Differential expression of genes by tumor cells of a low or a high malignancy phenotype: The case of murine and human Ly-6 proteins

Abstract

Progression of tumor cells toward a high malignancy phenotype and metastasis is a multi-event cascade involving inter alia alterations in the expression of various genes. The focus of our laboratory is on genes whose altered expression may lead, directly or indirectly, to an increased malignancy phenotype. The identification of such genes and the evaluation of the consequences of their altered expression is essential for attempts to halt tumor progression and prevent metastasis formation. Published work originating in our laboratory showed that members of the murine Ly-6 supergene family are involved in the progression of certain mouse tumors. The expression level of several members of this family was higher on highly malignant cells than on tumor cells expressing a lower malignancy phenotype. Sorting by flow cytometry of tumor cells to subpopulations expressing either high or low levels of Ly-6E.1 yielded correspondingly cells expressing a high or a low malignancy phenotype. The high malignancy, high Ly-6E.1-expressing cells also expressed high levels of the receptor for urokinase plasminogen activator (uPAR), whereas low malignancy, low Ly-6E.1-expressing cells also expressed low levels of uPAR. Transfection studies indicated that uPAR was causally involved in conferring a high malignancy phenotype upon tumor cells expressing high levels of Ly-6E.1. E48 is a human homologue of the murine ThB protein, a member of the Ly-6 supergene family (but distinct from the Ly-6E.1 protein mentioned above) and expressed on head and neck squamous carcinoma cells. Experiments currently in progress are aimed to find out whether E48 is involved in the progression of such cancer cells. Using the differential display technology, it was shown that ligation of E48 on tumor cells by the corresponding antibodies (serving as a surrogate for an as yet unidentified E48 ligand) upregulates an enzyme (FX) involved in the biosynthesis of GDP-L-fucose. Fucose is an essential component of certain selectin ligands.

A crucial function of PDGF in TGF-β-mediated cancer progression of hepatocytes

“…Induction of the TGF-b induced protease furin, which converts latent TGF-b to an active cytokine (Dubois et al, 2001), may contribute to the maintenance of the autocrine TGF-b loop. Furthermore, Ly6a.2, a cell surface marker particularly enriched on metastatic cells (Witz, 2000), was sharply increased (>50-fold) after prolonged TGFb1 treatment. Changes in integrin patterning displayed upregulation of the fibronectin receptor subunit integrin b1 and the concerted decrease of the parenchymalenriched isoform integrin b4.…”

Epidermal growth factor-induced hepatocellular carcinoma: gene expression profiles in precursor lesions, early stage and solitary tumours

“…We observed overexpression of minopontin (osteopontin), RRM2 and Ly6d in small tumours of EGF2B mice. Overexpression of the latter genes was observed in human cancers and correlated with invasiveness and metastatic potential (Chen et al, 2000;Witz, 2000;Gotoh et al, 2002).…”

Nonadherent culture method downregulates stem cell antigen-1 expression in mouse bone marrow mesenchymal stem cells

“…A previous study indicated that the upregulated expression of Sca-1 is associated with a more destructive tumor phenotype (25). Furthermore, in mouse models, Sca-1 has been shown to be associated with greater tumorigenic potential (26).…”