Alveolar rhabdomyosarcoma: Is the cell of origin a mesenchymal stem cell?

Charytonowicz, Elizabeth; Cordon‐Cardo, Carlos; Matushansky, Igor; Ziman, Mel

doi:10.1016/j.canlet.2008.09.039

Cited by 122 publications

(109 citation statements)

References 87 publications

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“…However, they can also arise at sites that normally lack skeletal muscle, such as the genitourinary and biliary tract. Despite extensive research, the exact cell of origin is still under debate (20)(21)(22). Our data now suggest that the cell of origin for ARMS may be the cells that transiently express PAX3-FOXO1 .…”

Section: Research Articlementioning

confidence: 73%

A Chimeric RNA Characteristic of Rhabdomyosarcoma in Normal Myogenesis Process

et al. 2013

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Gene fusions and their chimeric products are common features of neoplasia. Given that many cancers arise by the dysregulated recapitulation of processes in normal development, we hypothesized that comparable chimeric gene products may exist in normal cells. Here, we show that a chimeric RNA, PAX3-FOXO1 , identical to that found in alveolar rhabdomyosarcoma, is transiently present in cells undergoing differentiation from pluripotent cells into skeletal muscle. Unlike cells of rhabdomyosarcoma, these cells do not seem to harbor the t(2;13) chromosomal translocation. Importantly, both PAX3-FOXO1 RNA and protein could be detected in the samples of normal fetal muscle. Overexpression of the chimera led to continuous expression of MYOD and MYOG-two myogenic markers that are overexpressed in rhabdomyosarcoma cells. Our results are consistent with a developmental role of a specifi c chimeric RNA generated in normal cells without the corresponding chromosomal rearrangement at the DNA level seen in neoplastic cells presumably of the same lineage. SIGNIFICANCE:A chimeric fusion RNA, PAX3-FOXO1 , associated with alveolar rhabdomyosarcoma, is also present in normal non-cancer cells and tissues. Its transient expression nature and the absence of t(2;13) chromosomal translocation are consistent with a posttranscriptional mechanism. When constantly expressed, PAX3-FOXO1 interfered with the muscle differentiation process, which presumably contributes to tumorigenesis.

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Section: Research Articlementioning

confidence: 73%

A Chimeric RNA Characteristic of Rhabdomyosarcoma in Normal Myogenesis Process

et al. 2013

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“…Alveolar rhabdomyosarcoma (ARMS) is more common in older children and exhibits small round cells with primitive myoblast differentiation, embryonal rhabdomyosarcoma (ERMS) typically presents at an earlier age and is histopathologically analogous to embryonic skeletal muscle (15). We found that genes positively regulated by p73 were increased in ARMS (Fig.…”

Section: Genes Regulated By Mtor and P73 Classify Rhabdomyosarcomamentioning

confidence: 83%

“…These two subtypes of rhabdomyosarcoma are associated with different outcomes, molecular alterations, age groups, and histologic appearances (15). Alveolar rhabdomyosarcoma (ARMS) is more common in older children and exhibits small round cells with primitive myoblast differentiation, embryonal rhabdomyosarcoma (ERMS) typically presents at an earlier age and is histopathologically analogous to embryonic skeletal muscle (15).…”

Section: Genes Regulated By Mtor and P73 Classify Rhabdomyosarcomamentioning

confidence: 99%

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Differential regulation of the p73 cistrome by mammalian target of rapamycin reveals transcriptional programs of mesenchymal differentiation and tumorigenesis

Rosenbluth

Mays

Jiang

et al. 2011

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

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The transcription factor p73 plays critical roles during development and tumorigenesis. It exhibits sequence identity and structural homology with p53, and can engage p53-like tumor-suppressive programs. However, different pathways regulate p53 and p73, and p73 is not mutated in human tumors. Therefore, p73 represents a therapeutic target, and there is a critical need to understand genes and noncoding RNAs regulated by p73 and how they change during treatment regimens. Here, we define the p73 genomic binding profile and demonstrate its modulation by rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) and inducer of p73. Rapamycin selectively increased p73 occupancy at a subset of its binding sites. In addition, multiple determinants of p73 binding, activity, and function were evident, and were modulated by mTOR. We generated an mTOR-p73 signature that is enriched for p73 target genes and miRNAs that are involved in mesenchymal differentiation and tumorigenesis, can classify rhabdomyosarcomas by clinical subtype, and can predict patient outcome.p63 | ChIP-on-Chip | stem cell | muscle | consensus binding site

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“…There is also evidence that MSCs are the cells of origin for ARMS [72]. This tumor is characterized by the expression of either PAX3-FKHR or PAX7-FKHR fusion genes in MSCs, pushing MSC differentiation towards a myogenic lineage while inhibiting terminal differentiation.…”

Section: Arms Modelsmentioning

confidence: 99%

Modeling sarcomagenesis using multipotent mesenchymal stem cells

2011

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Because of their unique properties, multipotent mesenchymal stem cells (MSCs) represent one of the most promising adult stem cells being used worldwide in a wide array of clinical applications. Overall, compelling evidence supports the long-term safety of ex vivo expanded human MSCs, which do not seem to transform spontaneously. However, experimental data reveal a link between MSCs and cancer, and MSCs have been reported to inhibit or promote tumor growth depending on yet undefined conditions. Interestingly, solid evidence based on transgenic mice and genetic intervention of MSCs has placed these cells as the most likely cell of origin for certain sarcomas. This research area is being increasingly explored to develop accurate MSC-based models of sarcomagenesis, which will be undoubtedly valuable in providing a better understanding about the etiology and pathogenesis of mesenchymal cancer, eventually leading to the development of more specific therapies directed against the sarcoma-initiating cell. Unfortunately, still little is known about the mechanisms underlying MSC transformation and further studies are required to develop bona fide sarcoma models based on human MSCs. Here, we comprehensively review the existing MSC-based models of sarcoma and discuss the most common mechanisms leading to tumoral transformation of MSCs and sarcomagenesis.

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Alveolar rhabdomyosarcoma: Is the cell of origin a mesenchymal stem cell?

Cited by 122 publications

References 87 publications

A Chimeric RNA Characteristic of Rhabdomyosarcoma in Normal Myogenesis Process

A Chimeric RNA Characteristic of Rhabdomyosarcoma in Normal Myogenesis Process

Differential regulation of the p73 cistrome by mammalian target of rapamycin reveals transcriptional programs of mesenchymal differentiation and tumorigenesis

Modeling sarcomagenesis using multipotent mesenchymal stem cells

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