast cancer, while the underlying mechanism remains elusive. The aim of this study is to explore the potential mechanism by which AZD4547 inhibits breast tumor lung metastases at the level of the tumor microenvironment.
  
  
  METHODS
  First, through in vitro experiments, we investigated the efficacy of the FGFRs inhibitor AZD4547 on 4T1 tumor cells for their proliferation, apoptosis, migration, and invasion. Second, by in vivo animal experiments, we evaluated the effects of AZD4547 on tumor growth and lung metastases in 4T1 tumor-bearing mice. Finally, we examined the impact of AZD4547 on the infiltration of myeloid-derived suppressor cells (MDSCs) in lung, spleens, peripheral blood and tumor.
  
  
  RESULTS
  Through this study we found that AZD4547 could efficiently suppress tumor 4T1 cells through restraining their proliferation, blocking migration and invasion, and inducing apoptosis in vitro. In animal model we also demonstrated that AZD4547 was able to inhibit tumor growth and lung metastases, consistent with the decreased MDSCs accumulation in the tumor and lung tissues, respectively. Moreover, the reduced number of MDSCs in peripheral blood and spleens were also observed in the AZD4547-treated mice. Importantly, through the AZD4547 treatment, the CD4(+) and CD8(+) T-cells were significantly increased in tumor and spleens.
  
  
  CONCLUSIONS
  Our studies showed that AZD4547 can inhibit breast cancer cell proliferation, induce its apoptosis and block migration and invasion in vitro and suppress tumor growth and lung metastases by modulating the tumor immunologic microenvironment in vivo.
authors.affiliation: Department of Pharmaceutical and Bioengineering, School of Chemical Engineering, Sichuan University, Chengdu, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Ting Hong
authors.initials: TH
authors.lastname: Ye
authors.forename: Yuan Ping
authors.initials: YP
authors.lastname: Han
authors.forename: Hang
authors.initials: H
authors.lastname: Song
authors.forename: Yong Kui
authors.initials: YK
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Xia
authors.forename: Ning Yu
authors.initials: NY
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiong
authors.forename: Xue Jiao
authors.initials: XJ
authors.lastname: Song
authors.forename: Yong Xia
authors.initials: YX
authors.lastname: Zhu
authors.forename: De Liang
authors.initials: de L
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Zeng
authors.forename: Kai
authors.initials: K
authors.lastname: Ran
authors.forename: Cui Ting
authors.initials: CT
authors.lastname: Peng
authors.forename: Yu Quan
authors.initials: YQ
authors.lastname: Wei
authors.forename: Luo Ting
authors.initials: LT
authors.lastname: Yu
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology; D009362:Neoplasm Metastasis; D010879:Piperazines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*
chemical_list: C572463:AZD4547; D001549:Benzamides; D010879:Piperazines; D011720:Pyrazoles