CD44 variant isoforms promote metastasis formation by a tumor cell-matrix cross-talk that supports adhesion and apoptosis resistance.
CD44 designates a large family of proteins with a considerable structural and functional diversity, which are generated from one gene by alternative splicing. As such, the overexpression of CD44 variant isoform (CD44v) has been causally related to the metastatic spread of cancer cells. To study the underlying mechanism, stable knockdown clones with deletion of exon v7 containing CD44 isoforms (CD44v(kd)) of the highly metastatic rat adenocarcinoma line BSp73ASML (ASML(wt)) were established. ASML-CD44v(kd) clones hardly form lung metastases after intrafootpad application and the metastatic load in lymph nodes is significantly reduced. Rescuing, albeit at a reduced level, CD44v expression in ASML-CD44v(kd) cells (ASML-CD44v(rsc)) restores the metastatic potential. The following major differences in ASML(wt), ASML-CD44v(kd), and ASML-CD44v(rsc) clones were observed: (a) ASML(wt) cells produce and assemble a matrix in a CD44v-dependent manner, which supports integrin-mediated adhesion and favors survival. This feature is lost in the ASML-CD44v(kd) cells. (b) CD44v cross-linking initiates phosphatidylinositol 3-kinase/Akt activation in ASML(wt) cells. Accordingly, apoptosis resistance is strikingly reduced in ASML-CD44v(kd) cells. The capacity to generate an adhesive matrix but not apoptosis resistance is restored in ASML-CD44v(rsc) cells. These data argue for a 2-fold effect of CD44v on metastasis formation: CD44v-mediated matrix formation is crucial for the settlement and growth at a secondary site, whereas apoptosis resistance supports the efficacy of metastasis formation.
Klingbeil
Pamela
P
Department of Tumor Progression and Immune Defense, University Hospital of Surgery, University of Heidelberg, Heidelberg, Germany.
Marhaba
Rachid
R
Jung
Thorsten
T
Kirmse
Robert
R
Ludwig
Thomas
T
Zöller
Margot
M
D000230:Adenocarcinoma / Q000235:genetics / Q000556:secondary*; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D019921:Biotinylation; D015153:Blotting, Western; D002448:Cell Adhesion / Q000235:genetics*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D020868:Gene Silencing / Q000502:physiology; D018960:Hyaluronan Receptors / Q000235:genetics*; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary*; D008207:Lymphatic Metastasis; D018625:Microscopy, Atomic Force; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020033:Protein Isoforms; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014162:Transfection
D003432:Cross-Linking Reagents; D018960:Hyaluronan Receptors; D020033:Protein Isoforms; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt