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Tumorsphere Derivation and Treatment from Primary Tumor Cells Isolated from Mouse Rhabdomyosarcomas
Published on: September 13, 2019
Mice lacking dystrophin or alpha sarcoglycan spontaneously develop embryonal rhabdomyosarcoma with cancer-associated
Karen Fernandez1, Yelda Serinagaoglu, Sue Hammond
1Division of Hematology/Oncology, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.
Abstract:
Altered expression of proteins in the dystrophin-associated glycoprotein complex results in muscular dystrophy and has more recently been implicated in a number of forms of cancer. Here we show that loss of either of two members of this complex, dystrophin in mdx mice or alpha sarcoglycan in Sgca(-/-) mice, results in the spontaneous development of muscle-derived embryonal rhabdomyosarcoma (RMS) after 1 year of age. Many mdx and Sgca(-/-) tumors showed increased expression of insulin-like growth factor 2, retinoblastoma protein, and phosphorylated Akt and decreased expression of phosphatase and tensin homolog gene, much as is found in a human RMS. Further, all mdx and Sgca(-/-) RMS analyzed had increased expression of p53 and murine double minute (mdm)2 protein and contained missense p53 mutations previously identified in human cancers. The mdx RMS also contained missense mutations in Mdm2 or alternatively spliced Mdm2 transcripts that lacked an exon encoding a portion of the p53-binding domain. No Pax3:Fkhr or Pax7:Fkhr translocation mRNA products were evident in any tumor. Expression of natively glycosylated alpha dystroglycan and alpha sarcoglycan was reduced in mdx RMS, whereas dystrophin expression was absent in almost all human RMS, both for embryonal and alveolar RMS subtypes. These studies show that absence of members of the dystrophin-associated glycoprotein complex constitutes a permissive environment for spontaneous development of embryonal RMS associated with mutation of p53 and mutation or altered splicing of Mdm2.
Insights
Loss of dystrophin or alpha sarcoglycan proteins, key in muscular dystrophy, can lead to spontaneous rhabdomyosarcoma (RMS) development. This cancer formation involves p53 and Mdm2 gene mutations, similar to human forms.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Altered expression of proteins within the dystrophin-associated glycoprotein complex is linked to muscular dystrophy and various cancers.
- The dystrophin-associated glycoprotein complex plays a crucial role in maintaining muscle integrity and cellular signaling.
Purpose of the Study:
- To investigate the role of specific dystrophin-associated glycoprotein complex members in the spontaneous development of muscle-derived tumors.
- To characterize the molecular alterations associated with tumor formation in the absence of dystrophin or alpha sarcoglycan.
Main Methods:
- Utilized mdx mice (lacking dystrophin) and Sgca(-/-) mice (lacking alpha sarcoglycan) to study tumor development.
- Analyzed tumor tissues for expression levels of key proteins (e.g., IGF-2, Rb, Akt, PTEN, p53, mdm2) and mutations.
- Investigated the presence of specific genetic translocations (Pax3:Fkhr, Pax7:Fkhr) and protein glycosylation status.
Main Results:
- Loss of dystrophin or alpha sarcoglycan led to spontaneous embryonal rhabdomyosarcoma (RMS) development in mice after one year of age.
- Tumors exhibited molecular profiles similar to human RMS, including altered expression of IGF-2, Rb, Akt, PTEN, p53, and mdm2.
- All analyzed tumors showed increased p53 and mdm2 expression with missense p53 mutations; mdx RMS also had Mdm2 mutations or altered splicing.
- Absence of specific genetic translocations (Pax3:Fkhr, Pax7:Fkhr) was noted in all tumors.
Conclusions:
- Absence of dystrophin-associated glycoprotein complex members creates a permissive environment for spontaneous embryonal RMS development.
- Mutations in p53 and alterations in Mdm2 are critical events in the pathogenesis of RMS in these models.
- These findings highlight a novel link between muscular dystrophy-related proteins and rhabdomyosarcoma tumorigenesis.
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