INCREASED EXPRESSION OF NUCLEOSIDE DIPHOSPHATE KINASE NM23 AND C-HA-RAS MESSENGER-RNA IS ASSOCIATED WITH SPONTANEOUS LUNG METASTASIS IN RAT-TRANSPLANTABLE OSTEOSARCOMAS/

The relationship between expression of nucleoside diphosphate kinase ( NDP kinase)/nm23, c-Ha-ras, and c-myc genes and metastatic potential w as assessed in rat-transplantable osteosarcoma lines, derived from spo ntaneous and chemical carcinogen (4-hydroxyamino quinoline 1-oxide)-in duced osteosarcomas in Fischer 344/NS1c rats. These osteosarcomas poss ess metastatic potential and highly metastatic lines spontaneous osteo sarcoma-selected lung metastatic lesions and 4-hydroxyamino-quinoline 1-oxide-induced osteosarcoma-selected lung metastatic lesions were res pectively established by selectively transplanting lung metastatic les ions. Northern blot analysis revealed that the levels of NDP kinase/nm 23 and c-Ha-ras gene expression were increased in line with metastatic ability; thus transcript levels were remarkably greater in both spont aneous osteosarcoma-selected lung metastatic lesions and 4-hydroxyamin o-quinoline 1-oxide-induced osteosarcoma-selected lung metastatic lesi ons highly metastatic lines than in their respective low metastatic sp ontaneous and chemical carcinogen (4-hydroxyamino quinoline 1-oxide)-i nduced osteosarcoma counterparts. c-myc mRNA expression was observed i n all tumor lines, without any correlation with metastatic ability. So uthern blot analysis did not show evidence of gross rearrangement or a mplification of NDP kinase/nm23, c-Ha-ras, or c-myc genes suggesting r egulation of their gene expression at the transcriptional and/or postt ranscriptional level. These results indicate that NDP kinase/nm23 and c-Ha-ras might be cooperatively involved in a positive manner in signa l transduction processes, especially involving G-protein reactions, re sponsible for metastasis of rat-transplantable osteosarcomas.