TY - JOUR
T1 - CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis
AU - Todaro, Matilde
AU - Gaggianesi, Miriam
AU - Catalano, Veronica
AU - Benfante, Antonina
AU - Iovino, Flora
AU - Biffoni, Mauro
AU - Apuzzo, Tiziana
AU - Sperduti, Isabella
AU - Volpe, Silvia
AU - Cocorullo, Gianfranco
AU - Gulotta, Gaspare
AU - Dieli, Francesco
AU - De Maria, Ruggero
AU - Stassi, Giorgio
PY - 2014/3/6
Y1 - 2014/3/6
N2 - 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.
AB - 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.
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U2 - 10.1016/j.stem.2014.01.009
DO - 10.1016/j.stem.2014.01.009
M3 - Article
C2 - 24607406
AN - SCOPUS:84896115102
VL - 14
SP - 342
EP - 356
JO - Cell Stem Cell
JF - Cell Stem Cell
SN - 1934-5909
IS - 3
ER -