Cancer Cells-overexpressing Small Cell Lung myc Agar Cloning Ability of c-Softthe Altered Cell : Environmental Interactions and Enhanced 1 Integrin with β 3 α Association of the Decreased Expression of Updated Version

Small cell lung cancer (SCLC) is a highly invasive and metastatic tumor, and the decreased expression of «3/31integrin may contribute to its virulence. «3/ÕI 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 e-/««' 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 downregulated the expression of the c*3 integrin subunit at both the transcript and protein levels. This inverse relationship between the expression of the <*3integrin subunit and c-myc is mimicked by other c-myc-overexpressing SCLC cell lines. Restoring «3expression in the myotransfected 209 cells reversed the effects of c-myc: a3 transfection increased celiiceli adhesion and reduced soft agar cloning without affecting the in vitro doubling time. The diminished soft agar cloning produced by o3 transfection was re versed by an antibody that specifically engages a3ßl integrins, P1B5. These results suggest first, that <*3ßl integrin mediates homotypic adhe sion of SCLC cells, and second, that unengaged a3ßl 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-nyc-overexpressing SCLCs by allowing the growth of tumor cells that have reduced contact with ligand-expressing substratum or cells, a con dition that occurs during the growth of the primary tumor, tumor inva sion, and metastasis.

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