title: Modeling distinct osteosarcoma subtypes in vivo using Cre:lox and lineage-restricted transgenic shRNA.
abstract: Osteosarcoma is the most common primary cancer of bone and one that predominantly affects children and adolescents. Osteoblastic osteosarcoma represents the major subtype of this tumor, with approximately equal representation of fibroblastic and chondroblastic subtypes. We and others have previously described murine models of osteosarcoma based on osteoblast-restricted Cre:lox deletion of Trp53 (p53) and Rb1 (Rb), resulting in a phenotype most similar to fibroblastic osteosarcoma in humans. We now report a model of the most prevalent form of human osteosarcoma, the osteoblastic subtype. In contrast to other osteosarcoma models that have used Cre:lox mediated gene deletion, this model was generated through shRNA-based knockdown of p53. As is the case with the human disease the shRNA tumors most frequently present in the long bones and preferentially disseminate to the lungs; feature less consistently modeled using Cre:lox approaches. Our approach allowed direct comparison of the in vivo consequences of targeting the same genetic drivers using two different technologies, Cre:lox and shRNA. This demonstrated that the effects of Cre:lox and shRNA mediated knock-down are qualitatively different, at least in the context of osteosarcoma, and yielded distinct subtypes of osteosarcoma. Through the use of complementary genetic modification strategies we have established a model of the most common clinical subtype of osteosarcoma that was not previously represented and more fully recapitulated the clinical spectrum of this cancer.
authors.affiliation: St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Mutsaers
authors.forename: Alvin J M
authors.initials: AJ
authors.lastname: Ng
authors.forename: Emma K
authors.initials: EK
authors.lastname: Baker
authors.forename: Megan R
authors.initials: MR
authors.lastname: Russell
authors.forename: Alistair M
authors.initials: AM
authors.lastname: Chalk
authors.forename: Meaghan
authors.initials: M
authors.lastname: Wall
authors.forename: Brain J J
authors.initials: BJ
authors.lastname: Liddicoat
authors.forename: Patricia W M
authors.initials: PW
authors.lastname: Ho
authors.forename: John L
authors.initials: JL
authors.lastname: Slavin
authors.forename: Ankita
authors.initials: A
authors.lastname: Goradia
authors.forename: T John
authors.initials: TJ
authors.lastname: Martin
authors.forename: Louise E
authors.initials: LE
authors.lastname: Purton
authors.forename: Ross A
authors.initials: RA
authors.lastname: Dickins
authors.forename: Carl R
authors.initials: CR
authors.lastname: Walkley
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics*; D002462:Cell Membrane / Q000378:metabolism; D033481:Chromosomes, Mammalian / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D019426:Integrases / Q000378:metabolism*; D007621:Karyotyping; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D012516:Osteosarcoma / Q000145:classification* / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D019683:Penetrance; D010641:Phenotype; D034741:RNA, Small Interfering / Q000378:metabolism*; D011859:Radiography; D015398:Signal Transduction; D016019:Survival Analysis; D019076:Transgenes / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C045073:Cre recombinase; D019426:Integrases