Conditional mouse osteosarcoma, dependent on p53 loss and potentiated by loss of Rb, mimics the human disease

Abstract

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.[Keywords: Cancer; mouse model; osteocarcinoma] Supplemental material is available at http://www.genesdev.org.

c-MYC overexpression with loss of Ink4a/Arf transforms bone marrow stromal cells into osteosarcoma accompanied by loss of adipogenesis

“…Recent reports describing novel OS models indicate that OS originates from lineage-committed immature osteoblasts or MSCs (Berman et al, 2008;Walkley et al, 2008). Our model suggested that OS can originate from both types of cells.…”

“…Recently, novel mouse OS models were developed through targeted deletion of p53 and Rb in osterixexpressing cells (Berman et al, 2008;Walkley et al, 2008). INK4a/ARF exerts effects on both the Rb and p53 pathways (Collado et al, 2007).…”

Osteosarcoma

“…Histologic subtype does not appear to influence the clinical behavior of the disease. (1,3,4) Knockout mice with conditional loss of Rb and p53 function in a preosteoblastic (15) This suggests that the cell of origin is this preosteoblast. (15) However, the tumor that arises in this model system has been noted to express more primitive lineage markers than preosteoblasts.…”

“…(1,3,4) Knockout mice with conditional loss of Rb and p53 function in a preosteoblastic (15) This suggests that the cell of origin is this preosteoblast. (15) However, the tumor that arises in this model system has been noted to express more primitive lineage markers than preosteoblasts. (16) Although these markers may be acquired in the transformation process, it also has been suggested that a rare precursor cell that expresses markers of both mesenchymal stem cells and preosteoblasts may be the cell of origin.…”

The orally bioavailable met inhibitor PF-2341066 inhibits osteosarcoma growth and osteolysis/matrix production in a xenograft model

“…(31) Indeed, genomic profiling of human OS has not revealed recurrent genetic events, (1) although mouse genetic models implicating the p53 and pRb genes have been developed recently. (32,33) OS-specific oncogenic changes therefore may not exist, and OS initiation and progression instead may be driven by alterations that also occur in other cancers (eg, p53, pRb, and Met). (1) Met is one of the most commonly altered tyrosine kinases in human cancer, (4) and Met overexpression is a common feature of OS and the more prevalent soft tissue sarcomas (STSs).…”