Targeting oxidative stress in embryonal rhabdomyosarcoma.
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ABSTRACT:
SUBMITTER: Chen X
PROVIDER: S-EPMC3904731 | biostudies-literature | 2013 Dec
REPOSITORIES: biostudies-literature
Publications
Targeting oxidative stress in embryonal rhabdomyosarcoma.
Chen Xiang X Stewart Elizabeth E Shelat Anang A AA Qu Chunxu C Bahrami Armita A Hatley Mark M Wu Gang G Bradley Cori C McEvoy Justina J Pappo Alberto A Spunt Sheri S Valentine Marcus B MB Valentine Virginia V Krafcik Fred F Lang Walter H WH Wierdl Monika M Tsurkan Lyudmila L Tolleman Viktor V Federico Sara M SM Morton Chris C Lu Charles C Ding Li L Easton John J Rusch Michael M Nagahawatte Panduka P Wang Jianmin J Parker Matthew M Wei Lei L Hedlund Erin E Finkelstein David D Edmonson Michael M Shurtleff Sheila S Boggs Kristy K Mulder Heather H Yergeau Donald D Skapek Steve S Hawkins Douglas S DS Ramirez Nilsa N Potter Philip M PM Sandoval John A JA Davidoff Andrew M AM Mardis Elaine R ER Wilson Richard K RK Zhang Jinghui J Downing James R JR Dyer Michael A MA
Cancer cell 20131201 6
Rhabdomyosarcoma is a soft-tissue sarcoma with molecular and cellular features of developing skeletal muscle. Rhabdomyosarcoma has two major histologic subtypes, embryonal and alveolar, each with distinct clinical, molecular, and genetic features. Genomic analysis shows that embryonal tumors have more structural and copy number variations than alveolar tumors. Mutations in the RAS/NF1 pathway are significantly associated with intermediate- and high-risk embryonal rhabdomyosarcomas (ERMS). In con ...[more]
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Project description:Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and remains refractory to combined-modality therapy in patients with high risk disease. In skeletal myogenesis, Notch signaling prevents muscle differentiation and promotes proliferation of satellite cell progeny. Given its physiologic role in myogenesis and oncogenic role in other human cancers, we hypothesized that aberrant Notch signaling may contribute to RMS tumorigenesis and present novel therapeutic opportunities.Human RMS cell lines and tumors were evaluated by immunoblot, IHC, and RT-PCR to measure Notch ligand, receptor, and target gene expression. Manipulation of Notch signaling was accomplished using genetic and pharmacologic approaches. In vitro cell growth, proliferation, and differentiation were assessed using colorimetric MTT and BrdU assays, and biochemical/morphologic changes after incubation in differentiation-promoting media, respectively. In vivo tumorigenesis was assessed using xenograft formation in SCID/beige mice.Notch signaling is upregulated in human RMS cell lines and tumors compared with primary skeletal muscle, especially in the embryonal (eRMS) subtype. Inhibition of Notch signaling using Notch1 RNAi or ?-secretase inhibitors reduced eRMS cell proliferation in vitro. Hey1 RNAi phenocopied Notch1 loss and permitted modest myogenic differentiation, while overexpression of an activated Notch moiety, ICN1, promoted eRMS cell proliferation and rescued pharmacologic inhibition. Finally, Notch inhibition using RNAi or ?-secretase inhibitors blocked tumorigenesis in vivo.Aberrant Notch-Hey1 signaling contributes to eRMS by impeding differentiation and promoting proliferation. The efficacy of Notch pathway inhibition in vivo supports the development of Notch-Hey1 axis inhibitors in the treatment of eRMS.
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Project description:IntroductionRhabdomyosarcoma is a rare paediatric cancer, with the head and neck region representing a major anatomical site for rhabdomyosarcoma. In particular, orbital rhabdomyosarcoma is the most common region among children. However, rhabdomyosarcoma originating from the conjunctiva in paediatric population is a rare disease, and this knowledge is essential in order to ensure prompt treatment and early intervention.Case presentationWe discuss a rare case of primary conjunctival rhabdomyosarcoma in an 8-year-old Caucasian girl. She presented to a paediatric ophthalmology clinic with a 5-day history of a rapidly growing conjunctival lesion in the superior fornix of the right eye. An urgent excisional biopsy was performed which yielded a large 30-mm multilobulated, vascular, and papillomatous specimen with histopathological features consistent with embryonal rhabdomyosarcoma. She was urgently referred to oncology and was treated with systemic chemotherapy.ConclusionTherapeutical options and prognosis of rhabdomyosarcomas are based on clinical findings, tumour staging, and grouping, combined with histopathological and molecular features. Although rare, it is important to note that in the paediatric population, rhabdomyosarcoma can originate from the conjunctiva. Knowledge of its clinical, histopathological, and imaging characteristics is essential in order to achieve early diagnosis and timely treatment.
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