Expression of the CD44v2-10 isoform confers a metastatic phenotype: importance of the heparan sulfate attachment site CD44v3.
We expressed the full-length CD44v2-10 isoform in SKHep1 cells, a nonmetastatic human hepatocellular carcinoma cell line that does not express any endogenous CD44v isoforms. In SCID mice, expression of CD44v2-10 by SKHep1 cells had no effect on s.c. primary tumor development but caused pulmonary metastases in 41% (7 of 17) of animals compared with control SKHep1 cells (0 of 16; P < 0.01). CD44v2-10 expression by SKHep1 cells resulted in enhanced heparan sulfate (HS) attachment and an enhanced capacity to bind heparin-binding growth factors. Mutation of the v3 domain to prevent HS attachment and growth factor binding abolished the metastatic phenotype, demonstrating that HS modification of CD44v2-10 plays a critical role in the development of metastases in this model. However, in vitro proliferation, motility, and invasion were not altered by CD44v2-10 expression.
Barbour
Andrew P
AP
Cancer Metastasis Laboratory, University of Queensland and the Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
Reeder
Jennifer A
JA
Walsh
Michael D
MD
Fawcett
Jonathan
J
Antalis
Toni M
TM
Gotley
David C
DC
D017398:Alternative Splicing; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D006133:Growth Substances / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000556:secondary; D009362:Neoplasm Metastasis; D020033:Protein Isoforms; D014407:Tumor Cells, Cultured
D006133:Growth Substances; D006497:Heparan Sulfate; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D020033:Protein Isoforms; C121450:CD44V3,8-10