title: Mutations in the Ras-Raf Axis underlie the prognostic value of CD133 in colorectal cancer.
abstract: OBJECTIVE
  High expression of cancer stem cell (CSC) marker CD133 has been used as a predictor for prognosis in colorectal cancer (CRC), suggesting that enumeration of CSCs, using CD133, is predictive for disease progression. However, we showed recently that both CD133 mRNA and protein are not downregulated during differentiation of colon CSCs, pointing to an alternative reason for the prognostic value of CD133. We therefore set out to delineate the relation between CD133 expression and prognosis.
  
  
  METHODS
  A CRC patient series was studied for expression of CD133 and other CSC markers by microarray and quantitative PCR analysis. In addition, several common mutations were analyzed to determine the relation with CD133 expression.
  
  
  RESULTS
  CD133 mRNA expression predicted relapse-free survival in our patient series, whereas several other CSC markers could not. Moreover, no correlation was found between expression of other CSC markers and CD133. Interestingly, high CD133 expression was related to mutations in K-Ras and B-Raf, and inhibition of mutant K-Ras or downstream mitogen-activated protein kinase kinase (MEK) signaling decreases CD133 expression. In addition, an activated K-Ras gene expression signature could predict CD133 expression in our patient set as well as data sets of other tumor types.
  
  
  CONCLUSIONS
  CD133 expression is upregulated in CRC tumors that have a hyperactivated Ras-Raf-MEK-ERK pathway and is therefore related to mutations in K-Ras or B-Raf. As mutations in either gene have been related to poor prognosis, we conclude that CD133 expression is not indicative for CSC numbers but rather related to the mutation or activity status of the Ras-Raf pathway.
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Kristel
authors.initials: K
authors.lastname: Kemper
authors.forename: Miranda
authors.initials: M
authors.lastname: Versloot
authors.forename: Katherine
authors.initials: K
authors.lastname: Cameron
authors.forename: Selçuk
authors.initials: S
authors.lastname: Colak
authors.forename: Felipe
authors.initials: F
authors.lastname: de Sousa e Melo
authors.forename: Joan H
authors.initials: JH
authors.lastname: de Jong
authors.forename: Joanne
authors.initials: J
authors.lastname: Bleackley
authors.forename: Louis
authors.initials: L
authors.lastname: Vermeulen
authors.forename: Rogier
authors.initials: R
authors.lastname: Versteeg
authors.forename: Jan
authors.initials: J
authors.lastname: Koster
authors.forename: Jan Paul
authors.initials: JP
authors.lastname: Medema
mesh_terms: D000071916:AC133 Antigen; D015703:Antigens, CD / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics*; D018572:Disease-Free Survival; D011905:Genes, ras; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D014408:Biomarkers, Tumor; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases