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

Walkley, Carl R.; Qudsi, Rameez; Sankaran, Vijay G.; Gostissa, Monica; Roth, Stanford I.; Rodda, Stephen J.; Snay, Erin; Dunning, Patricia; Fahey, Frederic H.; Alt, Frederick W.; McMahon, Andrew P.; Orkin, Stuart H.

doi:10.1016/j.bone.2007.12.212

Cited by 47 publications

(95 citation statements)

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“…These data suggest that human MSCs can be successfully transformed into tumor initiation cells by using a combination of Rb knockdown and c‐Myc overexpression. Notably, in murine models, various studies have shown that genetic modifications on stem cells or osteoblastic cells , , induced tumorigenic transformation. However, the similar genetic modification to the murine model, such as combination silence of p53 and Rb in human MSCs, could not successfully induce transformation.…”

Section: Discussionmentioning

confidence: 99%

“…The transformation of MSCs has been achieved under the controlled expression or deletion of certain genes, such as by the expression of the EWS‐FLI‐1 chimeric gene to induce Ewing sarcoma , the deletion of p53 to induce leiomyosarcoma , and the deletion of the retinoblastoma ( Rb ) gene to induce liposarcoma . Mouse models that allow inactive mutation of both p53 and Rb, which are responsible for cell cycle regulation and apoptosis , in the osteoblastic lineage, induce OS . Interestingly, the inactive mutation of p53 and Rb has been noted in the osteoblastic lineage of OS patients .…”

Section: Introductionmentioning

confidence: 99%

“…Because most studies of MSC transformation use rodent MSCs , , , , which innately have more unstable genomes than human MSCs during ex vivo expansion , , the tumorigenic ability of human MSCs is still unclear. This study transforms human MSCs via genetic modification of several genes, including the knockdown of p53 and Rb and the overexpression of c‐Myc and Ras.…”

Section: Introductionmentioning

confidence: 99%

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Generation of Osteosarcomas from a Combination of Rb Silencing and c-Myc Overexpression in Human Mesenchymal Stem Cells

Wang

Chen

et al. 2016

Stem Cells Translational Medicine

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Osteosarcoma (OS) was a malignant tumor occurring with unknown etiology that made prevention and early diagnosis difficult. Mesenchymal stem cells (MSCs), which were found in bone marrow, were claimed to be a possible origin of OS but with little direct evidence. We aimed to characterize OS cells transformed from human MSCs (hMSCs) and identify their association with human primary OS cells and patient survival. Genetic modification with p53 or retinoblastoma (Rb) knockdown and c‐Myc or Ras overexpression was applied for hMSC transformation. Transformed cells were assayed for proliferation, differentiation, tumorigenecity, and gene expression profile. Only the combination of Rb knockdown and c‐Myc overexpression successfully transformed hMSCs derived from four individual donors, with increasing cell proliferation, decreasing cell senescence rate, and increasing ability to form colonies and spheres in serum‐free medium. These transformed cells lost the expression of certain surface markers, increased in osteogenic potential, and decreased in adipogenic potential. After injection in immunodeficient mice, these cells formed OS‐like tumors, as evidenced by radiographic analyses and immunohistochemistry of various OS markers. Microarray with cluster analysis revealed that these transformed cells have gene profiles more similar to patient‐derived primary OS cells than their normal MSC counterparts. Most importantly, comparison of OS patient tumor samples revealed that a combination of Rb loss and c‐Myc overexpression correlated with a decrease in patient survival. This study successfully transformed human MSCs to OS‐like cells by Rb knockdown and c‐Myc overexpression that may be a useful platform for further investigation of preventive and target therapy for human OS. Stem Cells Translational Medicine 2017;6:512–526

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Generation of Osteosarcomas from a Combination of Rb Silencing and c-Myc Overexpression in Human Mesenchymal Stem Cells

Wang

Chen

et al. 2016

Stem Cells Translational Medicine

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“…Because of their high frequency alterations, they were suspected to be part of the initiation step of osteosarcomagenesis, as already demonstrated in publications showing the MSC implication in the origins of OS. All these characteristics were also confirmed in genetically engineered mice where cell cycle genes are defective (Janeway & Walkley, 2011;Walkley et al, 2008).…”

Section: The Cell Cycle Genesmentioning

confidence: 48%

“…The dog seem to be also in OS a promising model because of multiple similarities with human cancer and it is offering the possibilities to study autochthonous tumors (Mueller et al, 2007). The in vivo model has to re-create human conditions to optimize the mechanistic understanding of osteosarcomagenesis, reason why several models of localized or metastatic OS were developed (Jones, 2011;Janeway & Walkley, 2011;Entz-Werlé et al, 2010;Walkley et al, 2008;Dass et al, 2007;Ek et al, 2006;Dass et al, 2006;Luu et al, 2005). All these animal models are outstanding tools to perform in vivo target validation, drug optimization and pre-clinical studies.…”

Section: Methodsmentioning

confidence: 99%

Bone Formation Deregulations Are the Oncogenesis Keys in Osteosarcomas

Entz‐Werlé¹

2012

Osteosarcoma

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Coamplification of Myc/Pvt1 and homozygous deletion of Nlrp1 locus are frequent genetics changes in mouse osteosarcoma

Rao

Zhao

et al. 2015

Genes Chromosomes & Cancer

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Osteosarcomas (OSs) are characterized by high levels of genomic instability (GI). To gain insights into the GI and its contribution toward understanding the genetic basis of OS, we characterized 19 primary and 13 metastatic mouse tumors in a genetically engineered novel mouse model of OS by a combination of genomic techniques. Through the bone-specific deletion of the wild-type Trp53 locus or activation of a metastatic-promoting missense R172Hp53 allele, C57BL/6 mice developed either localized or metastatic OS. Subsequent tumors were isolated and primary cultures created from primary bone and/or distal metastatic lesions, for example, lung and liver. These tumors exhibited high levels of GI with complex chromosomal rearrangements, amplifications, and deletions comparable to human OS. The combined genomic approaches identified frequent amplification of chromosome 15D1 and loss of 11B4 by CGH and/or SKY. Both 15D1 and 11B4 have homology with frequently altered chromosomal bands 8q24 and 17p13 in human OS, respectively. Subsequent array CGH, FISH, and qRT-PCR analysis identified coamplification and overexpression of Myc/Pvt1 transcripts from the 15D1 amplicon and loss and decreased expression of the Nlrp1b from 11B4. The Nlrp1 gene is the key mediator of apoptosis and interacts strongly with caspase 2.

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

Cited by 47 publications

References 0 publications

Generation of Osteosarcomas from a Combination of Rb Silencing and c-Myc Overexpression in Human Mesenchymal Stem Cells

Generation of Osteosarcomas from a Combination of Rb Silencing and c-Myc Overexpression in Human Mesenchymal Stem Cells

Bone Formation Deregulations Are the Oncogenesis Keys in Osteosarcomas

Coamplification of Myc/Pvt1 and homozygous deletion of Nlrp1 locus are frequent genetics changes in mouse osteosarcoma

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