Study of osteosarcoma development, progression and treatment: 1 gene profiling and tumorigenesis, 2 IGF-1R/MEK/ERK signalling and malignant potential, 3 IGF-1R targeted therapy enhances chemotherapy using doxorubicin

摘要

Understanding of osteosarcoma progression and molecular pathogenesis remains limited due to the complex genetic changes. Recently, osteosarcoma is redefined as a differentiation disease due to the disruption of osteoblast differentiation, opening up a new direction for investigations. The type I insulin-like growth factor receptor (IGF-1R) participates in promoting malignant potential in osteosarcoma, but the effectiveness of its inhibition has not been fully elucidated.Gene expression profile analysis of the two osteosarcoma cell lines showed that genes of cell-adhesion and nervous system were expressed differentially. These genes are known to participate in controlling osteoblast differentiation. Other genes known to be involved in osteoblast differentiation were also found in the analysis. This study suggests that the cell-adhesion and nervous system signalling pathways may involve in the disruption of osteoblast differentiation leading to the development of osteosarcoma. The detection of protein expression of IGF-1R downstream signal mediators in the primary and secondary xenograft tumour tissues showed for the first time that IGF-1R/MEK/ERK signalling is involved in the malignant potential and lung metastasis of osteosarcoma. In addition, the in vitro invasive ability of the osteosarcoma cell line was reduced after inhibition of MEK/ERK signalling. These results signify that MEK/ERK could be potential therapeutic targets for the treatment of metastatic osteosarcoma.Furthermore, it is also the first time that enhancement of growth inhibition and increased doxorubicin sensitivity were shown after IGF-1R inhibition and doxorubicin combination treatments in a panel of 6 human osteosarcoma cell lines and a self-established resistant sub-clone. Mechanism studies in osteosarcoma cell lines showed that the combination therapy has advantages over mono drug treatment in terms of enhances apoptosis, maintains clonogenic inhibition and improves cytotoxicity in therapeutic efficacy without addition of individual drug doses. This study indicates that inhibition of IGF-1R signalling and together with doxorubicin chemotherapy is a potential effective strategy to improve the treatment of both doxorubicin sensitive and resistant osteosarcoma.