Involvement of heparanase in tumor progression and normal differentiation.
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Animals↗
Biomedical subjects
R Eshel
Publications and source records attributed to R Eshel.
The FX enzyme is a functional component of lymphocyte activation.
Fucose is an essential constituent of selectin ligands. These molecules mediate the initial contact between extravasating leukocytes and endothelial cells. The generation of GDP-L-fucose by the FX enzyme is the final step of fucose biosynthesis. Recently, we demonstrated that outside-in signaling regulates the expression of the FX enzyme in certain cancer cells. The present study demonstrates that the polyclonal activation of T and B cells significantly up-regulated the expression of the FX enzyme and of the fucosylated selectin ligands sLe-x and CLA. Treatment of T cells with FX antisense oligonucleotides significantly decreased selectin ligand expression upon activation. We conclude that FX is regulated by outside-in signals also in lymphocytes and that this enzyme is involved in the biosynthesis of selectin ligands in such cells. We propose that FX takes part in the cascade of events leading to the extravasation of activated lymphocytes.
Antigens, CD19↗
The GPI-linked Ly-6 antigen E48 regulates expression levels of the FX enzyme and of E-selectin ligands on head and neck squamous carcinoma cells.
By differential display we demonstrated that antibody-mediated ligation of the GPI-linked protein product of E48, a newly discovered human Ly-6 gene, up-regulates the expression of the FX enzyme in 3 lines of head and neck squamous carcinoma cells. FX is responsible for the last step in the synthesis of GDP-L-fucose. The up-regulation of FX was E48 ligand-specific. 22AWT head and neck squamous carcinoma cells expressing high levels of E48 expressed significantly higher levels of FX than the E48 antisense transfected 22AWT cells (8-3 cells). The former cells also expressed higher levels of two major fucosylated glycans (the selectin ligand, Sialyl Lewis a, and VIM-2) than the E48 antisense transfectants. Conversely, transfection of cells from the 14CWT line expressing very low levels of E48 with E48 cDNA caused an up-regulated expression of FX and of the two fucosylated glycans in the 14C-CMV16 transfectants. Moreover, the expression levels of Sialyl Lewis a was significantly up-regulated on HNSCC upon ligation of E48 by anti-E48 antibodies. The functional significance of the E48-mediated up-regulation of Sialyl Lewis a was demonstrated in rolling experiments on E-selectin bearing surfaces under physiological conditions of shear flow and on tumor necrosis factor alpha-activated human umbilical venous endothelial cells. Only high E48/FX/Sialyl Lewis a expressing 14C-CMV16 cells could roll on purified E-selectin or establish E-selectin dependent rolling on the activated human umbilical venous endothelial cells. Low E48/FX/Sialyl Lewis a expressing 14CWT cells did not roll. These results show that E48 controls the expression of the FX enzyme and of certain fucosylated E-selectin ligands by HNSCC. E48 may thus function as a key regulator of the adhesiveness of these tumor cells to inflamed vessel walls expressing E-selectin.
Antigens, Ly↗
Expression of Ly-6, a marker for highly malignant murine tumor cells, is regulated by growth conditions and stress.
Ly-6E.1 is highly expressed in murine tumor cells with a high malignancy phenotype and may serve as a marker for such a phenotype. In this study, we examined the effects of various growth conditions and stress on the expression levels of Ly-6E.1 by tumor cells. Previous preliminary results have shown that murine DA3 mammary tumor cells expressing high levels of Ly-6E.1 (Ly-6(hi)) are more highly tumorigenic than the same tumor cells expressing low levels of this membrane protein (Ly-6(lo)). In this study, we demonstrate that mice bearing Ly-6(hi) DA3 tumors have a significantly higher burden of spontaneous pulmonary metastasis than mice bearing Ly-6(lo) DA3 tumors. Furthermore, the survival time of the former mice was significantly shorter than that of the latter ones. We further show that certain other members of the Ly-6 gene family such as Ly-6C.1 and Ly-6G.1 are coregulated with Ly-6E.1. This was shown to occur with respect to both DA3 cells as well as A3 tumor cells which are of fibroblast origin. However, these 2 cells differ with respect to regulation of Sca-2 (TSA1, another member of the Ly-6 family) expression on these cells. Levels of Sca-2 on A3 cells appear to be coregulated with Ly-6E.1 (i.e., Ly-6(hi) A3 cells express high levels of Sca-2 and Ly-6(lo) A3 cells express low levels of Sca-2). These 2 Ly-6 proteins were, however, not coregulated on DA3 cells. Both Ly-6(hi) as well as Ly-6(lo) DA3 cells express equal levels of Sca-2. Levels of Thy-1, another glycosylphosphatidylinositol (GPI)-anchored protein expressed by A3 tumor cells, were equally expressed by both Ly-6(hi) and Ly-6(lo) A3 tumor cells. Levels of Ly-6 (but not those of CD44) on A3 tumor cells were upregulated on cells from dense cultures but were not influenced by the position of the cells in the cell cycle. Stress conditions such as serum starvation or heat shock upregulated the expression of Ly-6 by the 2 types of tumor cells but did not induce apoptosis in these cells. The kinetics of the stress-dependent upregulation of Ly-6 expression differed, however, between the epithelial and fibroblastic tumor cells.
3T3 Cells↗
Microenvironmental factors regulate Ly-6 A/E expression on PyV-transformed BALB/c 3T3 cells.
In previous studies non-lymphoid murine tumor cells were sorted by flow cytometry, into 2 subpopulations. The one expressed high levels of the T-cell activation protein Ly-6 A/E and the other low levels of this protein. High Ly-6 A/E expression was associated with very high tumorigenicity and metastatic phenotypes. Cells expressing low levels of this protein expressed a significantly reduced malignancy phenotype as compared to unsorted tumor populations. In view of its direct (or indirect) involvement in tumor progression we studied, in the present work, the regulation by microenvironmental factors of Ly-6 A/E expression on A3C polyoma-virus transformed cells. Ligation of membrane Ly-6 A/E by the corresponding monoclonal antibodies resulted in up-regulated expression of this protein. Similar results were obtained by exposing A3C cells to interferon-alpha. In contrast, exposing tumor cells to tumor necrosis factor-alpha or to the extracellular matrix protein laminin resulted in a down-regulation of Ly-6 A/E expression on these cells. These results provide an additional insight into the role microenvironmental factors might play in tumor progression.
3T3 Cells↗
An association between high Ly-6A/E expression on tumor cells and a highly malignant phenotype.
Murine Ly-6 is a molecule expressed by various cells, including several types of hematopoietic cells such as pluripotent stem cells, and activated T cells. Ly-6 is also expressed on tumor cells originating from a variety of tissues. Preliminary observations suggested that the expression of Ly-6A/E is up-regulated on highly tumorigenic variants of polyoma-virus(PyV)-transformed BALB/c 3T3 cells as compared with weakly tumorigenic variants. On the basis of these observations, we sorted PyV-transformed A3C cells or DA3 mammary adenocarcinoma cells into stable sub-populations expressing high or low levels of membrane or mRNA Ly-6A/E. In vivo studies indicated that the high-Ly-6A/E-expressing cells in both tumor systems expressed a considerably more malignant phenotype (higher efficiency in local tumor production as well as in lung colonization) than low-Ly-6A/E expressors. Since the high-Ly-6A/E expressors did not exhibit any growth advantage in vitro over low Ly-6A/E expressors, we concluded that interactions of the former cells with micro-environmental factors operating in vivo (e.g., Ly-6A/E ligands) conferred upon these cells a highly malignant phenotype. Apart from the difference in Ly-6A/E expression, no other phenotypic characteristics distinguished highly from weakly malignant tumor cells. Similarly to T cells, where antibodies to Ly-6 transduce (or co-transduce) a proliferative signal, antibodies to Ly-6A/E were found to transduce a mitogenic signal to high-Ly-6A/E-expressing tumor cells but not to low-Ly-6A/E expressors. Taken together, these results show that Ly-6A/E expression is directly or indirectly associated in vivo with a highly malignant phenotype of 2 types of non-lymphoid murine tumors.
3T3 Cells↗
Autobiographical perspectives: severe communication handicaps.
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Autobiographies as Topic↗