Molecular Pathogenesis of Osteosarcoma

Kansara, Maya; Thomas, David M.

doi:10.1089/dna.2006.0505

Cited by 251 publications

(248 citation statements)

References 199 publications

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“…osx-cre ͉ Sca-1 ͉ hibernoma mouse model O steosarcomas account for Ϸ30% of malignant bone tumors and 3-4% of all childhood malignancies (1,2). They arise primarily around the knee joint, lower femur and upper tibia, which are all regions of active bone growth and repair.…”

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confidence: 99%

“…However, like other mesenchymal neoplasms, osteosarcomas are predisposed to metastasize via the hematogenous route, and thus, pulmonary metastasis is a major cause of death. Analyses of both sporadic and hereditary tumors show that inactivation of the p53 and RB-1 tumor suppressors plays a key role in the development of this tumor type (1,2). Li-Fraumeni patients, who often carry germ-line mutations in p53, are predisposed to a variety of tumors, 12% of which are bone sarcomas (3,4).…”

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Metastatic osteosarcoma induced by inactivation of Rb and p53 in the osteoblast lineage

Berman

Calo²,

Landman³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

246

267

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Mutation of the RB-1 and p53 tumor suppressors is associated with the development of human osteosarcoma. With the goal of generating a mouse model of this disease, we used conditional and transgenic mouse strains to inactivate Rb and/or p53 specifically in osteoblast precursors. The resulting Rb;p53 double mutant (DKO) animals are viable but develop early onset osteosarcomas with complete penetrance. These tumors display many of the characteristics of human osteosarcomas, including being highly metastatic. We established cell lines from the DKO osteosarcomas to further investigate their properties. These immortalized cell lines are highly proliferative and they retain their tumorigenic potential, as judged by their ability to form metastatic tumors in immunocompromised mice. Moreover, they can be induced to differentiate and, depending on the inductive signal, will adopt either the osteogenic or adipogenic fate. Consistent with this multipotency, a significant portion of these tumor cells express Sca-1, a marker that is typically associated with stem cells/uncommitted progenitors. By assaying sorted cells in transplant assays, we demonstrate that the tumorigenicity of the osteosarcoma cell lines correlates with the presence of the Sca-1 marker. Finally, we show that loss of Rb and p53 in Sca-1-positive mesenchymal stem/progenitor cells is sufficient to yield transformed cells that can initiate osteosarcoma formation in vivo.osx-cre ͉ Sca-1 ͉ hibernoma mouse model O steosarcomas account for Ϸ30% of malignant bone tumors and 3-4% of all childhood malignancies (1, 2). They arise primarily around the knee joint, lower femur and upper tibia, which are all regions of active bone growth and repair. These tumors are predominantly osteoblastic in nature, although there is a correlation between loss of differentiation and poor prognosis. The generation of new therapeutic treatments for osteosarcoma has improved the 5-year survival rate of affected individuals. However, like other mesenchymal neoplasms, osteosarcomas are predisposed to metastasize via the hematogenous route, and thus, pulmonary metastasis is a major cause of death. Analyses of both sporadic and hereditary tumors show that inactivation of the p53 and RB-1 tumor suppressors plays a key role in the development of this tumor type (1, 2). Li-Fraumeni patients, who often carry germ-line mutations in p53, are predisposed to a variety of tumors, 12% of which are bone sarcomas (3, 4). p53 mutations are also observed in 20-60% of sporadic osteosarcomas (5-7). Similarly, patients carrying germline mutations in RB-1 have an Ϸ500-fold higher incidence of osteosarcoma than the general population (8). Moreover, RB-1 mutations are detected in 70% of all adolescent osteosarcomas (9). Finally, human osteosarcomas can carry mutations in both p53 and RB-1 (10).Mouse models have provided considerable insight into the role of p53 in bone development and tumorigenesis. Experiments from three different settings suggest that p53 plays an important role in bone development by modul...

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confidence: 99%

mentioning

confidence: 99%

Metastatic osteosarcoma induced by inactivation of Rb and p53 in the osteoblast lineage

Berman

Calo²,

Landman³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

246

267

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“…5 Gene expression and proteomic studies have identified the possible role of ezrin in metastasis. 6,7 The identification of ezrin expression is a necessary component in osteosarcoma metastasis and it makes the study of this protein crucial in understanding the molecular pathways involved in metastatic diffusion.…”

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Phosphorylated ezrin is located in the nucleus of the osteosarcoma cell

et al. 2010

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The survival of osteosarcoma patients is connected to metastasis. The ezrin expression is associated with the development of metastasis and poor outcome in osteosarcoma. Ezrin is present in the cytoplasm and after phosphorylation assumes an active form and links F-actin to the cell membrane. This study evaluated ezrin and phosphorylated ezrin at site Tyr354 and Thr567 expression and its subcellular localization in osteosarcoma. We studied 50 osteosarcoma patients (mean follow-up 9.8 years). Ezrin expression was assessed using immunohistochemical and immunofluorescence analysis on tissue microarray and cultured cells of human osteosarcoma 143B. The western blot analysis was carried out on cultured cells. The majority of osteosarcomas, showing cytoplasmic positivity for ezrin, phosphorylated and unphosphorylated, were associated with membranous and nuclear positivity for phosphorylated ezrin Thr567 and phosphorylated ezrin Tyr354, respectively. Ezrin expression was associated with high-grade osteosarcoma (P ¼ 0.04), with metastasis (P ¼ 0.04) and with tumors that developed metastasis (P ¼ 0.04); phosphorylated ezrin Thr567 expression was present mostly in tumors with metastasis (P ¼ 0.01) and in osteosarcomas that did not develop metastasis (P ¼ 0.002). The osteosarcoma patients with ezrin expression have a short survival. The cytoplasmic ezrin expression in osteosarcoma matches its role of membrane-cytoskeleton linker protein. The subcellular trafficking of ezrin is not blocked and it is linked to ezrin phosphorylation, also in cancer. The phosphorylated ezrin Tyr354 nuclear localization suggests its possible role as a nuclear factor in osteosarcoma. The phosphorylated ezrin Thr567 phosphorylation may not be necessary in osteosarcoma metastatic progression but it was modulated. The ezrin expression is associated with more aggressive osteosarcomas and with metastasis.

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“…It transactivates genes that encoded apoptotic proteins, and it translocates to mitochondria where it interacts with Bcl-2 proteins (Moll et al, 2001). Many OSAs exhibit p53 abnormalities, and mice expressing p53-null osteoblast progenitor cells will develop OSAs (Lengner et al, 2006;Kansara et al, 2007). Suggesting that Bcl-2 proteins are important for the regulation of the p53 in the OSA.…”

Section: Cdks Play An Import Role In the Pathogenesis Of The Osamentioning

confidence: 99%

Review of the Molecular Pathogenesis of Osteosarcoma

Hao²,

Wang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

124

109

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Treating the osteosarcoma (OSA) remains a challenge. Current strategies focus on the primary tumor and have limited efficacy for metastatic OSA. A better understanding of the OSA pathogenesis may provide a rational basis for innovative treatment strategies especially for metastases. The aim of this review is to give an overview of the molecular mechanisms of OSA tumorigenesis, OSA cell proliferation, apoptosis, migration, and chemotherapy resistance, and how improved understanding might contribute to designing a better treatment target for OSA.

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Molecular Pathogenesis of Osteosarcoma

Cited by 251 publications

References 199 publications

Metastatic osteosarcoma induced by inactivation of Rb and p53 in the osteoblast lineage

Metastatic osteosarcoma induced by inactivation of Rb and p53 in the osteoblast lineage

Phosphorylated ezrin is located in the nucleus of the osteosarcoma cell

Review of the Molecular Pathogenesis of Osteosarcoma

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