Genetically engineered mouse models and human osteosarcoma

Abstract

Osteosarcoma is the most common form of bone cancer. Pivotal insight into the genes involved in human osteosarcoma has been provided by the study of rare familial cancer predisposition syndromes. Three kindreds stand out as predisposing to the development of osteosarcoma: Li-Fraumeni syndrome, familial retinoblastoma and RecQ helicase disorders, which include Rothmund-Thomson Syndrome in particular. These disorders have highlighted the important roles of P53 and RB respectively, in the development of osteosarcoma. The association of OS with RECQL4 mutations is apparent but the relevance of this to OS is uncertain as mutations in RECQL4 are not found in sporadic OS. Application of the knowledge or mutations of P53 and RB in familial and sporadic OS has enabled the development of tractable, highly penetrant murine models of OS. These models share many of the cardinal features associated with human osteosarcoma including, importantly, a high incidence of spontaneous metastasis. The recent development of these models has been a significant advance for efforts to improve our understanding of the genetics of human OS and, more critically, to provide a high-throughput genetically modifiable platform for preclinical evaluation of new therapeutics.

Figure 1

Schematic representation of osteoblasticlineage commitment and differentiationfrom mesenchymal progenitors andthe models developed ingenetically engineered murine models.A) Normal osteoblast development from mesenchymal stem cells. Genes associated with the commitment and differentiation of osteoblasts are listed along with an approximation of the developmental state of the osteoblastic cells. B) Using the differentiation schematic, the different Cre lines that have been described are in bold with an approximation of the putative cells expressing the Cre. The alleles that are disrupted (loss of function for p53 and pRb; over-expression for SV40TAg) are shown on the arrows. Other tumour types associated with the different models are also highlighted. For further information on these alleles see Table 2.