Summary
We have studied the role of adhesion molecules in metastasis formation by lymphoma and carcinoma cells, particularly in the liver. Certain lymphomas invade the liver extensively, and this process can be mimicked in vitro in hepatocyte cultures. Normal activated T-lymphocytes invade similarly, suggesting that lymphomas use normal lymphocyte invasion mechanisms. Indeed, T-cell hybridomas made by fusion of activated T-cells with a non-metastatic T-lymphoma, metastasize extensively to the liver. In addition, the hybrids disseminate to many other sites, and this correlates with their ability to invade monolayers of embryonic fibroblasts. It is noteworthy that cytotoxic T-cell (CTL) clones are highly invasive in these models, even in the resting state, and CTL hybridomas metastasize widely, suggesting that resting memory CTL can move freely into many tissues. Analysis of known T-cell adhesion molecules in panels of hybrids showed that CD2, VLA4-α and L-selectin are not expressed, and are therefore not indispensable. LFA-1, VLA-6 and CD44 are present on all invasive hybrids.
We have generated LFA-1-deficient mutants of a T-cell hybridoma that showed greatly reduced invasive and metastatic potential. Revenants with LFA-1 expression above a threshold level reacquired invasiveness, further supporting the notion that LFA-1 is required. Transfection of LFA-1α- and β-cDNA into α- and β-deficient mutants, respectively, reversed invasive and metastatic capacity only to a limited extent, suggesting that additional involved molecules were also repressed in the mutants.
Invasion and metastasis of the hybrids is strongly reduced by pretreatment with pertussis toxin, implying that an extracellular ligand that binds to a G-protein-coupled receptor, is required for efficient invasion. We present evidence that this ligand is neither a serum factor nor an autocrine motility factor, but is probably derived from the fibroblasts and hepatocytes. Furthermore, we show that one of the effects of the ligand is the functional activation of LFA-1, because pertussis toxin inhibition can be partially reversed by artificial activation of LFA-1 by Mn2+.
Adhesion of TA3 mammary carcinoma cells to hepatocytes is one of the steps in liver metastasis formation. This adhesion was inhibited by Fab fragments made from polyclonal anti-TA3 IgG. We found that a relevant antigen is a 195 kD molecule that we identified as the β4-integrin subunit. Monospecific anti-α6β4 antibodies purified from the anti-TA3 serum inhibited TA3-hepatocyte adhesion. This shows that α6β4, which so far has only been implicated in cell-matrix adhesion, can also mediate intercellular interactions, and suggests that the high levels of α6β4 often expressed by metastatic carcinoma cells contributes to liver metastasis formation.
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© 1993 Plenum Press, New York
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La Rivière, G., Kemperman, H., Driessens, M. (1993). Adhesion Mechanisms in Lymphoma and Carcinoma Metastasis. In: Hemler, M.E., Mihich, E. (eds) Cell Adhesion Molecules. Pezcoller Foundation Symposia, vol 4. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-2830-2_16
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DOI: https://doi.org/10.1007/978-1-4615-2830-2_16
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