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 exami ne possible relationships between amplification/over-expression of the N-myc oncogene and altered regulation of expression of specific integ rin subunits during tumor progression. Subcutaneous (ectopic) or intra -adrenal (orthotopic) injection of the neuroblastoma cell lines SK-N-S H or IMR-32 has generated a number of derivative tumor cell lines. Tum or 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 ra tes when re-injected into the subcutaneous space of nude mice. Moreove r, cell lines derived from tumors initiated by IMR-32 cells exhibit sh orter latent periods than do IMR-32 cells direct from tissue culture. With regard to integrin subunit expression, SK-N-SH and related cell l ines 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 pro duced is not associated with common (a)lpha subunits. LaN1 cells, whic h express N-myc at even higher levels than do IMR-32 cells, express ev en less beta(1). Interestingly, the tumor-derived cell lines (especial ly those from tumors initiated in adrenal glands) also exhibit reduced integrin expression compared with the parental cell lines; this reduc tion is associated with the enhanced tumor take rate observed when the cells are re-injected into nude mice. Our results raise the possibili ty of a relationship between over-expression of N-myc and down-regulat ion of beta(1) integrin expression (possibly some a subunits also). In addition, the data suggest that human neuroblastoma-derived cell line s which exhibit reduced integrin expression display more aggressive tu mor growth in nude mice.