Stem cell CD44v isoforms promote intestinal cancer formation in Apc(min) mice downstream of Wnt signaling

TY - JOUR

T1 - Stem cell CD44v isoforms promote intestinal cancer formation in Apc(min) mice downstream of Wnt signaling

AU - Zeilstra, J

AU - Joosten, S P J

AU - van Andel, H

AU - Tolg, C

AU - Berns, A

AU - Snoek, M

AU - van de Wetering, M

AU - Spaargaren, M

AU - Clevers, H

AU - Pals, S T

PY - 2014/1/30

Y1 - 2014/1/30

N2 - A gene signature specific for intestinal stem cells (ISCs) has recently been shown to predict relapse in colorectal cancer (CRC) but the tumorigenic role of individual signature genes remains poorly defined. A prominent ISC-signature gene is the cancer stem cell marker CD44, which encodes various splice variants comprising a diverse repertoire of adhesion and signaling molecules. Using Lgr5 as ISC marker, we have fluorescence-activated cell sorting-purified ISCs to define their CD44 repertoire. ISCs display a specific set of CD44 variant isoforms (CD44v), but remarkably lack the CD44 standard (CD44s) isoform. These CD44v also stand-out in transformed human ISCs isolated from microadenomas of familial adenomatous polyposis patients. By employing knock-in mice expressing either CD44v4-10 or CD44s, we demonstrate that the CD44v isoform, but not CD44s, promotes adenoma initiation in Apc(Min/+)mice. Our data identify CD44v as component of the ISCs program critical for tumor initiation, and as potential treatment target in CRC.

AB - A gene signature specific for intestinal stem cells (ISCs) has recently been shown to predict relapse in colorectal cancer (CRC) but the tumorigenic role of individual signature genes remains poorly defined. A prominent ISC-signature gene is the cancer stem cell marker CD44, which encodes various splice variants comprising a diverse repertoire of adhesion and signaling molecules. Using Lgr5 as ISC marker, we have fluorescence-activated cell sorting-purified ISCs to define their CD44 repertoire. ISCs display a specific set of CD44 variant isoforms (CD44v), but remarkably lack the CD44 standard (CD44s) isoform. These CD44v also stand-out in transformed human ISCs isolated from microadenomas of familial adenomatous polyposis patients. By employing knock-in mice expressing either CD44v4-10 or CD44s, we demonstrate that the CD44v isoform, but not CD44s, promotes adenoma initiation in Apc(Min/+)mice. Our data identify CD44v as component of the ISCs program critical for tumor initiation, and as potential treatment target in CRC.

KW - Adenomatous Polyposis Coli

KW - Animals

KW - Antigens, CD44

KW - Cell Transformation, Neoplastic

KW - Flow Cytometry

KW - Gene Expression Profiling

KW - Gene Knock-In Techniques

KW - Intestinal Neoplasms

KW - Mice

KW - Mice, Transgenic

KW - Neoplastic Stem Cells

KW - Protein Isoforms

KW - Receptors, G-Protein-Coupled

KW - Tumor Cells, Cultured

KW - Wnt Signaling Pathway

U2 - 10.1038/onc.2012.611

DO - 10.1038/onc.2012.611

M3 - Article

C2 - 23318432

SN - 0950-9232

VL - 33

SP - 665

EP - 670

JO - Oncogene

JF - Oncogene

IS - 5

ER -