title: CD133(+)CXCR4(+) colon cancer cells exhibit metastatic potential and predict poor prognosis of patients.
abstract: BACKGROUND
  Colorectal cancer (CRC), which frequently metastasizes to the liver, is one of the three leading causes of cancer-related deaths worldwide. Growing evidence suggests that a subset of cells exists among cancer stem cells. This distinct subpopulation is thought to contribute to liver metastasis; however, it has not been fully explored in CRC yet.
  
  
  METHODS
  Flow cytometry analysis was performed to detect distinct subsets with CD133 and CXCR4 markers in human primary and metastatic CRC tissues. The 'stemness' and metastatic capacities of different subpopulations derived from the colon cancer cell line HCT116 were compared in vitro and in vivo. The roles of epithelial-mesenchymal transition (EMT) and stromal-cell derived factor-1 (SDF-1) in the metastatic process were also investigated. A survival curve was used to explore the correlation between the content of CD133(+)CXCR4(+) cancer cells and patient survival.
  
  
  RESULTS
  In human specimens, the content of CD133(+)CXCR4(+) cells was higher in liver metastases than in primary colorectal tumors. Clonogenic and tumorigenic cells were restricted to CD133(+) cells in the HCT116 cell line, with CXCR4 expression having no impact on the 'stemness' properties. We found that CD133(+)CXCR4(+)cancer cells had a high metastatic capacity in vitro and in vivo. Compared with CD133(+)CXCR4(-) cells, CD133(+)CXCR4(+)cancer cells experienced EMT, which contributed partly to their metastatic phenotype. We then determined that SDF-1/CXCL12 treatment could further induce EMT in CD133(+)CXCR4(+)cancer cells and enhance their invasive behavior, while this could not be observed in CD133(+)CXCR4- cancer cells. Blocking SDF-1/CXCR4 interaction with a CXCR4 antagonist, AMD3100 (1,10-[1,4-phenylenebis(methylene)]bis-1,4,8,11 -tetraazacyclotetradecane octahydrochloride), inhibited metastatic tumor growth in a mouse hepatic metastasis model. Finally, a high percentage of CD133(+)CXCR4(+)cells in human primary CRC was associated with a reduced two-year survival rate.
  
  
  CONCLUSIONS
  Strategies targeting the SDF-1/CXCR4 interaction may have important clinical applications in the suppression of colon cancer metastasis. Further investigations on how high expression of CXCR4 and EMT occur in this identified cancer stem cell subset are warranted to provide insights into our understanding of tumor biology.
authors.affiliation: Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Shan-shan
authors.initials: SS
authors.lastname: Zhang
authors.forename: Zhi-peng
authors.initials: ZP
authors.lastname: Han
authors.forename: Ying-ying
authors.initials: YY
authors.lastname: Jing
authors.forename: Shuang-fen
authors.initials: SF
authors.lastname: Tao
authors.forename: Tie-jun
authors.initials: TJ
authors.lastname: Li
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Xue
authors.initials: X
authors.lastname: Zhao
authors.forename: Xiao-dong
authors.initials: XD
authors.lastname: Xu
authors.forename: En-da
authors.initials: ED
authors.lastname: Yu
authors.forename: Yao-cheng
authors.initials: YC
authors.lastname: Rui
authors.forename: Hou-jia
authors.initials: HJ
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Li-xin
authors.initials: LX
authors.lastname: Wei
mesh_terms: D000071916:AC133 Antigen; D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D003110:Colonic Neoplasms / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005434:Flow Cytometry; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000737:chemistry / Q000378:metabolism / Q000556:secondary; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D019718:Receptors, CXCR4