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Association of the Decreased Expression of 3ß1 Integrin with the Altered Cell: Environmental Interactions and Enhanced Soft Agar Cloning Ability of c-myc-overexpressing Small Cell Lung Cancer Cells¹

Departments of Medicine [L. F. B., S. E. C., B. S. B., C. V. D.] and Oncology [L. F. B., C. V. D.], Johns Hopkins University School of Medicine, Baltimore, Maryland 21287

Small cell lung cancer (SCLC) is a highly invasive and metastatic tumor, and the decreased expression of 3ß1 integrin may contribute to its virulence. 3ß1 is a critical integrin for pulmonary development and epithelial integrity, and its reduced expression has been linked to the increased malignancy and invasion of other cancers. The amplification of the c-myc oncogene is seen frequently in relapsed SCLC tumors and is associated with a worsened prognosis. In the present study using a model of SCLC tumor progression, overexpression of c-myc in a classic SCLC cell line, NCI H209, enhanced in vitro features of tumorigenesis, altered the relationships between cell and environment, and markedly down-regulated the expression of the 3 integrin subunit at both the transcript and protein levels. This inverse relationship between the expression of the 3 integrin subunit and c-myc is mimicked by other c-myc-overexpressing SCLC cell lines. Restoring 3 expression in the myc-transfected 209 cells reversed the effects of c-myc: 3 transfection increased cell:cell adhesion and reduced soft agar cloning without affecting the in vitro doubling time. The diminished soft agar cloning produced by 3 transfection was reversed by an antibody that specifically engages 3ß1 integrins, P1B5. These results suggest first, that 3ß1 integrin mediates homotypic adhesion of SCLC cells, and second, that unengaged 3ß1 integrin suppresses the growth of disaggregated SCLC cells. Thus, the down-regulation of the 3 integrin subunit may contribute to the enhanced tumorigenicity of c-myc-overexpressing SCLCs by allowing the growth of tumor cells that have reduced contact with ligand-expressing substratum or cells, a condition that occurs during the growth of the primary tumor, tumor invasion, and metastasis.

¹ Supported by NIH K11 CA01685 and American Cancer Society IRG 58-005-39-IRG (to L. F. B.); NIH R01 CA57341 (to C. V. D.); and P01 HL 49545 (to B. S. B.)

² To whom requests for reprints should be addressed, at Division of Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, 600 North Wolfe Street, Blalock 910, Baltimore, MD 21287. Phone: (410) 955-3467; Fax: (410) 955-0036; E-mail: jadams@welchlink.welch.jhu.edu.

Received 5/22/98. Accepted 10/ 5/98.

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