title: CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis.
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.
authors.affiliation: Surgical and Oncological Sciences, University of Palermo, 90127 Palermo, Italy; Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, 90127 Palermo, Italy.
authors.forename: Matilde
authors.initials: M
authors.lastname: Todaro
authors.affiliation: Surgical and Oncological Sciences, University of Palermo, 90127 Palermo, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Gaggianesi
authors.affiliation: Surgical and Oncological Sciences, University of Palermo, 90127 Palermo, Italy; Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, 90127 Palermo, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Catalano
authors.affiliation: Surgical and Oncological Sciences, University of Palermo, 90127 Palermo, Italy; Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, 90127 Palermo, Italy.
authors.forename: Antonina
authors.initials: A
authors.lastname: Benfante
authors.affiliation: Surgical and Oncological Sciences, University of Palermo, 90127 Palermo, Italy.
authors.forename: Flora
authors.initials: F
authors.lastname: Iovino
authors.affiliation: Department of Hematology and Oncology, Istituto Superiore di Sanità, 00161 Rome, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Biffoni
authors.affiliation: Surgical and Oncological Sciences, University of Palermo, 90127 Palermo, Italy; Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, 90127 Palermo, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Apuzzo
authors.affiliation: Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Sperduti
authors.affiliation: Surgical and Oncological Sciences, University of Palermo, 90127 Palermo, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Volpe
authors.affiliation: Surgical and Oncological Sciences, University of Palermo, 90127 Palermo, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Cocorullo
authors.affiliation: Surgical and Oncological Sciences, University of Palermo, 90127 Palermo, Italy.
authors.forename: Gaspare
authors.initials: G
authors.lastname: Gulotta
authors.affiliation: Biopathology and Biomedical Methodologies, University of Palermo, 90134 Palermo, Italy; Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, 90127 Palermo, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Dieli
authors.affiliation: Regina Elena National Cancer Institute, 00144 Rome, Italy. Electronic address: demaria@ifo.it.
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Maria
authors.affiliation: Surgical and Oncological Sciences, University of Palermo, 90127 Palermo, Italy. Electronic address: giorgio.stassi@unipa.it.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Stassi
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D063646:Carcinogenesis / Q000473:pathology; D065150:Cellular Reprogramming; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D015398:Signal Transduction; D016896:Treatment Outcome; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D019485:Bone Morphogenetic Proteins; D018960:Hyaluronan Receptors; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met; D051153:Wnt Proteins; C112697:CD44v6 antigen