INVESTIGATOR AWARD Osteosarcoma and Osteoblastic Differentiation A New Perspective on Oncogenesis

In addition to changes in cellular pathways, loss of differen-tiation is a notable feature of osteosarcoma. We hypothesized that blocks to normal differentiation may be a common fea-ture of osteosarcoma, and may be one of many critical events that occur during oncogenesis in osteosarcoma. Further-more, therapies that restore normal programs of differentia-tion may be attractive new treatment strategies for chemo-therapy and/or chemoprevention. We exposed an osteosar-coma cell line to two highly osteogenic bone morphogenetic proteins and noted increased tumor volume and no evidence of osteoinduction in vivo. We then used expression profile analysis to identify downstream targets of the osteogenic bone morphogenetic proteins, revealing up-regulation of the inhibitor of differentiation genes 1, 2, and 3, and the nuclear receptor, peroxisome proliferator activated receptor . W