CD44s expression in human colon carcinomas influences growth of liver metastases.
CD44 is a family of cell-surface adhesion molecules which exist in several isoforms arising from mRNA alternative. Malignant transformation of colonic mucosa is associated with alterations in CD44 expression, which result in up-regulation of high-molecular-weight CD44 isoforms and down-regulation of CD44s. We have demonstrated that stable transfection of CD44s into colon-carcinoma cell lines reduces their tumorigenicity. To understand the influence of CD44s expression on the metastatic potential of human colon carcinomas, we measured the ability of several different CD44s-transfected colon carcinomas to establish experimental liver metastases following splenic inoculation in mice. We observed that introduction of CD44s into 2 different human colon carcinoma cell lines, HT29 and KM12C6, resulted in reduced growth of liver metastases by as much as 75%. To explore the relationship between hyaluronate adhesion and metastasis, we transfected HT29 cells with cDNA encoding a mutant CD44s that does not bind to hyaluronate. HT29 transfectants expressing this mutant CD44s demonstrate an 84% reduction in growth of liver metastases, despite minimal binding to hyaluronate by the mutant CD44s. In concert, these results indicate that CD44s down-regulation, which occurs with malignant transformation of colonic mucosa, is associated with enhanced growth of experimental liver metastases. Consequently, the functional consequences of CD44s down-regulation in colon carcinomas may be just as significant as the consequences of up-regulation of other CD44 isoforms.
Choi
S H
SH
Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Takahashi
K
K
Eto
H
H
Yoon
S S
SS
Tanabe
K K
KK
D017398:Alternative Splicing; D000818:Animals; D002455:Cell Division; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000502:physiology*; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D018960:Hyaluronan Receptors; D020033:Protein Isoforms; D011994:Recombinant Proteins