Deficiency in surface expression of E-selectin ligand promotes lung colonization in a mouse model of breast cancer.
Expression of sialyl Lewis(x) (sLe(x)) and sLe(a) on tumor cells is thought to facilitate metastasis by promoting cell adhesion to selectins on vascular endothelial cells. Experiments supporting this concept usually bypass the early steps of the metastatic process by employing tumor cells that are injected directly into the blood. We investigated the relative role of sLe(x) oligosaccharide in the dissemination of breast carcinoma, employing a spontaneous murine metastasis model. An sLe(x) deficient subpopulation of the 4T1 mammary carcinoma cell line was produced by negative selection using the sLe(x)-reactive KM93 MAb. This subpopulation was negative for E-selectin binding but retained P-selectin binding. Both sLe(x)-negative and -positive cells grew at the same rate; however, sLe(x)-negative cells spread more efficiently on plates and had greater motility in wound-scratch assays. Mice inoculated in the mammary fat pad with sLe(x)-negative and -positive variants produced lung metastases. However, the number of lung metastases was significantly increased in the group inoculated with the sLe(x)-negative variant (p = 0.0031), indicating that negative selection for the sLe(x) epitope resulted in enrichment for a subpopulation of cells with a high metastatic phenotype. Cell variants demonstrated significant differences in cellular morphology and pattern of tumor growth in primary and secondary tumor sites. These results strongly suggest that loss of sLe(x) may facilitate the metastatic process by contributing to escape from the primary tumor mass.
Monzavi-Karbassi
Behjatolah
B
Arkansas Cancer Research Center and Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Whitehead
Tracy L
TL
Jousheghany
Fariba
F
Artaud
Cecile
C
Hennings
Leah
L
Shaaf
Saeid
S
Slaughter
Aubrey
A
Korourian
Soheila
S
Kelly
Thomas
T
Blaszczyk-Thurin
Magdalena
M
Kieber-Emmons
Thomas
T
D000818:Animals; D019040:E-Selectin / Q000235:genetics; D005260:Female; D008024:Ligands; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009844:Oligosaccharides / Q000235:genetics*; D000080506:Sialyl Lewis X Antigen
D019040:E-Selectin; D008024:Ligands; D009844:Oligosaccharides; D000080506:Sialyl Lewis X Antigen