title: Antiangiogenic therapy using sunitinib combined with rapamycin retards tumor growth but promotes metastasis.
abstract: BACKGROUND
  This study investigated the synergistic effect of sunitinib and rapamycin on tumor growth and metastasis in murine breast cancer model.
  
  
  METHODS
  The synergistic antitumor effect of sunitinib and rapamycin on tumor growth and metastasis was investigated. Myeloid-derived suppressor cells (MDSCs) in spleens and lungs were assessed. Tumor hypoxia, vessel density and micrometastasis were evaluated. Versican, indoleamine 2,3-dioxygenase (IDO), arginase 1, interleukin-6 (IL-6), IL-10, and transforming growth factor β (TGF-β) in the lungs and tumors were examined. IL-6 and TGF-β in the blood were evaluated.
  
  
  RESULTS
  Synergism between sunitinib and rapamycin on tumor growth was observed. Sunitinib plus rapamycin reduced splenomegaly, MDSCs in spleens and lungs, and microvessel density in tumor microenvironment, while exacerbated hypoxia and promoted cancer lung metastasis. Sunitinib plus rapamycin markedly induced versican, IDO, arginase 1, IL-6, and TGF-β expression in the lungs, whereas it reduced IDO and IL-10 expression in the primary tumor tissues. IL-6 levels in the circulation were increased after rapamycin and combination therapies.
  
  
  CONCLUSIONS
  The combination of sunitinib plus rapamycin reduced the tumor growth but promoted tumor metastasis. This study warrants that further mTOR inhibition treatment should be closely watched in clinical setting, especially combined with antiangiogenic therapy.
authors.affiliation: State Key Laboratory of Biotherapy, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China. Electronic address: yintao03073@163.com.
authors.forename: Tao
authors.initials: T
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Biotherapy, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China. Electronic address: chrinstina-hesisi@yahoo.cn.
authors.forename: Sisi
authors.initials: S
authors.lastname: He
authors.affiliation: State Key Laboratory of Biotherapy, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China. Electronic address: yetinghong0908@163.com.
authors.forename: Tinghong
authors.initials: T
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Biotherapy, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China. Electronic address: shengguobo@126.com.
authors.forename: Guobo
authors.initials: G
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Biotherapy, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China. Electronic address: wanyang1110@gmail.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wan
authors.affiliation: State Key Laboratory of Biotherapy, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China; Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China. Electronic address: wangys75@gmail.com.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Wang
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