Conditional mouse osteosarcoma, dependent on p53 loss and potentiated by loss of Rb, mimics the human disease.
Osteosarcoma is the most common primary malignant tumor of bone. Analysis of familial cancer syndromes and sporadic cases has strongly implicated both p53 and pRb in its pathogenesis; however, the relative contribution of these mutations to the initiation of osteosarcoma is unclear. We describe here the generation and characterization of a genetically engineered mouse model in which all animals develop short latency malignant osteosarcoma. The genetically engineered mouse model is based on osteoblast-restricted deletion of p53 and pRb. Osteosarcoma development is dependent on loss of p53 and potentiated by loss of pRb, revealing a dominance of p53 mutation in the development of osteosarcoma. The model reproduces many of the defining features of human osteosarcoma including cytogenetic complexity and comparable gene expression signatures, histology, and metastatic behavior. Using a novel in silico methodology termed cytogenetic region enrichment analysis, we demonstrate high conservation of gene expression changes between murine osteosarcoma and known cytogentically rearranged loci from human osteosarcoma. Due to the strong similarity between murine osteosarcoma and human osteosarcoma in this model, this should provide a valuable platform for addressing the molecular genetics of osteosarcoma and for developing novel therapeutic strategies.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Division of Hematology/Oncology, Boston, MA 02115, USA.
Carl R
CR
Walkley
Rameez
R
Qudsi
Vijay G
VG
Sankaran
Jennifer A
JA
Perry
Monica
M
Gostissa
Sanford I
SI
Roth
Stephen J
SJ
Rodda
Erin
E
Snay
Patricia
P
Dunning
Frederic H
FH
Fahey
Frederick W
FW
Alt
Andrew P
AP
McMahon
Stuart H
SH
Orkin
D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology; D016000:Cluster Analysis; D003198:Computer Simulation; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D019426:Integrases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology; D016160:Retinoblastoma Protein / Q000235:genetics*; D047368:Tumor Burden / Q000235:genetics
D016160:Retinoblastoma Protein; C045073:Cre recombinase; D019426:Integrases