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Tumor Biology |
vß8 in the Negative Regulation of Epithelial Cell Growth1
Departments of Anatomic Pathology [S. C., D-z. M., D. O., K. B., S. L. N.], Medicine [W-h. L., V. C. B.], and the Lung Biology Center [S. C., D-z. M., D. O., K. B., W-h. L., V. C. B., S. L. N.], University of California at San Francisco, San Francisco, California 94143, and the Pulmonary and Mediastinal Pathology Section of the Armed Forces Institute of Pathology, Washington, DC 20306 [W. T.]
The control of cell growth is regulated through coordinated responses to
growth factors and cell-extracellular matrix (ECM) interactions.
Integrins, the major family of cell-ECM receptors, are vital to these
coordinated responses. Although much is known of the role of integrins
in growth promotion, specific examples of integrin-mediated cell growth
inhibition are few. On the basis of our findings that the integrin ß8
subunit is expressed in airway epithelial cells and is absent in lung
cancers, we investigated the role and mechanism of the integrin
vß8 in mediating growth inhibition. When introduced into either a
lung or colon carcinoma cell line, ß8 inhibited cell growth without
inducing apoptosis. Ligation of vß8 also induced cell rounding,
inhibited focal contact formation, and initiated an inhibitory
signaling pathway as demonstrated by increased expression of the
cyclin-dependent kinase inhibitor p21Cip1. The cytoplasmic
domain of ß8 was capable of both growth inhibition and causing cell
shape changes as shown by the use of a chimeric integrin construct
consisting of the ß8-cytoplasmic domain coupled to the
ß6-extracellular domain. Finally, when tested in vivo,
ß8 potently inhibited tumor growth in nude mice. Together, these
results implicate vß8 as a novel growth-regulatory molecule of
epithelial cells.
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