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Santos Carlos Chandler Karen Zimmer Stephen Fisher Paul B. Gunthert Ursula Anderson Kimberly Ward 《Cell biochemistry and biophysics》1995,26(1):1-19
A parallel-plate flow chamber was used to quantify the detachment of normal cloned rat embryo fibroblasts (CREF) fibroblasts,ras-transformed CREF fibroblasts (CREF T24), and CREF T24 fibroblasts transfected with a Krev/RAP1A suppressor gene (HK B1) from
a confluent monolayer of normal CREF fibroblasts to determine if the expression patterns of CD44 variants (mol wt 110 and
140 kDa) corresponded with detachment properties and metastatic potential. In the detachment assay, known shear stresses ranging
from 20–24 dyn/cm2 were applied to the adherent cells and the number of cells detached from the monolayer after 180 s was determined. Results
showed that cellular expression of CD44 variants correlated with the metastatic potential of the cells and with the cells’
ability to detach from a monolayer of normal cells. Western blot analysis showed a low level of expression of the CD44 variants
in the normal cell line, CREF, and the lowly metastatic cell line, HK B1. Detachment studies showed a low percentage of detachment
of both of these cell lines from a normal cell monolayer. Tumor-derived (HK B1-T) and lung nodule-derived (HK B1-M) cell lines
were established and both formed tumors and metastasis with reduced latency periods as compared to HK B1, but still showed
a markedly delayed latency period compared to the highly metastatic cell line, CREF T24. Both of these cell lines showed a
higher expression of the CD44 variants as compared to CREF and HK B1, and detached easier than CREF and HK B1. CREF T24 showed
a much higher level of expression of the variants and had a higher percentage detachment than all other cell lines. To further
test the role of the CD44 variants in the ability of the cells to detach from the normal monolayer, CREF cells were transfected
with a DNA construct that constitutively expresses the CD44 variants and the detachment properties of three randomly selected
clones were studied. Clones 2 and 3 showed a low level of expression of the CD44 variants after transfection and detached
from the normal monolayer similar to CREF. Clone 1 showed a high level of expression of the CD44 variants and the detachment
of these cells was significantly higher than CREF. From these results, it is concluded that in the five cell lines studied,
expression of the CD44 variants play a significant role in the ability of the cells to detach from a monolayer of normal cells.
It is hypothesized that this detachment may be an important component of a cell’s ability to metastasize. 相似文献
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McKallip RJ Fisher M Do Y Szakal AK Gunthert U Nagarkatti PS Nagarkatti M 《The Journal of biological chemistry》2003,278(44):43818-43830
In the current study, we investigated the nature and role of CD44 variant isoforms involved in endothelial cell (EC) injury and tumor cell cytotoxicity mediated by IL-2-activated killer (LAK) cells. Treatment of CD44 wild-type lymphocytes with IL-2 led to increased gene expression of CD44 v6 and v7 variant isoforms and to significant induction of vascular leak syndrome (VLS). CD44v6-v7 knockout (KO) and CD44v7 KO mice showed markedly reduced levels of IL-2-induced VLS. The decreased VLS in CD44v6-v7 KO and CD44v7 KO mice did not result from differential activation and expansion of CD8+ T cells, NK, and NK-T cells or from altered degree of perivascular lymphocytic infiltration in the lungs. LAK cells from CD44v7 KO mice showed a significant decrease in their ability to adhere to and mediate lysis of EC but not lysis of P815 tumor cells in vitro. CD44v7-mediated lysis of EC by LAK cells was dependent on the activity of phosphatidylinositol 3-kinase and tyrosine kinases. Interestingly, IL-2-activated LAK cells expressing CD44hi but not CD44lo were responsible for EC lysis. Furthermore, lysis of EC targets could be blocked by addition of soluble or enzymatic cleavage of CD44v6-v7-binding glycosaminoglycans. Finally, anti-CD44v7 mAbs caused a significant reduction in the adherence to and killing of EC and led to suppression of IL-2-induced VLS. Together, this study suggests that the expression of CD44v7 on LAK cells plays a specific role in EC injury and that it may be possible to reduce EC injury but not tumor cell killing by specifically targeting CD44v7. 相似文献
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