title: Atorvastatin (Lipitor) attenuates the effects of aspirin on pancreatic cancerogenesis and the chemotherapeutic efficacy of gemcitabine on pancreatic cancer by promoting M2 polarized tumor associated macrophages.
abstract: BACKGROUND
  Interactions of inflammatory cells with pancreatic cancer cells play crucial roles in pancreatic cancer, however the dynamic changes of inflammatory cell populations in pancreatic cancerogensis and after chemotherapy have not been well eclucidated. The combinational use of aspirin and atrovastatin (Lipitor) have been widely prescribled for cardio-cerebral vascular diseases mainly by regulation of inflammations, and they have been also reported to have plausible anti-tumor effects, however their potential roles in pancreatic cancerogenesis and chemotherapeutic effects have been seldom investigated. We scanned the dynamic changes of pan-inflammatory cell populations in pancreatic cancerogensis and after chemotherapy and found the potential target cell populations. Then we tested the roles of aspirin and Lipitor to regulate these inflammatory cell populations and their effects on pancreatic cancerogenesis and chemotherapeutic effects.
  
  
  METHODS
  Cancerogen, dimethylbenzanthracene (DMBA), was used to induce pancreatic cancerogenesis and subcatunous implantation of syngenic murine Panc02 pancreatic cancer cells was adopted as well. Gemcitabine was used for chemotherapy. The peripheral blood, pancreatic lesions and tumor samples were harvested and analyzed to search for the potential target cell populations. The roles of aspirin and Lipitor to regulate these cell populations and their potential effects on pancreatic cancerogenesis and chemotherapeutic efficacy were investigated both in vitro and in vivo.
  
  
  RESULTS
  We found progressive accumulations of myeloid-derived suppressor cells (MDSC) and M2-polarzied tumor associated macrophages(M2) in pancreatic lesions accompanied with dynamic reducations of cytotoxic T cells(CTL) and helper T cells(Th) in the progression of pancreatic cancerogenesis. After gemcitabine treatment, the MDSC significantly reduced, however M2 soared up unexpectedly. Aspirin could significantly inhibit the MDSC and M2 to prevent pancreatic cancerogenesis and improve chemotherapeutic effects of gemcitabine, however Lipitor did not significantly affect MDSC, instead it could promote M2 to attenuate the postive effects of aspirin and gemcitabine.
  
  
  CONCLUSIONS
  MDSC and M2 accumulate in progression of pancreatic cancerogenesis and gemcitabine can induce M2. Aspirin could prevent pancreatic cancerogenesis and improve efficacy of gemcitabine partially by inhibiting MDSC and M2, however when used in combination, Lipitor could weaken the efficacy of aspirin and gemcitabine partially by promoting M2.
authors.affiliation: Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1# Shuai Fu Yuan, Dong Dan District, Beijing, 100730, China. qfliu@pumch.cams.cn.
authors.forename: Qiaofei
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China. liyuan_6@263.net.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1# Shuai Fu Yuan, Dong Dan District, Beijing, 100730, China. liuzheyu@163.com.
authors.forename: Zheyu
authors.initials: Z
authors.lastname: Niu
authors.affiliation: Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1# Shuai Fu Yuan, Dong Dan District, Beijing, 100730, China. 18810488153@163.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zong
authors.affiliation: Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1# Shuai Fu Yuan, Dong Dan District, Beijing, 100730, China. wangmengyi_1987@163.com.
authors.forename: Mengyi
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1# Shuai Fu Yuan, Dong Dan District, Beijing, 100730, China. yaolutian@gmail.com.
authors.forename: Lutian
authors.initials: L
authors.lastname: Yao
authors.affiliation: Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China. path2008@163.com.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1# Shuai Fu Yuan, Dong Dan District, Beijing, 100730, China. lqpumc@126.com.
authors.forename: Quan
authors.initials: Q
authors.lastname: Liao
authors.affiliation: Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1# Shuai Fu Yuan, Dong Dan District, Beijing, 100730, China. zhao8028@263.net.
authors.forename: Yupei
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology; D001241:Aspirin / Q000008:administration & dosage / Q000009:adverse effects*; D000069059:Atorvastatin / Q000008:administration & dosage* / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D015127:9,10-Dimethyl-1,2-benzanthracene; D000069059:Atorvastatin; D001241:Aspirin; D000093542:Gemcitabine