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A role for the integrin alphavbeta8 in the negative regulation of epithelial cell growth
S Cambier1, D Z Mu, D O'Connell
1Department of Anatomic Pathology, University of California at San Francisco, 94143, USA.
Abstract:
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 beta8 subunit is expressed in airway epithelial cells and is absent in lung cancers, we investigated the role and mechanism of the integrin alphavbeta8 in mediating growth inhibition. When introduced into either a lung or colon carcinoma cell line, beta8 inhibited cell growth without inducing apoptosis. Ligation of alphavbeta8 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 beta8 was capable of both growth inhibition and causing cell shape changes as shown by the use of a chimeric integrin construct consisting of the beta8-cytoplasmic domain coupled to the beta6-extracellular domain. Finally, when tested in vivo, beta8 potently inhibited tumor growth in nude mice. Together, these results implicate alphavbeta8 as a novel growth-regulatory molecule of epithelial cells.
Insights
Integrin alphavbeta8, absent in lung cancers, inhibits epithelial cell growth and tumor growth in vivo. This discovery reveals integrin alphavbeta8 as a novel growth-regulatory molecule.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Cell growth is regulated by growth factors and cell-extracellular matrix (ECM) interactions.
- Integrins are key cell-ECM receptors crucial for cellular responses.
- While integrin roles in growth promotion are known, integrin-mediated growth inhibition is less understood.
Purpose of the Study:
- Investigate the role of integrin alphavbeta8 in mediating cell growth inhibition.
- Determine the mechanism by which integrin alphavbeta8 regulates cell growth.
Main Methods:
- Expressing integrin beta8 subunit in lung and colon carcinoma cell lines.
- Utilizing chimeric integrin constructs to analyze the beta8 cytoplasmic domain function.
- Assessing tumor growth inhibition in vivo using nude mouse models.
Main Results:
- Integrin beta8 expression inhibited cell growth without inducing apoptosis.
- Ligation of alphavbeta8 led to cell rounding, reduced focal contacts, and increased p21Cip1 expression.
- The beta8 cytoplasmic domain alone mediated growth inhibition and cell shape changes.
- In vivo studies showed potent inhibition of tumor growth by beta8.
Conclusions:
- Integrin alphavbeta8 acts as a novel growth-regulatory molecule in epithelial cells.
- The findings suggest alphavbeta8's potential as a therapeutic target for cancers lacking its expression.