CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis

Ruggero De Maria Marchiano, Matilde Todaro, Miriam Gaggianesi, Veronica Catalano, Antonina Benfante, Flora Iovino, Mauro Biffoni, Tiziana Apuzzo, Isabella Sperduti, Silvia Volpe, Gianfranco Cocorullo, Gaspare Gulotta, Francesco Dieli, Giorgio Stassi

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

417 Citazioni (Scopus)

Abstract

Cancer stem cells drive tumor formation and metastasis, but how they acquire metastatic traits is not well understood. Here, we show that all colorectal cancer stem cells (CR-CSCs) express CD44v6, which is required for their migration and generation of metastatic tumors. CD44v6 expression is low in primary tumors but demarcated clonogenic CR-CSC populations. Cytokines hepatocyte growth factor (HGF), osteopontin (OPN), and stromal-derived factor 1α (SDF-1), secreted from tumor associated cells, increase CD44v6 expression in CR-CSCs by activating the Wnt/β-catenin pathway, which promotes migration and metastasis. CD44v6(-) progenitor cells do not give rise to metastatic lesions but, when treated with cytokines, acquire CD44v6 expression and metastatic capacity. Importantly, phosphatidylinositol 3-kinase (PI3K) inhibition selectively killed CD44v6 CR-CSCs and reduced metastatic growth. In patient cohorts, low levels of CD44v6 predict increased probability of survival. Thus, the metastatic process in colorectal cancer is initiated by CSCs through the expression of CD44v6, which is both a functional biomarker and therapeutic target.
Lingua originaleEnglish
pagine (da-a)342-356
Numero di pagine15
RivistaCell Stem Cell
Volume14
DOI
Stato di pubblicazionePubblicato - 2014

Keywords

  • Animals
  • Antigens, CD44
  • Biomarkers, Tumor
  • Bone Morphogenetic Proteins
  • Carcinogenesis
  • Cellular Reprogramming
  • Colonic Neoplasms
  • Fibroblasts
  • Humans
  • Mice, SCID
  • Neoplasm Metastasis
  • Neoplasm Proteins
  • Neoplastic Stem Cells
  • Phosphatidylinositol 3-Kinases
  • Prognosis
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-met
  • Signal Transduction
  • Treatment Outcome
  • Wnt Proteins

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