title: Hypoxia-induced cell stemness leads to drug resistance and poor prognosis in lung adenocarcinoma.
abstract: BACKGROUND
  Since cancer stem cells exhibit embryonic-like self-renewal characteristics and malignant behavior, including drug resistance and metastasis, they may be the origin of tumorigenesis and cancer recurrence. Cancer cell stemness is also highly relevant to cancer in hypoxic environments.
  
  
  METHODS
  In our study, we used cobalt dichloride (CoCl2) to create a hypoxic environment for lung adenocarcinoma A549 cells and the cisplatine-resistant cell line A549/DDP. The cancer stem-like CD166 positive population and the cells' stemness were detected by flowcytometry and quantitative real-time PCR after separation using magnetic antibodies. Drug resistance to cisplatine, docetaxel and pemetrexed was also measured. Finally, a tissue array was used to analyze the relationship between hypoxia-induced stemness and overall survival after radical surgery.
  
  
  RESULTS
  Data showed that chemical-induced hypoxia changed cell stemness by enhancing stem cell transcription factors and markers of chemotherapeutic drug resistance. The CD166-positive cancer stem cell-like population showed greater drug resistance than the CD166-negative cells. Tissue array studies also suggested a poorer prognosis for patients whose tissue expressed higher CD166 levels.
  
  
  CONCLUSIONS
  Our findings indicate that chemical hypoxia may augment cancer cell stemness and drug resistance in CD166-positive stem cells. Therefore, targeting the stem-like cell population, especially CD166-positive cells, may represent a novel therapeutic strategy to treat lung cancer.
authors.affiliation: Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
authors.forename: Mingchuan
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Oncology, Fuda Hospital, School of Medicine, Jinan University, Guangzhou, China.
authors.forename: Yishi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Thoracic Surgery, Huashan Hospital, School of Medicine, Fudan University, Shanghai, China.
authors.forename: Huijun
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Thoracic Surgery, Huashan Hospital, School of Medicine, Fudan University, Shanghai, China.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Center for Translational Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
authors.forename: Heyong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Zeng
authors.affiliation: Department of Thoracic Surgery, Huashan Hospital, School of Medicine, Fudan University, Shanghai, China. Electronic address: cxf3166@126.com.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Chen
authors.affiliation: Center for Translational Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China. Electronic address: liugt2000@gmail.com.
authors.forename: Gentao
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
authors.forename: Caicun
authors.initials: C
authors.lastname: Zhou
mesh_terms: D020410:Activated-Leukocyte Cell Adhesion Molecule / Q000235:genetics / Q000378:metabolism; D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D015415:Biomarkers; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D016130:Immunophenotyping; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D020410:Activated-Leukocyte Cell Adhesion Molecule; D000970:Antineoplastic Agents; D015415:Biomarkers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger
keywords: CD166; Cancer stem cells; Drug resistance; Hypoxia; Lung adenocarcinoma