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Stimulation of ß₁ Integrin Down-Regulates ICAM-1 Expression and ICAM-1-dependent Adhesion of Lung Cancer Cells through Focal Adhesion Kinase¹

Second Department of Surgery [M. Y., M. S., T. S., M. Tak., K. Y.], First Department of Internal Medicine [Y. T., K. F.], and Kidney Center [M. Tam.], School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu 807-8555, Japan

Adhesion molecules are involved in intracellular signaling in various physiological and pathological processes including metastasis and growth of tumor cells. Tumor cells interact with various host cells as well as with extracellular matrices through certain adhesion molecules such as integrins. We here propose that stimulation of ß1 integrin reduces intercellular adhesion molecule (ICAM)-1-mediated interaction of lung cancer cells with CTLs. This concept is based on the following findings: (a) engagement of ß1 integrins on certain lung cancer cells by a specific antibody or by ligand matrices such as fibronectin and collagen markedly reduced ICAM-1 expression on the cell surface and induced sICAM-1; (b) down-regulation of ICAM-1 by stimulation of ß1 integrins was abrogated by tyrosine kinase inhibitors or by transfection of dominant negative truncations of focal adhesion kinase (FAK); (c) engagement of ß1 integrins also reduced ICAM-1-dependent adhesion of lung cancer cells to T cells, a process completely inhibited by tyrosine kinase inhibitors and by transfection of dominant negative forms of FAK; and (d) stimulation of ß1 integrins prevented killing of lung cancer cells by autologous CTLs. In malignant tumors, cancer cells, including lung cancer cells, are surrounded by extracellular matrix proteins such as fibronectin and collagen. This suggests that the engagement of ß1 integrins by matrix proteins potentially occurs in cancer cells in vivo and that continuous stimulation via ß1 integrins reduces ICAM-1-expression, ICAM-1-mediated adhesion of cancer cells to CTLs and their killing by CTLs. Our results suggest that such processes can lead to the escape of lung cancer cells in vivo from immunological surveillance.

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