INVERSE EXPRESSIONS OF THE N-MYC ONCOGENE AND BETA(1) INTEGRIN IN HUMAN NEUROBLASTOMA - RELATIONSHIPS TO DISEASE PROGRESSION IN A NUDE-MOUSE MODEL SYSTEM

A nude mouse model for human neuroblastoma has been developed to examine possible relationships between amplification/over-expression of the N-myc oncogene and altered regulation of expression of specific integrin subunits during tumor progression. Subcutaneous (ectopic) or intra-adrenal (orthotopic) injection of the neuroblastoma cell lines SK-N-SH or IMR-32 has generated a number of derivative tumor cell lines. Tumor cell lines derived from SK-N-SH cells (which do not express N-myc) or IMR-32 cells (which over-express N-myc) produce tumors at higher rates when re-injected into the subcutaneous space of nude mice. Moreover, cell lines derived from tumors initiated by IMR-32 cells exhibit shorter latent periods than do IMR-32 cells direct from tissue culture. With regard to integrin subunit expression, SK-N-SH and related cell lines express high levels of beta(1) integrin, which is associated with the alpha(2) and alpha(3) integrin subunits (predominantly alpha(3)) IMR-32 cells display reduced beta(1) expression, and that which is produced is not associated with common (a)lpha subunits. LaN1 cells, which express N-myc at even higher levels than do IMR-32 cells, express even less beta(1). Interestingly, the tumor-derived cell lines (especially those from tumors initiated in adrenal glands) also exhibit reduced integrin expression compared with the parental cell lines; this reduction is associated with the enhanced tumor take rate observed when the cells are re-injected into nude mice. Our results raise the possibility of a relationship between over-expression of N-myc and down-regulation of beta(1) integrin expression (possibly some a subunits also). In addition, the data suggest that human neuroblastoma-derived cell lines which exhibit reduced integrin expression display more aggressive tumor growth in nude mice.