DEVELOPMENT OF A NOVEL SPONTANEOUS METASTASIS MODEL OF HUMAN OSTEOSARCOMA TRANSPLANTED ORTHOTOPICALLY INTO BONE OF ATHYMIC MICE

There is a pressing need for in vivo models in which potential antitum or agents can be tested for their ability to inhibit the growth and me tastatic spread of human sarcomas. A recent advance in this regard has been the development of a v-Ki-ras-oncogene-transformed human osteosa rcoma cell line (KRIB) that efficiently colonizes the lungs of athymic nude mice when cells (1 x 10(5)) are administered by i.v. injection. In the present study, we have utilized this cell line to develop a spo ntaneous metastasis model in which a small number of tumor cells are i njected into the tibial bones of athymic mice. When as few as 1000 KRI B cells are orthotopically implanted into the tibial bones of nude mic e, bone tumors, which are radio-graphically and histologically similar to primary human osteosarcoma, develop within 4 weeks. Furthermore, a s in the human disease, cells from these primary tumors subsequently s eed the animals' lungs, resulting in reproducible and quantifiable pul monary metastasis evident both upon gross inspection of the lungs and histologically 6 weeks after tumor inoculation. Surgical amputation of the tumor inoculation site up to 2 weeks after tumor injection preven ts pulmonary metastasis, indicating that substantial local (tibial) gr owth and invasion of the primary tumor for at least 2 weeks is require d for subsequent metastasis. Implantation of s.c. 5000 KRIB cells fail s to produce local or metastatic tumors. We anticipate that this model will prove to be a powerful tool with which to study the mechanisms o f human osteosarcoma growth and pulmonary metastasis, and to assess th e efficacy of promising therapeutic agents.