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AlMulai I, Fahad A, Nagshabandi Z. Cervical Rhabdomyosarcoma: A Case Report. Cureus 2025; 17:e77902. [PMID: 39991364 PMCID: PMC11847311 DOI: 10.7759/cureus.77902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/24/2025] [Indexed: 02/25/2025] Open
Abstract
Rhabdomyosarcomas are rare in adults, and primary cervical rhabdomyosarcomas are even rarer. Due to its rarity, literature on the presentation and management of cervical rhabdomyosarcoma is scarce. We present the case of a 35-year-old woman who presented with abnormal uterine bleeding, one of the most common complaints in gynecology outpatient clinics. Following evaluation and investigations, she was diagnosed with cervical rhabdomyosarcoma. Timely diagnosis and appropriate treatment ensured a good prognosis for the patient. This case report underlines the importance of histopathology in attaining the appropriate diagnosis, which can be lifesaving.
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Affiliation(s)
- Israa AlMulai
- Obstetrics and Gynaecology, Latifa Hospital, Dubai Health, Dubai, ARE
| | - Asma Fahad
- Obstetrics and Gynaecology, Latifa Hospital, Dubai Health, Dubai, ARE
| | - Zuhdi Nagshabandi
- Obstetrics and Gynaecology, Latifa Hospital, Dubai Health, Dubai, ARE
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2
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Graef S, DeAngelis D, Gupta AA, Wan MJ. Ocular manifestations and long-term complications of rhabdomyosarcoma in children. Eye (Lond) 2024; 38:2907-2911. [PMID: 38907018 PMCID: PMC11461851 DOI: 10.1038/s41433-024-03175-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 05/07/2024] [Accepted: 06/06/2024] [Indexed: 06/23/2024] Open
Abstract
BACKGROUND/OBJECTIVES The purpose of the study was to describe the ocular manifestations of rhabdomyosarcoma in a large cohort of children. SUBJECT/METHODS This was a retrospective observational cohort study. The medical records of all pediatric patients with head and neck rhabdomyosarcoma diagnosed between 1997 and 2021 at a tertiary-care pediatric hospital were analyzed. The main outcome measures were the incidence and prognostic role of ocular findings at presentation and long-term ocular complications. RESULTS There were 77 children with head and neck rhabdomyosarcoma in the study cohort with 38 patients showing ocular manifestations at presentation. Median age at diagnosis was 6.0 years, the median follow-up was 5.7 years and 54.5% were male. At last follow-up, 70.1% had no evidence of progression, 26.0% were deceased, and 2.6% were on palliative treatment. Orbital signs were common (44.2%). The most common ocular findings were proptosis (18.2%), restriction of extraocular motility (28.6%), strabismus/diplopia (22.1%) and ptosis (16.9%). The most common long-term complications were bony hypoplasia/facial asymmetry (40.3%) and keratopathy/dry eye (31.2%). Poor visual acuity (≤20/200) was noted in 13 (16.9%) patients with 5 (6.5%) patients requiring an exenteration. Survival was 100% in primary orbital RMS (p = 0.02), whereas any or a combination of cranial nerve palsies carried a poor prognosis (42% survival, p = 0.008). CONCLUSIONS In our cohort, half of children with rhabdomyosarcoma had ocular manifestations at presentation with about one-third showing orbital tumor involvement. Cranial nerve involvement carried a significantly worse prognosis for survival.
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Affiliation(s)
- Sybille Graef
- Department of Ophthalmology and Vision Sciences, University of Toronto and Hospital for Sick Children, Toronto, ON, Canada
| | - Dan DeAngelis
- Department of Ophthalmology and Vision Sciences, University of Toronto and Hospital for Sick Children, Toronto, ON, Canada
| | - Abha A Gupta
- Department of Pediatrics, Division of Hematology/Oncology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Michael J Wan
- Department of Ophthalmology and Vision Sciences, University of Toronto and Hospital for Sick Children, Toronto, ON, Canada.
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3
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Omami G, Yeoh M. Malignant Lesions of the Oral Region. Dent Clin North Am 2024; 68:319-335. [PMID: 38417993 DOI: 10.1016/j.cden.2023.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2024]
Abstract
This article focuses on the radiographic presentations of various malignant conditions that affect the oral region and delineates the role of CT, MR imaging, and PET in oral cancer imaging.
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Affiliation(s)
- Galal Omami
- Division of Oral Diagnosis, Oral Medicine, and Oral Radiology, Department of Oral Health Practice, University of Kentucky College of Dentistry, 770 Rose Street, MN320, Lexington, KY 40536, USA.
| | - Melvyn Yeoh
- Division of Oral and Maxillofacial Surgery, University of Kentucky College of Dentistry, 770 Rose Street, D-528, Lexington, KY 40536, USA
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4
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Weiss AR, Harrison DJ. Soft Tissue Sarcomas in Adolescents and Young Adults. J Clin Oncol 2024; 42:675-685. [PMID: 37967293 DOI: 10.1200/jco.23.01275] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/24/2023] [Accepted: 09/15/2023] [Indexed: 11/17/2023] Open
Abstract
Soft tissue sarcomas (STS) represent a heterogeneous group of extraskeletal mesenchymal tumors that affect individuals throughout the entire age continuum. Despite this pervasive influence, key differences exist in the presentation of these sarcomas across varying age groups that have prevented a more uniform approach to management. Notably, rhabdomyosarcoma (RMS) is more common in children, while most nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) subtypes are more prevalent in adults. Older patients with NRSTS appear to have more molecularly complex biology and often present with more advanced disease compared with children. Poorer outcome disparities are observed in older patients with RMS despite receiving similar treatment as younger patients. In this review, we highlight differences in epidemiology, biology, and management paradigms for pediatric and adult patients with STS and explore opportunities for a unified approach to enhance the care and outcomes within the AYA population.
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Affiliation(s)
- Aaron R Weiss
- Department of Pediatrics, Maine Medical Center, Portland, ME
| | - Douglas J Harrison
- Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, TX
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Bachman JF, Chakkalakal JV. Insights into muscle stem cell dynamics during postnatal development. FEBS J 2022; 289:2710-2722. [PMID: 33811430 PMCID: PMC9947813 DOI: 10.1111/febs.15856] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/17/2021] [Accepted: 03/31/2021] [Indexed: 12/11/2022]
Abstract
During development, resident stem cell populations contribute to the growth and maturation of tissue and organs. In skeletal muscle, muscle stem cells, or satellite cells (SCs), are responsible for the maturation of postnatal myofibers. However, the role SCs play in later stages of postnatal growth, and thus, when they enter a mature quiescent state is controversial. Here, we discuss the current literature regarding the role SCs play in all stages of postnatal growth, from birth to puberty onset to young adulthood. We additionally highlight the implications of SC loss or dysfunction during developmental stages, both in the context of experimental paradigms and disease settings.
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Affiliation(s)
- John F Bachman
- Department of Pathology and Laboratory Medicine, Cell Biology of Disease Graduate Program, University of Rochester Medical Center, Rochester NY, United States.,Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester NY, United States
| | - Joe V Chakkalakal
- Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester NY, United States.,Department of Biomedical Engineering, University of Rochester, Rochester NY, United States.,Wilmot Cancer Institute, University of Rochester Medical Center, Rochester NY, United States.,Stem Cell and Regenerative Medicine Institute, and The Rochester Aging Research Center, University of Rochester Medical Center, Rochester NY, United States.,Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester NY, United States
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6
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Khurshid S, Montes M, Comiskey DF, Shane B, Matsa E, Jung F, Brown C, Bid HK, Wang R, Houghton PJ, Roberts R, Rigo F, Chandler D. Splice-switching of the insulin receptor pre-mRNA alleviates tumorigenic hallmarks in rhabdomyosarcoma. NPJ Precis Oncol 2022; 6:1. [PMID: 35017650 PMCID: PMC8752779 DOI: 10.1038/s41698-021-00245-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 12/16/2021] [Indexed: 01/07/2023] Open
Abstract
Rhabdomyosarcoma (RMS) is an aggressive pediatric tumor with a poor prognosis for metastasis and recurrent disease. Large-scale sequencing endeavors demonstrate that Rhabdomyosarcomas have a dearth of precisely targetable driver mutations. However, IGF-2 signaling is known to be grossly altered in RMS. The insulin receptor (IR) exists in two alternatively spliced isoforms, IR-A and IR-B. The IGF-2 signaling molecule binds both its innate IGF-1 receptor as well as the insulin receptor variant A (IR-A) with high affinity. Mitogenic and proliferative signaling via the canonical IGF-2 pathway is, therefore, augmented by IR-A. This study shows that RMS patients express increased IR-A levels compared to control tissues that predominantly express the IR-B isoform. We also found that Hif-1α is significantly increased in RMS tumors, portraying their hypoxic phenotype. Concordantly, the alternative splicing of IR adapts to produce more IR-A in response to hypoxic stress. Upon examining the pre-mRNA structure of the gene, we identified a potential hypoxia-responsive element, which is also the binding site for the RNA-binding protein CUG-BP1 (CELF1). We designed Splice Switching Oligonucleotides (SSO) against this binding site to decrease IR-A levels in RMS cell lines and, consequently, rescue the IR-B expression levels. SSO treatment resulted in a significant reduction in cell proliferation, migration, and angiogenesis. Our data shows promising insight into how impeding the IGF-2 pathway by reducing IR-A expression mitigates tumor growth. It is evident that Rhabdomyosarcomas use IR alternative splicing as yet another survival strategy that can be exploited as a therapeutic intervention in conjunction with already established anti-IGF-1 receptor therapies.
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Affiliation(s)
- Safiya Khurshid
- Department of Pediatrics and the Center for RNA Biology, The Ohio State University, Columbus, OH, 43210, USA
- Center for Childhood Cancer, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, 43205, USA
| | - Matias Montes
- Department of Pediatrics and the Center for RNA Biology, The Ohio State University, Columbus, OH, 43210, USA
- Center for Childhood Cancer, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, 43205, USA
| | - Daniel F Comiskey
- Department of Pediatrics and the Center for RNA Biology, The Ohio State University, Columbus, OH, 43210, USA
- Center for Childhood Cancer, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, 43205, USA
| | - Brianne Shane
- Department of Pediatrics and the Center for RNA Biology, The Ohio State University, Columbus, OH, 43210, USA
- Center for Childhood Cancer, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, 43205, USA
| | - Eleftheria Matsa
- Department of Pediatrics and the Center for RNA Biology, The Ohio State University, Columbus, OH, 43210, USA
- Center for Childhood Cancer, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, 43205, USA
| | - Francesca Jung
- Department of Pediatrics and the Center for RNA Biology, The Ohio State University, Columbus, OH, 43210, USA
- Center for Childhood Cancer, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, 43205, USA
| | - Chelsea Brown
- Department of Pediatrics and the Center for RNA Biology, The Ohio State University, Columbus, OH, 43210, USA
- Center for Childhood Cancer, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, 43205, USA
| | | | - Ruoning Wang
- Department of Pediatrics and the Center for RNA Biology, The Ohio State University, Columbus, OH, 43210, USA
- Center for Childhood Cancer, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, 43205, USA
| | - Peter J Houghton
- Greenhey Children's Cancer Research Institute, UT Health, San Antonio, TX, 78229, USA
| | - Ryan Roberts
- Department of Pediatrics and the Center for RNA Biology, The Ohio State University, Columbus, OH, 43210, USA
- Center for Childhood Cancer, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, 43205, USA
| | - Frank Rigo
- Ionis Pharmaceuticals, Carlsbad, CA, 92010, USA
| | - Dawn Chandler
- Department of Pediatrics and the Center for RNA Biology, The Ohio State University, Columbus, OH, 43210, USA.
- Center for Childhood Cancer, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, 43205, USA.
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Shrestha R, Mohankumar K, Martin G, Hailemariam A, Lee SO, Jin UH, Burghardt R, Safe S. Flavonoids kaempferol and quercetin are nuclear receptor 4A1 (NR4A1, Nur77) ligands and inhibit rhabdomyosarcoma cell and tumor growth. J Exp Clin Cancer Res 2021; 40:392. [PMID: 34906197 PMCID: PMC8670039 DOI: 10.1186/s13046-021-02199-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 11/26/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Flavonoids exhibit both chemopreventive and chemotherapeutic activity for multiple tumor types, however, their mechanisms of action are not well defined. Based on some of their functional and gene modifying activities as anticancer agents, we hypothesized that kaempferol and quercetin were nuclear receptor 4A1 (NR4A1, Nur77) ligands and confirmed that both compounds directly bound NR4A1 with KD values of 3.1 and 0.93 μM, respectively. METHODS The activities of kaempferol and quercetin were determined in direct binding to NR4A1 protein and in NR4A1-dependent transactivation assays in Rh30 and Rh41 rhabdomyosarcoma (RMS) cells. Flavonoid-dependent effects as inhibitors of cell growth, survival and invasion were determined in XTT and Boyden chamber assays respectively and changes in protein levels were determined by western blots. Tumor growth inhibition studies were carried out in athymic nude mice bearing Rh30 cells as xenografts. RESULTS Kaempferol and quercetin bind NR4A1 protein and inhibit NR4A1-dependent transactivation in RMS cells. NR4A1 also regulates RMS cell growth, survival, mTOR signaling and invasion. The pro-oncogenic PAX3-FOXO1 and G9a genes are also regulated by NR4A1 and, these pathways and genes are all inhibited by kaempferol and quercetin. Moreover, at a dose of 50 mg/kg/d kaempferol and quercetin inhibited tumor growth in an athymic nude mouse xenograft model bearing Rh30 cells. CONCLUSION These results demonstrate the clinical potential for repurposing kaempferol and quercetin for clinical applications as precision medicine for treating RMS patients that express NR4A1 in order to increase the efficacy and decrease dosages of currently used cytotoxic drugs.
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Affiliation(s)
- Rupesh Shrestha
- Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, 77843, USA
| | - Kumaravel Mohankumar
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX, 77843-4466, USA
| | - Greg Martin
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX, 77843-4466, USA
| | - Amanuel Hailemariam
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX, 77843-4466, USA
| | - Syng-Ook Lee
- Department of Food Science and Technology, Keimyung University, Daegu, 42601, Republic of Korea
| | - Un-Ho Jin
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX, 77843-4466, USA
| | - Robert Burghardt
- Department of Veterinary Integrated Biosciences, Texas A&M University, College Station, TX, 77843, USA
| | - Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX, 77843-4466, USA.
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Król SK, Bębenek E, Dmoszyńska-Graniczka M, Sławińska-Brych A, Boryczka S, Stepulak A. Acetylenic Synthetic Betulin Derivatives Inhibit Akt and Erk Kinases Activity, Trigger Apoptosis and Suppress Proliferation of Neuroblastoma and Rhabdomyosarcoma Cell Lines. Int J Mol Sci 2021; 22:12299. [PMID: 34830180 PMCID: PMC8624615 DOI: 10.3390/ijms222212299] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/08/2021] [Accepted: 11/11/2021] [Indexed: 12/12/2022] Open
Abstract
Neuroblastoma (NB) and rhabdomyosarcoma (RMS), the most common pediatric extracranial solid tumors, still represent an important clinical challenge since no effective treatment is available for metastatic and recurrent disease. Hence, there is an urgent need for the development of new chemotherapeutics to improve the outcome of patients. Betulin (Bet), a triterpenoid from the bark of birches, demonstrated interesting anti-cancer potential. The modification of natural phytochemicals with evidenced anti-tumor activity, including Bet, is one of the methods of receiving new compounds for potential implementation in oncological treatment. Here, we showed that two acetylenic synthetic Bet derivatives (ASBDs), EB5 and EB25/1, reduced the viability and proliferation of SK-N-AS and TE671 cells, as measured by MTT and BrdU tests, respectively. Moreover, ASBDs were also more cytotoxic than temozolomide (TMZ) and cisplatin (cis-diaminedichloroplatinum [II], CDDP) in vitro, and the combination of EB5 with CDDP enhanced anti-cancer effects. We also showed the slowdown of cell cycle progression at S/G2 phases mediated by EB5 using FACS flow cytometry. The decreased viability and proliferation of pediatric cancers cells after treatment with ASBDs was linked to the reduced activity of kinases Akt, Erk1/2 and p38 and the induction of apoptosis, as investigated using Western blotting and FACS. In addition, in silico analyses of the ADMET profile found EB5 to be a promising anti-cancer drug candidate that would benefit from further investigation.
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Affiliation(s)
- Sylwia K. Król
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Medical University of Lublin, Chodźki 1, 20-093 Lublin, Poland; (M.D.-G.); (A.S.)
| | - Ewa Bębenek
- Department of Organic Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Jagiellońska 4, 41-200 Sosnowiec, Poland; (E.B.); (S.B.)
| | - Magdalena Dmoszyńska-Graniczka
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Medical University of Lublin, Chodźki 1, 20-093 Lublin, Poland; (M.D.-G.); (A.S.)
| | - Adrianna Sławińska-Brych
- Department of Cell Biology, Faculty of Biology and Biotechnology, Institute of Biological Sciences, Maria Curie-Sklodowska University, Akademicka 19, 20-033 Lublin, Poland;
| | - Stanisław Boryczka
- Department of Organic Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Jagiellońska 4, 41-200 Sosnowiec, Poland; (E.B.); (S.B.)
| | - Andrzej Stepulak
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Medical University of Lublin, Chodźki 1, 20-093 Lublin, Poland; (M.D.-G.); (A.S.)
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Generali M, Satheesha S, Bode PK, Wanner D, Schäfer BW, Casanova EA. High Frequency of Tumor Propagating Cells in Fusion-Positive Rhabdomyosarcoma. Genes (Basel) 2021; 12:genes12091373. [PMID: 34573355 PMCID: PMC8469567 DOI: 10.3390/genes12091373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/26/2021] [Accepted: 08/30/2021] [Indexed: 11/16/2022] Open
Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Fusion-positive RMS (FPRMS), expressing the PAX3/7-FOXO1, has a worse prognosis compared to the more common fusion-negative RMS (FNRMS). Although several studies reported hierarchical organization for FNRMS with the identification of cancer stem cells, the cellular organization of FPRMS is not yet clear. In this study we investigated the expression of key stem cell markers, developed a sphere assay, and investigated the seven most common FPRMS cell lines for subpopulations of tumor propagating cancer stem-like cells, also called cancer stem cells (CSCs). Moreover, loss- and gain-of-functions of the stem cell genes SOX2, OCT4, and NANOG were investigated in the same cells. Single-cell clonal analysis was performed in vitro as well as in vivo. We found that no stable CSC subpopulation could be enriched in FPRMS. Unlike depletion of PAX3-FOXO1, neither overexpression nor siRNA-mediated downregulation of SOX2, OCT4, and NANOG affected physiology of RMS cells. Every single subclone-derived cell clone initiated tumor growth in mice, despite displaying considerable heterogeneity in gene expression. FPRMS appears to contain a high frequency of tumor propagating stem-like cells, which could explain their higher propensity for metastasis and relapse. Their dependency on PAX3-FOXO1 activity reinforces the importance of the fusion protein as the key therapeutic target.
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Affiliation(s)
- Melanie Generali
- Center for Therapy Development and Good Manufacturing Practice, Institute for Regenerative Medicine (IREM), University of Zurich, 8044 Zurich, Switzerland; (M.G.); (D.W.)
| | - Sampoorna Satheesha
- Department of Oncology and Children’s Research Center, University Children’s Hospital Zurich, 8032 Zurich, Switzerland;
| | - Peter K. Bode
- Department of Pathology and Molecular Pathology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland;
| | - Debora Wanner
- Center for Therapy Development and Good Manufacturing Practice, Institute for Regenerative Medicine (IREM), University of Zurich, 8044 Zurich, Switzerland; (M.G.); (D.W.)
| | - Beat W. Schäfer
- Department of Oncology and Children’s Research Center, University Children’s Hospital Zurich, 8032 Zurich, Switzerland;
- Correspondence: (B.W.S.); (E.A.C.); Tel.: +41-44-266-7553 (B.W.S.); +41-44-255-1976 (E.A.C.)
| | - Elisa A. Casanova
- Division of Trauma Surgery, Center for Clinical Research, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland
- Correspondence: (B.W.S.); (E.A.C.); Tel.: +41-44-266-7553 (B.W.S.); +41-44-255-1976 (E.A.C.)
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Peng H, Jiang J, Huang X. Uterine rhabdomyosarcoma complicated by cerebral venous thrombosis and uterine inversion in a young woman: case report and literature review. BMC WOMENS HEALTH 2021; 21:314. [PMID: 34445980 PMCID: PMC8390075 DOI: 10.1186/s12905-021-01459-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 08/20/2021] [Indexed: 11/28/2022]
Abstract
Background Uterine rhabdomyosarcoma is an extremely rare malignant tumor that usually affects young women and has a poor prognosis. Case presentation A 19-year-old nulliparous woman presented to the emergency department under sedation due to seizures. Imaging examination revealed cerebral venous thrombosis. During thrombolytic therapy, she developed vaginal bleeding followed by uterine inversion secondary to uterine rhabdomyosarcoma. The inverted uterus was mistaken for a cervical tumour and was removed vaginally. The patient’s disease progressed despite chemotherapy with vincristine, actinomycin D and cyclophosphamide and she died within 6 months. To our knowledge, this is the first case of uterine rhabdomyosarcoma complicated with cerebral venous thrombosis. Conclusions Malignancy is an important diagnostic in patients with cerebral venous thrombosis with no obvious cause. This case demonstrates the importance of considering uterine neoplasms in the differential diagnosis of adolescent girls with abnormal uterine bleeding. Further, careful anatomical evaluation of vaginal masses should be performed prior to surgical intervention.
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Affiliation(s)
- Hongfa Peng
- Department of Obstetrics and Gynecology, Second Hospital of Hebei Medical University, Heping West Road No. 215, Shijiazhuang City, 050000, Hebei Province, China.
| | - Jingjing Jiang
- Department of Obstetrics and Gynecology, Hebei General Hospital, Shijiazhuang, 050051, China
| | - Xianghua Huang
- Department of Obstetrics and Gynecology, Second Hospital of Hebei Medical University, Heping West Road No. 215, Shijiazhuang City, 050000, Hebei Province, China
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Abstract
This is the case of a parameningeal alveolar rhabdomyosarcoma (ARMS) in a 13-year-old boy who presented with painless loss of vision in the right eye, but very few other physical signs. The ARMS diagnosis was confirmed with imaging and molecular characterisation of the tumour. Despite tolerating the initial chemotherapy and radiotherapy regimens, there was leptomeningeal recurrence and the patient unfortunately passed away. Parameningeal ARMS occurs in an area of the body, which leads to a wide variety of possible presenting symptoms, creating a long list of differentials that can delay treatment. This tumour subtype has a poor prognosis, and due to the location of the tumour around vital structures in the head, treatment toxicities must be taken into account. This highlights the necessity for having a strong index of suspicion for this tumour in atypical presentations in children, and the necessity for prompt treatment to prevent leptomeningeal disease from occurring.
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Affiliation(s)
- Abhinav Kumar
- Medical School, University College London, London, UK
| | - Vijay Pothula
- ENT Department, Wrightington Wigan and Leigh NHS Foundation Trust, Wigan, UK
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12
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Population-based survival of pediatric rhabdomyosarcoma of the head and neck over four decades. Int J Pediatr Otorhinolaryngol 2021; 142:110599. [PMID: 33422992 DOI: 10.1016/j.ijporl.2020.110599] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 12/04/2020] [Accepted: 12/26/2020] [Indexed: 11/24/2022]
Abstract
OBJECTIVES Clinical trials have reported increases in the survival of pediatric rhabdomyosarcoma (RMS) from 25% in 1970 to 73% in 2001. The purpose of this study was to examine whether survival of pediatric patients with RMS of the head and neck improved at the US population level. METHODS A population-based cohort of patients with rhabdomyosarcoma of the head and neck aged 0-19 years in the Surveillance, Epidemiology, and End Results (SEER) registry from 1973 to 2013 was queried. The cumulative incidence competing risks (CICR) method was used to estimate risk and survival trends. RESULTS 718 cases were identified for analysis. Survival rates at 1-, 5-, and 10-years after diagnosis were 91.2%, 73.2%, and 69.4% respectively. Survival rates at 1 year after diagnosis increased from 82.6% to 93.1% during the study period. In the subdistributional hazard analysis, there was a significantly improved disease-specific risk of death in the first year after diagnosis. Overall risk of death did not improve significantly. Favorable prognostic factors included age <10 years at diagnosis, smaller tumor size, absence of distant metastasis, localized tumors, earlier stage at presentation, grossly complete surgical resection, and embryonal or botryoid histology. CONCLUSIONS Disease-specific survival in the first year following diagnosis improved, but the change in overall survival at the population level was not statistically significant. These findings should be interpreted in light of the inclusion of patients with distant metastasis at diagnosis, who have poor prognoses, together with the limited statistical power afforded in studies of rare diseases.
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Chemoradiation impairs myofiber hypertrophic growth in a pediatric tumor model. Sci Rep 2020; 10:19501. [PMID: 33177579 PMCID: PMC7659015 DOI: 10.1038/s41598-020-75913-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 10/19/2020] [Indexed: 01/05/2023] Open
Abstract
Pediatric cancer treatment often involves chemotherapy and radiation, where off-target effects can include skeletal muscle decline. The effect of such treatments on juvenile skeletal muscle growth has yet to be investigated. We employed a small animal irradiator to administer fractionated hindlimb irradiation to juvenile mice bearing implanted rhabdomyosarcoma (RMS) tumors. Hindlimb-targeted irradiation (3 × 8.2 Gy) of 4-week-old mice successfully eliminated RMS tumors implanted one week prior. After establishment of this preclinical model, a cohort of tumor-bearing mice were injected with the chemotherapeutic drug, vincristine, alone or in combination with fractionated irradiation (5 × 4.8 Gy). Single myofiber analysis of fast-contracting extensor digitorum longus (EDL) and slow-contracting soleus (SOL) muscles was conducted 3 weeks post-treatment. Although a reduction in myofiber size was apparent, EDL and SOL myonuclear number were differentially affected by juvenile irradiation and/or vincristine treatment. In contrast, a decrease in myonuclear domain (myofiber volume/myonucleus) was observed regardless of muscle or treatment. Thus, inhibition of myofiber hypertrophic growth is a consistent feature of pediatric cancer treatment.
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14
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Zhang Y, He C, Lian Y, Xiao H. Score for the Survival Probability of Patients With Orbital Rhabdomyosarcoma After Surgery: A Long-Term and Large Cohort Study. Front Oncol 2020; 10:1590. [PMID: 32974196 PMCID: PMC7482652 DOI: 10.3389/fonc.2020.01590] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 07/23/2020] [Indexed: 12/05/2022] Open
Abstract
Orbital rhabdomyosarcoma (RMS) is a relatively rare primary malignancy occurring in children. The objective of this study was to evaluate the cumulative incidence of cancer-specific death and competing risk of death among RMS patients after surgery and to build nomograms to predict overall survival (OS) and cancer-specific survival (CSS) based on a large population-based cohort. The records of 217 patients who were pathologically diagnosed with an orbital RMS between 1973 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database were retrospectively analyzed. The 10-, 20-, and 40-years OS rates and cancer-specific mortality were 82.5, 72.2, and 48.9%, respectively, and 14.8, 21.7, and 21.7%, respectively. The established nomograms were well-calibrated and validated, with a concordance index (C-index) of 0.901 and 0.944 for OS prediction, 0.923 and 0.904, for CSS prediction in the training and validation cohorts, respectively. The values of area under the receiver operating characteristic curve (AUC) for 10-, 20-, and 40-years OS and CSS prediction were 0.908, 0.826, and 0.847, and 0.924, 0.863, and 0.863, respectively. The established nomogram showed relatively good performances and could be convenient individualized predictive tools for prognostic prediction in RMS patients.
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Affiliation(s)
- Yu Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Chaobin He
- State Key Laboratory of Oncology in South China, Department of Pancreaobiliary Surgery, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yu Lian
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Huiming Xiao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
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The impact of 18F-FDG PET on initial staging and therapy planning of pediatric soft-tissue sarcoma patients. Pediatr Radiol 2020; 50:252-260. [PMID: 31628508 DOI: 10.1007/s00247-019-04530-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 08/15/2019] [Accepted: 09/06/2019] [Indexed: 10/25/2022]
Abstract
BACKGROUND Soft-tissue sarcomas in children are a histologically heterogenous group of malignant tumors accounting for approximately 7% of childhood cancers. There is a paucity of data on the value of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) for initial staging and whether PET influenced management of these patients. OBJECTIVE The aim of this analysis is to assess the use of 18F-FDG PET exclusively, and as a supplement to cross-sectional imaging in comparison to typical imaging protocols (CT and magnetic resonance imaging [MRI]) for initial staging as well as therapy planning in pediatric soft-tissue sarcoma patients. MATERIALS AND METHODS The list of 18F-FDG PET/CT performed for soft-tissue sarcoma between March 2007 and October 2017 was obtained from the Hospital Information System database. Twenty-six patients who had received 18F-FDG PET, MRI and/or CT at initial diagnosis were included in the study. 18F-FDG PET and concurrent diagnostic CT and MRI at initial staging were independently reviewed to note the number of primary and metastatic lesions detected by each modality. A chart review was conducted to collect information on final diagnosis, staging and treatment plan. RESULTS During the study period, 26 patients (15 females) ages 1.3-17.9 years (median age: 6 years) had received 18F-FDG PET/CT at initial diagnosis of soft-tissue sarcoma. Diagnostic CT was available for comparison in all 26 patients and MRI was available in 18 patients. The mean interval between cross-sectional imaging and 18F-FDG PET was 5.9 days (range: 0-30 days). All 26 primary lesions were equally detected by 18F-FDG PET compared to CT and MRI. From 84 metastatic lesions, 16 were detected by PET as well as CT and MRI, 12 by 18F-FDG PET only (included mainly lymph node metastases) and 56 by CT and MRI only (included mainly lung metastases). 18F-FDG PET changed therapy planning in 5 patients out of 26 (19%) by showing additional lesions not detected by CT and MRI. CONCLUSION 18F-FDG PET proved to be a valuable tool for precise initial staging of pediatric soft-tissue sarcoma patients, especially in detecting lymph node metastasis, and could be included in their initial work-up. Given the relative rarity and heterogeneity of this group of tumors, additional investigations are required to definitely establish a role for 18F-FDG PET in the initial staging and therapy planning of soft-tissue sarcoma in the pediatric population.
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Popović-Vuković M, Nidžović B, Nikitović M. Modern radiotherapy for pediatric rhabdomyosarcoma. MEDICINSKI PODMLADAK 2020. [DOI: 10.5937/mp71-24163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
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17
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Smad7:β-catenin complex regulates myogenic gene transcription. Cell Death Dis 2019; 10:387. [PMID: 31097718 PMCID: PMC6522533 DOI: 10.1038/s41419-019-1615-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 03/30/2019] [Accepted: 04/23/2019] [Indexed: 12/17/2022]
Abstract
Recent reports indicate that Smad7 promotes skeletal muscle differentiation and growth. We previously documented a non-canonical role of nuclear Smad7 during myogenesis, independent of its role in TGF-β signaling. Here further characterization of the myogenic function of Smad7 revealed β-catenin as a Smad7 interacting protein. Biochemical analysis identified a Smad7 interaction domain (SID) between aa575 and aa683 of β-catenin. Reporter gene analysis and chromatin immunoprecipitation demonstrated that Smad7 and β-catenin are cooperatively recruited to the extensively characterized ckm promoter proximal region to facilitate its muscle restricted transcriptional activation in myogenic cells. Depletion of endogenous Smad7 and β-catenin in muscle cells reduced ckm promoter activity indicating their role during myogenesis. Deletion of the β-catenin SID substantially reduced the effect of Smad7 on the ckm promoter and exogenous expression of SID abolished β-catenin function, indicating that SID functions as a trans dominant-negative regulator of β-catenin activity. β-catenin interaction with the Mediator kinase complex through its Med12 subunit led us to identify MED13 as an additional Smad7-binding partner. Collectively, these studies document a novel function of a Smad7-MED12/13-β-catenin complex at the ckm locus, indicating a key role of this complex in the program of myogenic gene expression underlying skeletal muscle development and regeneration.
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Adamus A, Peer K, Ali I, Lisec J, Falodun A, Frank M, Seitz G, Engel N. Berberis orthobotrys - A promising herbal anti-tumorigenic candidate for the treatment of pediatric alveolar rhabdomyosarcoma. JOURNAL OF ETHNOPHARMACOLOGY 2019; 229:262-271. [PMID: 30315865 DOI: 10.1016/j.jep.2018.10.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 10/04/2018] [Accepted: 10/07/2018] [Indexed: 06/08/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Berberis orthobotrys (BORM) is a medical plant with a long history in traditional usage for the treatment of wounds, cancer, gastrointestinal malady and several other diseases. Our previous studies identified the endemic Pakistani plant Berberis orthobotrys Bien. ex Aitch. as promising source for the treatment of breast cancer and osteosarcoma. AIM OF THE STUDY The present study was aimed to evaluate the anti-cancer properties of 26 plant derived extracts and compounds including the methanolic root extract of Berberis orthobotrys (BORM) on pediatric alveolar rhabdomyosarcoma (RMA), which is known to develop drug resistance, metastatic invasion and potential tumor progression. MATERIALS AND METHODS The main anti-tumor activity of BORM was verified by focusing on morphological, cell structural and metabolic alterations via metabolic profiling, cell viability measurements, flow cytometry, western blotting and diverse microscopy-based methods using the human RMA cell line Rh30. RESULTS Exposure of 25 µg/ml BORM exerts an influence on the cell stability, the degradation of oncosomes as well as the shutdown of the metabolic activity of RMA cells, primarily by downregulation of the energy metabolism. Therefore glycyl-aspartic acid and N-acetyl serine decreased moderately, and uracil increased intracellularly. On healthy, non-transformed muscle cells BORM revealed very low metabolic alterations and nearly no cytotoxic impact. Furthermore, BORM is also capable to reduce Rh30 cell migration (~50%) and proliferation (induced G2/M cycle arrest) as well as to initiate apoptosis confirmed by reduced Bcl-2, Bax and PCNA expression and induced PARP-1 cleavage. CONCLUSIONS The study provides the first evidence, that BORM treatment is effective against RMA cells with low side effects on healthy cells.
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Affiliation(s)
- Anna Adamus
- Department of Pediatric Surgery, University Hospital Marburg, Baldingerstraße, 35033 Marburg, Germany
| | - Katharina Peer
- Department of Pediatric Surgery, University Hospital Marburg, Baldingerstraße, 35033 Marburg, Germany
| | - Iftikhar Ali
- Department of Chemistry, Karakoram International University, 15100 Gilgit, Pakistan
| | - Jan Lisec
- Division 1.7 Analytical Chemistry, Federal Institute for Materials Research and Testing (BAM), Richard-Willstätter-Straße 11, Berlin 12489 Germany
| | - Abiodun Falodun
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Benin, Benin City 300001, Nigeria
| | - Marcus Frank
- Medical Biology and Electron Microscopy Centre, Rostock University Medical Center, Strempelstraße 14, Rostock 18057, Germany
| | - Guido Seitz
- Department of Pediatric Surgery, University Hospital Marburg, Baldingerstraße, 35033 Marburg, Germany
| | - Nadja Engel
- Department of Pediatric Surgery, University Hospital Marburg, Baldingerstraße, 35033 Marburg, Germany; Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, Rostock University Medical Center, Schillingallee 35, 18057 Rostock, Germany.
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Lacey A, Hedrick E, Cheng Y, Mohankumar K, Warren M, Safe S. Interleukin-24 (IL24) Is Suppressed by PAX3-FOXO1 and Is a Novel Therapy for Rhabdomyosarcoma. Mol Cancer Ther 2018; 17:2756-2766. [PMID: 30190424 PMCID: PMC6279487 DOI: 10.1158/1535-7163.mct-18-0118] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 05/08/2018] [Accepted: 08/29/2018] [Indexed: 12/17/2022]
Abstract
Alveolar rhabdomyosarcoma (ARMS) patients have a poor prognosis, and this is primarily due to overexpression of the oncogenic fusion protein PAX3-FOXO1. Results of RNA-sequencing studies show that PAX3-FOXO1 represses expression of interleukin-24 (IL24), and these two genes are inversely expressed in patient tumors. PAX3-FOXO1 also regulates histone deacetylase 5 (HDAC5) in ARMS cells, and results of RNA interference studies confirmed that PAX3-FOXO1-mediated repression of IL24 is HDAC5-dependent. Knockdown of PAX3-FOXO1 decreases ARMS cell proliferation, survival, and migration, and we also observed similar responses in cells after overexpression of IL24, consistent with results reported for this tumor suppressor-like cytokine in other solid tumors. We also observed in double knockdown studies that the inhibition of ARMS cell proliferation, survival, and migration after knockdown of PAX3-FOXO1 was significantly (>75%) reversed by knockdown of IL24. Adenoviral-expressed IL24 was directly injected into ARMS tumors in athymic nude mice, and this resulted in decreased tumor growth and weight. Because adenoviral IL24 has already successfully undergone phase I in clinical trials, this represents an alternative approach (alone and/or combination) for treating ARMS patients who currently undergo cytotoxic drug therapies.
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Affiliation(s)
- Alexandra Lacey
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas
| | - Erik Hedrick
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas
| | - Yating Cheng
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas
| | - Kumaravel Mohankumar
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas
| | - Melanie Warren
- Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, Texas
| | - Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas.
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20
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Sachedina A, Chan K, MacGregor D, Campbell M, Grover SR. More than Grapes and Bleeding: An Updated Look at Pelvic Rhabdomyosarcoma in Young Women. J Pediatr Adolesc Gynecol 2018; 31:522-525. [PMID: 29421342 DOI: 10.1016/j.jpag.2018.01.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2017] [Revised: 01/20/2018] [Accepted: 01/24/2018] [Indexed: 01/11/2023]
Abstract
STUDY OBJECTIVE To review our local experience with urogenital rhabdomyosarcoma (RMS) to determine the most common clinical presentation(s). DESIGN Retrospective case series of all female patients with urogenital RMS who presented to a tertiary pediatric hospital between 1996 and 2016. All institutional electronic pathology reports were screened for RMS and those that were pelvic in origin and occurred in female patients were included for further analysis. Seventeen cases of urogenital RMS in female patients were identified and reviewed. SETTING This study was conducted at The Royal Children's Hospital in Melbourne, Australia. This is a tertiary referral center for the state of Victoria and surrounding areas, which services more than 1.5 million pediatric patients. PARTICIPANTS Female pediatric patients (ages 0-18 years) who presented to The Royal Children's Hospital with eventual pathologic tissue diagnosis of urogenital RMS. MAIN OUTCOME MEASURES The cases were reviewed for clinical presentation, duration of symptoms before initial presentation, time to tissue diagnosis, and outcomes of treatment. RESULTS Of the 17 cases reviewed, 5 (29%) presented with perineal mass, 4 (24%) presented with each of abdominal mass and grape-like lesions/hemorrhagic mass at the introitus, 3 (18%) with nonspecific symptoms only, and 1 (6%) with vulvar inflammation. CONCLUSION The clinical presentation of urogenital RMS in women is heterogeneous, and the classically described presentation of grape-like lesions at the introitus and vaginal bleeding represents only a small proportion of clinical presentations. Awareness of other presentations, which appear to be more common than previously recognized, needs to be increased to ensure timely diagnosis and treatment.
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Affiliation(s)
- Aalia Sachedina
- Department of Gynecology, The Royal Children's Hospital Melbourne, Melbourne, Australia; Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada.
| | - Kiri Chan
- Department of Gynecology, The Royal Children's Hospital Melbourne, Melbourne, Australia; Department of Adolescent Gynaecology, Monash Children's Hospital, Clayton, Australia
| | - Duncan MacGregor
- Department of Anatomical Pathology, The Royal Children's Hospital Melbourne, Melbourne, Australia
| | - Martin Campbell
- Children's Cancer Centre, The Royal Children's Hospital Melbourne, Melbourne, Australia
| | - Sonia R Grover
- Department of Gynecology, The Royal Children's Hospital Melbourne, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia
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21
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Arrob A, Fiqhi MK, N'diaye A, El Khatib K, Abouchadi A. [Craniofacial adulthood rhabdomyosarcoma: a case with poor prognosis]. Pan Afr Med J 2018; 30:3. [PMID: 30123406 PMCID: PMC6093595 DOI: 10.11604/pamj.2018.30.3.14690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2017] [Accepted: 04/14/2018] [Indexed: 11/25/2022] Open
Abstract
Le rhabdomyosarcome est la tumeur mésenchymateuse la plus fréquente chez l'enfant et l'adolescent. Il représente 60 à 70% des tumeurs mésenchymateuses et environ 5% de l'ensemble des tumeurs solides à ces âges. Près de la moitié des rhabdomyosarcomes surviennent au niveau de la tête et du cou. Nous rapportons le cas d'un rhabdomyosarcome agressif à localisation temporo-pariétale. Chez un jeune adolescent de 20 ans avec une forme histologique nouvelle.
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Affiliation(s)
- Adil Arrob
- Service de Chirurgie Plastique, Maxillo-faciale et Stomatologie, Hôpital Militaire Avicenne, Marrakech, Maroc
| | - Mohammed Kamal Fiqhi
- Service de Chirurgie Plastique, Maxillo-faciale et Stomatologie, Hôpital Militaire d'Instruction Mohammed V, Rabat, Maroc
| | - Abibou N'diaye
- Service de Chirurgie Plastique, Maxillo-faciale et Stomatologie, Hôpital Militaire d'Instruction Mohammed V, Rabat, Maroc
| | - Karim El Khatib
- Service de Chirurgie Plastique, Maxillo-faciale et Stomatologie, Hôpital Militaire d'Instruction Mohammed V, Rabat, Maroc
| | - Abdeljalil Abouchadi
- Service de Chirurgie Plastique, Maxillo-faciale et Stomatologie, Hôpital Militaire Avicenne, Marrakech, Maroc
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22
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Sanli Y, Yilmaz E, Subramaniam RM. Precision Medicine and PET-Computed Tomography in Pediatric Malignancies. PET Clin 2017; 12:423-435. [PMID: 28867113 DOI: 10.1016/j.cpet.2017.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Fluorine-18 fluorodeoxyglucose (18F-FDG) PET-computed tomography (CT) plays a significant role in diagnosis, staging, therapy selection, and therapy assessment of multiple pediatric malignancies and facilitating precision medicine delivery in pediatric patients. In patients with Hodgkin lymphoma, interim fludeoxyglucose 18F-FDG PET/CT is highly sensitive and specific for predicting survival and multiple trials with FDG PET/CT-based adaptive therapies are currently ongoing. It is superior to iodine-131 metaiodobenzylguanidine (131I-MIBG) scintigraphy and bone scintigraphy for detecting metastases in neuroblastoma patients and sarcoma patients. It may predict histologic differentiation and neoadjuvant therapy assessment in Wilms tumor.
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Affiliation(s)
- Yasemin Sanli
- Department of Nuclear Medicine, Medical Faculty of Istanbul, Istanbul University, Sehremini, Istanbul 34370, Turkey; Department of Radiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8896, USA.
| | - Ebru Yilmaz
- Department of Nuclear Medicine, Medical Faculty of Istanbul, Istanbul University, Sehremini, Istanbul 34370, Turkey
| | - Rathan M Subramaniam
- Department of Radiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8896, USA; Department of Clinical Sciences, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8896, USA; Department of Biomedical Engineering, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8896, USA; Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8896, USA; Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8896, USA
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23
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Liu J, Wang Z, Li X, Zhang X, Zhang C. Inhibition of centrosomal protein 164 sensitizes rhabdomyosarcoma cells to radiotherapy. Exp Ther Med 2017; 13:2311-2315. [PMID: 28565843 PMCID: PMC5443223 DOI: 10.3892/etm.2017.4281] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2015] [Accepted: 01/06/2017] [Indexed: 01/30/2023] Open
Abstract
Rhabdomyosarcoma is the second most common malignant tumor of the heart in infants and children and cannot often be resected completely. Chemotherapy and radiotherapy have a critical role in relieving symptoms and prolonging survival; therefore, enhancing the sensitivity of rhabdomyosarcoma to radiotherapy is an important area of investigation in order to improve the prognosis of patients. It has been reported that centrosomal protein 164 (CEP164) has a key role in the DNA damage-activated signaling cascade. CEP164 is often overexpressed in tumors and is associated with poor prognosis in various types of cancer. In the present study, the influence of CEP164 on the radiosensitivity of rhabdomyosarcoma cells was investigated. Results demonstrated that CEP164 is involved in the radiation-induced cellular response. CEP164 is increased upon radiation and influences the cell cycle, cell viability and cell apoptosis. CEP164 depletion enhanced cellular sensitivity to radiation, promoted cell apoptosis, decreased cell viability and induced gap 2/mitosis arrest of the cell cycle. The present study identified the function of CEP164 in radiation resistance in rhabdomyosarcoma, providing a potential therapeutic target for rhabdomyosarcoma treatment by disrupting CEP164.
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Affiliation(s)
- Jianzhou Liu
- Department of Cardiac Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, P.R. China
| | - Zhiju Wang
- Department of Physiology, School of Basic Medicine Science, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Xiaofeng Li
- Department of Cardiac Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, P.R. China
| | - Xu Zhang
- Department of Cardiac Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, P.R. China
| | - Chaoji Zhang
- Department of Cardiac Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, P.R. China
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Lacey A, Rodrigues-Hoffman A, Safe S. PAX3-FOXO1A Expression in Rhabdomyosarcoma Is Driven by the Targetable Nuclear Receptor NR4A1. Cancer Res 2017; 77:732-741. [PMID: 27864345 PMCID: PMC5290192 DOI: 10.1158/0008-5472.can-16-1546] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Revised: 10/14/2016] [Accepted: 10/21/2016] [Indexed: 12/24/2022]
Abstract
Alveolar rhabdomyosarcoma (ARMS) is a devastating pediatric disease driven by expression of the oncogenic fusion gene PAX3-FOXO1A. In this study, we report overexpression of the nuclear receptor NR4A1 in rhabdomyosarcomas that is sufficient to drive high expression of PAX3-FOXO1A there. RNAi-mediated silencing of NR4A1 decreased expression of PAX3-FOXO1A and its downstream effector genes. Similarly, cell treatment with the NR4A1 small-molecule antagonists 1,1-bis(3-indolyl)-1-(p-hydroxy or p-carbomethoxyphenyl)methane (C-DIM) decreased PAX3-FOXO1A. Mechanistic investigations revealed a requirement for the NR4A1/Sp4 complex to bind GC-rich promoter regions to elevate transcription of the PAX3-FOXO1A gene. In parallel, NR4A1 also regulated expression of β1-integrin, which with PAX3-FOXO1A, contributed to tumor cell migration that was blocked by C-DIM/NR4A1 antagonists. Taken together, our results provide a preclinical rationale for the use of NR4A1 small-molecule antagonists to treat ARMS and other rhabdomyosarcomas driven by PAX3-FOXO1A. Cancer Res; 77(3); 732-41. ©2016 AACR.
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Affiliation(s)
- Alexandra Lacey
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas
| | | | - Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas.
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25
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Eguía-Aguilar P, López-Martínez B, Retana-Contreras C, Perezpeña-Diazconti M. Alveolar rhabdomyosarcoma: origin and prognostic implications of molecular findings. BOLETIN MEDICO DEL HOSPITAL INFANTIL DE MEXICO 2016; 73:405-410. [PMID: 29421285 DOI: 10.1016/j.bmhimx.2016.09.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Accepted: 09/28/2016] [Indexed: 11/26/2022] Open
Abstract
We present the case of a 2-year-old male patient with a facial tumor partially treated with chemotherapy before his admission to our institution. The tumor involved from the frontal region to the maxillary floor, the orbit, and the maxillary and sphenoid sinuses. The histopathological diagnosis revealed a stage IV alveolar rhabdomyosarcoma with infiltration to bone marrow and cerebrospinal fluid. He was managed with four cycles of adriamycin, actinomycin, cyclophosphamide and vincristine; cisplatin and irinotecan were added to the last cycle. The tumor had a 50% size reduction, but the patient died after a neutropenia and fever episode. The aggressive behavior of alveolar rhabdomyosarcoma has been associated with the expression of oncogenic fusion proteins resulting from chromosomal translocations, particularly t(2;13) (q35;q14) PAX3/FOXO1, and t(1;13) (p36;q14) PAX7/FOXO1 which were present in this patient.
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Affiliation(s)
- Pilar Eguía-Aguilar
- Departmento de Patología Clínica y Experimental, Hospital Infantil de México Federico Gómez, Mexico City, Mexico
| | - Briceida López-Martínez
- Subdirección de Diagnóstico y Servicios Auxiliares, Hospital Infantil de México Federico Gómez, Mexico City, Mexico
| | - Carmen Retana-Contreras
- Departmento de Patología Clínica y Experimental, Hospital Infantil de México Federico Gómez, Mexico City, Mexico
| | - Mario Perezpeña-Diazconti
- Departmento de Patología Clínica y Experimental, Hospital Infantil de México Federico Gómez, Mexico City, Mexico.
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26
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Rabdomiosarcoma infantil. RADIOLOGIA 2016; 58:481-490. [DOI: 10.1016/j.rx.2016.09.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 08/20/2016] [Accepted: 09/14/2016] [Indexed: 12/31/2022]
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Li L, Xue T, Xu W, Zhou B. Effect of matrine combined with cisplatin on the expression of XIAP in human rhabdomyosarcoma RD cells. Oncol Lett 2016; 12:3793-3798. [PMID: 27895732 PMCID: PMC5104167 DOI: 10.3892/ol.2016.5150] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2016] [Accepted: 09/16/2016] [Indexed: 12/13/2022] Open
Abstract
The combined effects of matrine (Mat) and cisplatin on the survival and apoptosis of rhabdomyosarcoma (RMS) RD cells, as well as the possible mechanism of the synergistic effect of Mat and cisplatin were investigated in the present study. RMS RD cells were divided and treated as follows: control group, 5 mg/l cisplatin group, Mat groups (0.5, 1.0 and 1.5 g/l), and Mat (0.5, 1.0 and 1.5 g/l) combined with 5 mg/l cisplatin groups. An MTT assay and flow cytometry were applied to detect the survival and apoptotic rates, respectively, while RT-PCR was applied to detect the expression levels of X-linked inhibitor of apoptosis protein (XIAP) mRNA in the RD cells of each group. The survival rates of RD cells in each experimental group were lower than in the control group, and the apoptotic rates were higher than those in the control group (P<0.05). An increase in drug concentrations led to the cell proliferation inhibitory and apoptotic rates of the single Mat groups increasing as a function of dose (pairwise comparison among the groups, P<0.05), while the proliferation inhibitory and apoptotic rates of Mat combined with the cisplatin groups under different concentration were significantly higher than those of the single Mat and single cisplatin groups under the same concentration (P<0.01). The expression levels of XIAP mRNA in the RD cells of each experimental group were lower than those in the control group (P<0.05). Additionally, the expression levels of XIAP mRNA in the group treated with Mat and cisplatin were significantly lower than those of the single cisplatin and single Mat groups (P<0.01). In conclusion, Mat and cisplatin are capable of inhibiting the proliferation of RD cells and inducing apoptosis by suppressing the XIAP mRNA expression levels.
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Affiliation(s)
- Li Li
- Department of Pediatrics, Xuzhou Central Hospital, Xuzhou, Jiangsu 221009, P.R. China; Department of Pediatrics, The Affiliated XuZhou Hospital of Medical College of Southeast University, Jiangsu 221009, P.R. China; Department of Pediatrics, Xuzhou Clinical Medical College of Nanjing University of Chinese Medicine, Jiangsu 221009, P.R. China; Department of Pediatrics, XuZhou Clinical School of Xuzhou Medical College, Xuzhou, Jiangsu 221000, P.R. China
| | - Tianyang Xue
- Pediatric Hospital of The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu 221000, P.R. China
| | - Wei Xu
- Pediatric Hospital of The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu 221000, P.R. China
| | - Bin Zhou
- Department of Pediatrics, Xuzhou Central Hospital, Xuzhou, Jiangsu 221009, P.R. China; Department of Pediatrics, The Affiliated XuZhou Hospital of Medical College of Southeast University, Jiangsu 221009, P.R. China; Department of Pediatrics, Xuzhou Clinical Medical College of Nanjing University of Chinese Medicine, Jiangsu 221009, P.R. China; Department of Pediatrics, XuZhou Clinical School of Xuzhou Medical College, Xuzhou, Jiangsu 221000, P.R. China
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Leiser D, Calaminus G, Malyapa R, Bojaxhiu B, Albertini F, Kliebsch U, Mikroutsikos L, Morach P, Bolsi A, Walser M, Timmermann B, Lomax T, Schneider R, Weber DC. Tumour control and Quality of Life in children with rhabdomyosarcoma treated with pencil beam scanning proton therapy. Radiother Oncol 2016; 120:163-8. [PMID: 27247053 DOI: 10.1016/j.radonc.2016.05.013] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 05/11/2016] [Accepted: 05/16/2016] [Indexed: 11/18/2022]
Abstract
PURPOSE To assess clinical outcomes in children with rhabdomyosarcoma (RMS) treated with pencil beam scanning (PBS) proton therapy (PT). METHODS AND MATERIALS Eighty-three RMS (embryonal, n=74; 89%) patients treated between January 2000 and December 2014 were included. The median age was 4.5years (range, 0.8-15.5). All patients received systemic chemotherapy according to prospective protocols. Patients had low-, intermediate-, and high-risk disease in 24%, 63%, and 13% of cases, respectively. The median total dose delivered was 54Gy(RBE) (range, 41.4-64.8). RESULTS After a median follow-up time of 55.5 months (range, 0.9-126.3), local failure occurred in 16 patients. The 5-year local-control survival rate was 78.5% [95% confidence interval (CI), 69.5-88.5%]. Significant predictors for local failure were group/stage, tumour location, and size. Fourteen patients (16%) died, all from tumour progression. The 5-year overall survival was 80.6% (95%CI, 71.8-90.0%). The 5-year incidence of grade 3 non-ocular late toxicity was 3.6% (95%CI, 1-12%). No grade 4-5 late toxicities were observed. One radiation-induced malignancy was observed (1.2%). The Quality of Life (QoL) scores increased significantly after PT compared to baseline values. CONCLUSIONS PBS PT led to excellent outcome in children with RMS. Late non-ocular toxicity was minimal and QoL good.
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Affiliation(s)
- Dominic Leiser
- Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Switzerland; Center for Proton Therapy, Paul Scherrer Institute, Switzerland
| | - Gabriele Calaminus
- Department of Pediatric Hematology and Oncology, University Hospital Münster, Germany
| | - Robert Malyapa
- Center for Proton Therapy, Paul Scherrer Institute, Switzerland
| | - Beat Bojaxhiu
- Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Switzerland; Center for Proton Therapy, Paul Scherrer Institute, Switzerland
| | | | - Ulrike Kliebsch
- Center for Proton Therapy, Paul Scherrer Institute, Switzerland
| | | | - Petra Morach
- Center for Proton Therapy, Paul Scherrer Institute, Switzerland
| | | | - Marc Walser
- Center for Proton Therapy, Paul Scherrer Institute, Switzerland
| | - Beate Timmermann
- Clinic for Particle Therapy, University Hospital Essen, West German Proton Therapy Center Essen (WPE), Germany
| | - Tony Lomax
- Department of Pediatric Hematology and Oncology, University Hospital Münster, Germany; ETH Zürich, Switzerland
| | - Ralf Schneider
- Center for Proton Therapy, Paul Scherrer Institute, Switzerland
| | - Damien C Weber
- Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Switzerland; Center for Proton Therapy, Paul Scherrer Institute, Switzerland; University of Bern, Switzerland; University of Zürich, Switzerland.
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Lacey A, Hedrick E, Li X, Patel K, Doddapaneni R, Singh M, Safe S. Nuclear receptor 4A1 (NR4A1) as a drug target for treating rhabdomyosarcoma (RMS). Oncotarget 2016; 7:31257-31269. [PMID: 27144436 PMCID: PMC5058754 DOI: 10.18632/oncotarget.9112] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 04/16/2016] [Indexed: 01/05/2023] Open
Abstract
The orphan nuclear receptor NR4A1 is expressed in tumors from rhabdomyosarcoma (RMS) patients and Rh30 and RD RMS cell lines, and we used RNA interference (RNAi) to investigate the role of this receptor in RMS cells. Knockdown of NR4A1 in Rh30 cells decreased cell proliferation, induced Annexin V staining and induced polyADPribose polymerase (PARP) cleavage and these results were similar to those observed in other solid tumors. Previous studies show that NR4A1 regulates expression of growth promoting/pro-survival genes with GC-rich promoters, activates mTOR through suppression of p53, and maintains low oxidative stress by regulating expression of isocitrate dehydrogenase 1 (IDH1) and thioredoxin domain containing 5 (TXNDC5). Results of RNAi studies demonstrated that NR4A1 also regulates these pathways and associated genes in RMS cells and thereby exhibits pro-oncogenic activity. 1,1-Bis(3-indolyl)-1-(p-substituted phenyl)methane (C-DIM) analogs containing p-hydroxyl (DIM-C-pPhOH) and p-carboxymethyl (DIM-C-pPhCO2Me) substituents are NR4A1 ligands that decreased NR4A1-dependent transactivation in RMS cells and inhibited RMS cell and tumor growth and induced apoptosis. Moreover, the effects of NR4A1 knockdown and the C-DIM/NR4A1 antagonists were comparable as inhibitors of NR4A1-dependent genes/pathways. Both NR4A1 knockdown and treatment with DIM-C-pPhOH and DIM-C-pPhCO2Me also induced ROS which activated stress genes and induced sestrin 2 which activated AMPK and inhibited mTOR in the mutant p53 RMS cells. Since NR4A1 regulates several growth-promoting/pro-survival pathways in RMS, the C-DIM/NR4A1 antagonists represent a novel mechanism-based approach for treating this disease alone or in combination and thereby reducing the adverse effects of current cytotoxic therapies.
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Affiliation(s)
- Alexandra Lacey
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, 77843, TX, USA
| | - Erik Hedrick
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, 77843, TX, USA
| | - Xi Li
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, 77843, TX, USA
| | - Ketan Patel
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, 32307, FL, USA
| | - Ravi Doddapaneni
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, 32307, FL, USA
| | - Mandip Singh
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, 32307, FL, USA
| | - Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, 77843, TX, USA
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30
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Chen X, Sun XZ, Xie WL, Dai QS, Hu S, Deng CH. A giant adult paratesticular rhabdomyosarcomar. Asian J Androl 2016; 19:382-383. [PMID: 27004538 PMCID: PMC5427798 DOI: 10.4103/1008-682x.174851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Affiliation(s)
- Xu Chen
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Xiang-Zhou Sun
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Wen-Lin Xie
- Department of Pathology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Qiang-Sheng Dai
- Department of Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Shan Hu
- Department of Radiology, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangzhou 510000, China
| | - Chun-Hua Deng
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
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31
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Schoot RA, Theunissen EAR, Slater O, Lopez-Yurda M, Zuur CL, Gaze MN, Chang YC, Mandeville HC, Gains JE, Rajput K, Pieters BR, Davila Fajardo R, Talwar R, Caron HN, Balm AJM, Dreschler WA, Merks JHM. Hearing loss in survivors of childhood head and neck rhabdomyosarcoma: a long-term follow-up study. Clin Otolaryngol 2016; 41:276-83. [PMID: 26293165 DOI: 10.1111/coa.12527] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/10/2015] [Indexed: 11/26/2022]
Abstract
OBJECTIVES To determine the hearing status of survivors treated for head and neck rhabdomyosarcoma (HNRMS) at long-term follow-up. DESIGN Cross-sectional long-term follow-up study. SETTING Tertiary comprehensive cancer centre. PARTICIPANTS Survivors treated for HNRMS during childhood in two concurrent cohorts; survivors in London had been treated with external beam radiotherapy (EBRT-based local therapy); survivors in Amsterdam were treated with AMORE (Ablative surgery, MOuld technique afterloading brachytherapy and surgical REconstruction) if feasible, otherwise EBRT (AMORE-based local therapy). MAIN OUTCOME MEASURES We assessed hearing status of HNRMS survivors at long-term follow-up. Hearing thresholds were obtained by pure-tone audiometry. METHODS We assessed the hearing thresholds, the number of patients with clinically relevant hearing loss and hearing impairment graded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAEv4) and Boston criteria. Furthermore, we compared hearing loss between survivors treated with EBRT-based local therapy (London) and AMORE-based local therapy (Amsterdam). RESULTS Seventy-three survivors were included (median follow-up 11 years). We found clinically relevant hearing loss at speech frequencies in 19% of survivors. Multivariable analysis showed that survivors treated with EBRT-based treatment and those with parameningeal tumours had significantly more hearing impairment, compared to survivors treated with AMORE-based treatment and non-parameningeal tumours. CONCLUSIONS One in five survivors of HNRMS developed clinically relevant hearing loss. AMORE-based treatment resulted in less hearing loss compared to EBRT-based treatment. As hearing loss was highly prevalent and also occurred in survivors with orbital primaries, we recommend systematic audiological follow-up in all HNRMS survivors.
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Affiliation(s)
- R A Schoot
- Department of Paediatric Oncology, Emma Children's Hospital, Academic Medical Centre, Amsterdam, the Netherlands
| | - E A R Theunissen
- Department of Head and Neck Oncology and Surgery, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - O Slater
- Department of Paediatric Oncology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - M Lopez-Yurda
- Department of Epidemiology and Biostatistics, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - C L Zuur
- Department of Head and Neck Oncology and Surgery, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - M N Gaze
- Department of Paediatric Oncology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.,Department of Oncology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Y-C Chang
- Department of Paediatric Oncology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.,Department of Oncology, University College London Hospitals NHS Foundation Trust, London, UK
| | - H C Mandeville
- Department of Radiotherapy, The Royal Marsden NHS Foundation Trust, Sutton, UK
| | - J E Gains
- Department of Paediatric Oncology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.,Department of Oncology, University College London Hospitals NHS Foundation Trust, London, UK
| | - K Rajput
- Department of Audiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - B R Pieters
- Department of Radiation Oncology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - R Davila Fajardo
- Department of Radiation Oncology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - R Talwar
- Department of Otorhinolaryngology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - H N Caron
- Department of Paediatric Oncology, Emma Children's Hospital, Academic Medical Centre, Amsterdam, the Netherlands
| | - A J M Balm
- Department of Head and Neck Oncology and Surgery, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - W A Dreschler
- Department of Audiology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - J H M Merks
- Department of Paediatric Oncology, Emma Children's Hospital, Academic Medical Centre, Amsterdam, the Netherlands
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32
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Clement S, Schoot R, Slater O, Chisholm J, Abela C, Balm A, van den Brekel M, Breunis W, Chang Y, Davila Fajardo R, Dunaway D, Gajdosova E, Gaze M, Gupta S, Hartley B, Kremer L, van Lennep M, Levitt G, Mandeville H, Pieters B, Saeed P, Smeele L, Strackee S, Ronckers C, Caron H, van Santen H, Merks J. Endocrine disorders among long-term survivors of childhood head and neck rhabdomyosarcoma. Eur J Cancer 2016; 54:1-10. [DOI: 10.1016/j.ejca.2015.10.064] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Revised: 10/23/2015] [Accepted: 10/27/2015] [Indexed: 11/28/2022]
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Lychou SE, Gustafsson GG, Ljungman GE. Higher rates of metastatic disease may explain the declining trend in Swedish paediatric rhabdomyosarcoma survival rates. Acta Paediatr 2016; 105:74-81. [PMID: 26331464 PMCID: PMC4738396 DOI: 10.1111/apa.13172] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2015] [Revised: 05/06/2015] [Accepted: 08/28/2015] [Indexed: 11/27/2022]
Abstract
AIM Positive outcomes for paediatric rhabdomyosarcoma (RMS) were high in Sweden during the 1990s, but the last decade has seen decreasing trends in overall survival rates. We investigated the incidence, patient and disease characteristics, treatment and outcome of RMS to see whether any reason could be found for this decline. METHODS This study included 210 children under the age of 15 who were diagnosed with RMS and whose details were recorded in the population-based Swedish Childhood Cancer Registry from 1984 to 2010. RESULTS The overall annual incidence of RMS was 4.9 per million, and the 5-year overall survival rates were 59 ± 7% in 1984-1989, 78 ± 5% in 1990-1999 and 71 ± 5% in 2000-2010. When patients with localised disease were analysed separately, there was no difference in the 5-year survival rates between 1990 and 1999 (82 ± 5%) and 2000-2010 (81 ± 5%), but the outcome in 1984-1989 (53 ± 8%) was significantly worse. The prevalence of metastatic disease was unexpectedly high during 2000-2010 (28%, p = 0.010), compared to an overall mean of 18% for the whole study period. CONCLUSION Our results suggest that a higher rate of metastatic disease may explain the declining trend in overall survival rates in paediatric RMS in Sweden over the last decade.
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Affiliation(s)
- Sara E. Lychou
- Department of Women's and Children's Health Uppsala University Uppsala Sweden
| | | | - Gustaf E. Ljungman
- Department of Women's and Children's Health Uppsala University Uppsala Sweden
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34
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Sangkhathat S. Current management of pediatric soft tissue sarcomas. World J Clin Pediatr 2015; 4:94-105. [PMID: 26566481 PMCID: PMC4637813 DOI: 10.5409/wjcp.v4.i4.94] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 07/21/2015] [Accepted: 09/29/2015] [Indexed: 02/06/2023] Open
Abstract
Pediatric soft tissue sarcomas are a group of malignant neoplasms arising within embryonic mesenchymal tissues during the process of differentiation into muscle, fascia and fat. The tumors have a biphasic peak for age of incidence. Rhabdomyosarcoma (RMS) is diagnosed more frequently in younger children, whereas adult-type non-RMS soft tissue sarcoma is predominately observed in adolescents. The latter group comprises a variety of rare tumors for which diagnosis can be difficult and typically requires special studies, including immunohistochemistry and molecular genetic analysis. Current management for the majority of pediatric sarcomas is based on the data from large multi-institutional trials, which has led to great improvements in outcomes over recent decades. Although surgery remains the mainstay of treatment, the curative aim cannot be achieved without adjuvant treatment. Pre-treatment staging and risk classification are of prime importance in selecting an effective treatment protocol. Tumor resectability, the response to induction chemotherapy, and radiation generally determine the risk-group, and these factors are functions of tumor site, size and biology. Surgery provides the best choice of local control of small resectable tumors in a favorable site. Radiation therapy is added when surgery leaves residual disease or there is evidence of regional spread. Chemotherapy aims to reduce the risk of relapse and improve overall survival. In addition, upfront chemotherapy reduces the aggressiveness of the required surgery and helps preserve organ function in a number of cases. Long-term survival in low-risk sarcomas is feasible, and the intensity of treatment can be reduced. In high-risk sarcoma, current research is allowing more effective disease control.
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35
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Hedrick E, Crose L, Linardic CM, Safe S. Histone Deacetylase Inhibitors Inhibit Rhabdomyosarcoma by Reactive Oxygen Species-Dependent Targeting of Specificity Protein Transcription Factors. Mol Cancer Ther 2015; 14:2143-2153. [PMID: 26162688 PMCID: PMC4618474 DOI: 10.1158/1535-7163.mct-15-0148] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Accepted: 06/25/2015] [Indexed: 11/16/2022]
Abstract
The two major types of rhabdomyosarcoma (RMS) are predominantly diagnosed in children, namely embryonal (ERMS) and alveolar (ARMS) RMS, and patients are treated with cytotoxic drugs, which results in multiple toxic side effects later in life. Therefore, development of innovative chemotherapeutic strategies is imperative, and a recent genomic analysis suggested the potential efficacy of reactive oxygen species (ROS)-inducing agents. Here, we demonstrate the efficacy of the potent histone deacetylase (HDAC) inhibitors, panobinostat and vorinostat, as agents that inhibit RMS tumor growth in vivo, induce apoptosis, and inhibit invasion of RD and Rh30 RMS cell lines. These effects are due to epigenetic repression of cMyc, which leads to decreased expression of cMyc-regulated miRs-17, -20a, and -27a; upregulation of ZBTB4, ZBTB10, and ZBTB34; and subsequent downregulation of Sp transcription factors. We also show that inhibition of RMS cell growth, survival and invasion, and repression of Sp transcription factors by the HDAC inhibitors are independent of histone acetylation but reversible after cotreatment with the antioxidant glutathione. These results show a novel ROS-dependent mechanism of antineoplastic activity for panobinostat and vorinostat that lies outside of their canonical HDAC-inhibitory activity and demonstrates the potential clinical utility for treating RMS patients with ROS-inducing agents.
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Affiliation(s)
- Erik Hedrick
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas
| | - Lisa Crose
- Department of Pediatrics, Duke University Medical Center, Durham, North Carolina
| | - Corinne M Linardic
- Department of Pediatrics, Duke University Medical Center, Durham, North Carolina. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina
| | - Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas. Institute of Biosciences and Technology, Texas A&M Health Sciences Center, Houston, Texas.
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36
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Farnia B, Majumder MA, Paulino AC. Ethical analysis as a tool for addressing treatment controversies: radiotherapy timing in children with orbital rhabdomyosarcoma as a case example. J Am Coll Radiol 2014; 12:484-90. [PMID: 25544244 DOI: 10.1016/j.jacr.2014.10.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 10/16/2014] [Accepted: 10/20/2014] [Indexed: 11/26/2022]
Abstract
PURPOSE The treatment of orbital rhabdomyosarcoma is a topic of debate between North American and European clinicians, with the utility of radiation therapy as part of initial management in question. Despite differences in philosophy, the dominant North American approach of upfront radiation and the dominant European approach of radiation only in the event of recurrence yield a similar rate of overall survival. We sought to identify the ethical arguments for each approach. METHODS Established moral principles and appeals in contemporary medical ethics were utilized to identify the ethical arguments supporting each treatment approach. The potential for technologic advances to alter the analysis was considered. RESULTS Emphasizing the principle of beneficence, the North American approach seeks to reduce recurrence rates. In contrast, the European approach seeks to avoid radiation-induced sequelae, emphasizing the principle of nonmaleficence. Both approaches are based on well-established ethical principles, evidence, and clinical experience. Thus, both approaches currently appear to have legitimacy and should be included in the informed consent process. However, if treatment-related toxicity is reduced through improvements in radiation delivery, the North American approach could emerge as ethically superior. CONCLUSIONS Ethical analysis can aid in addressing challenges that arise when professional practices and perspectives differ in the management of cancer patients.
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Affiliation(s)
- Benjamin Farnia
- Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mary A Majumder
- Center for Medical Ethics and Health Policy, Baylor College of Medicine, Houston, Texas
| | - Arnold C Paulino
- Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
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Egas-Bejar D, Huh WW. Rhabdomyosarcoma in adolescent and young adult patients: current perspectives. ADOLESCENT HEALTH MEDICINE AND THERAPEUTICS 2014; 5:115-25. [PMID: 24966711 PMCID: PMC4069040 DOI: 10.2147/ahmt.s44582] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Rhabdomyosarcoma (RMS), a malignant tumor of mesenchymal origin, is the third most common extracranial malignant solid tumor in children and adolescents. However, in adults, RMS represents <1% of all solid tumor malignancies. The embryonal and alveolar histologic variants are more commonly seen in pediatric patients, while the pleomorphic variant is rare in children and seen more often in adults. Advances in the research of the embryonal and alveolar variants have improved our understanding of certain genes and biologic pathways that are involved in RMS, but much less is known for the other variants. Multimodality therapy that includes surgery and chemotherapy with or without radiation therapy is the mainstay of treatment for RMS. Improvements in the risk stratification of the pediatric patients based on presurgical (primary tumor site, tumor size, regional lymph node involvement, presence of metastasis) and postsurgical parameters (completeness of resection or presence of residual disease or metastasis) has allowed for the treatment assignment of patients in different studies and therapeutic trials, leading to increases in 5-year survival from 25%–70% over the past 40 years. However, for adult patients, in great part due to rarity of the disease and the lack of consensus on optimal treatment, clinical outcome is still poor. Many factors have been implicated for the differing outcomes between pediatric RMS versus adult RMS, such as the lack of standardized treatment protocols for adult RMS patients and the increased prevalence of advanced presentations. Now that there are increased numbers of survivors, we can appreciate the sequelae from therapy in these patients, such as bone growth abnormalities, endocrinopathies, and infertility. Improvements in risk stratification have led to clinical trials using lower doses of chemotherapy or radiation therapy with the intention of decreasing the incidence of side effects without compromising survival outcome.
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Affiliation(s)
- Daniela Egas-Bejar
- Division of Pediatrics, The Children's Cancer Hospital, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Winston W Huh
- Division of Pediatrics, The Children's Cancer Hospital, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Wolf S, Hagl B, Kappler R. Identification of BMP2 as an epigenetically silenced growth inhibitor in rhabdomyosarcoma. Int J Oncol 2014; 44:1727-35. [PMID: 24585058 DOI: 10.3892/ijo.2014.2312] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Accepted: 02/06/2014] [Indexed: 11/06/2022] Open
Abstract
Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of infancy and although therapy has improved over the years, mortality is still fairly high. The establishment of new treatments has been hampered by the limited knowledge of the molecular mechanisms driving development of RMS. One characteristic of cancer cells is aberrant DNA methylation, which could lead to silencing of tumor suppressor genes. However, only a few epigenetically silenced genes have been described in RMS so far. We performed an expression profiling analysis of three RMS cell lines that were treated with the demethylating agent 5'-aza-2'-deoxycytidine (5-Aza‑dC) facilitating re-expression of epigenetically silenced genes. This treatment induced the gene BMP2 (bone morphogenetic protein 2) throughout all cell lines. Detailed methylation analysis of CpG sites in the BMP2 promoter region by bisulfite sequencing and methylation-specific PCR revealed that a high degree of DNA methylation is causatively associated with the suppression of BMP2 in RMS cells. Consequently, treatment of the RMS cell lines with 5-Aza-dC resulted in DNA demethylation of the BMP2 promoter, most prominently in alveolar RMS. Supplementation of recombinant human BMP2 (rhBMP2) led to a reduced viability of RMS cells. Altogether, these findings suggest that suppression of BMP2 by epigenetic silencing may play a critical role in the genesis of RMS, thereby providing a rationale for the development of a new treatment strategy for RMS.
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Affiliation(s)
- Sebastian Wolf
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, D-80337 Munich, Germany
| | - Beate Hagl
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, D-80337 Munich, Germany
| | - Roland Kappler
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, D-80337 Munich, Germany
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Glycogen synthase kinase 3β represses MYOGENIN function in alveolar rhabdomyosarcoma. Cell Death Dis 2014; 5:e1094. [PMID: 24577092 PMCID: PMC3944270 DOI: 10.1038/cddis.2014.58] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Revised: 01/20/2014] [Accepted: 01/21/2014] [Indexed: 11/17/2022]
Abstract
MYOGENIN is a member of the muscle regulatory factor family that orchestrates an obligatory step in myogenesis, the terminal differentiation of skeletal muscle cells. A paradoxical feature of alveolar rhabdomyosarcoma (ARMS), a prevalent soft tissue sarcoma in children arising from cells with a myogenic phenotype, is the inability of these cells to undergo terminal differentiation despite the expression of MYOGENIN. The chimeric PAX3-FOXO1 fusion protein which results from a chromosomal translocation in ARMS has been implicated in blocking cell cycle arrest, preventing myogenesis from occurring. We report here that PAX3-FOXO1 enhances glycogen synthase kinase 3β (GSK3β) activity which in turn represses MYOGENIN activity. MYOGENIN is a GSK3β substrate in vitro on the basis of in vitro kinase assays and MYOGENIN is phosphorylated in ARMS-derived RH30 cells. Constitutively active GSK3β(S9A) increased the level of a phosphorylated form of MYOGENIN on the basis of western blot analysis and this effect was reversed by neutralization of the single consensus GSK3β phosphoacceptor site by mutation (S160/164A). Congruently, GSK3β inhibited the trans-activation of an E-box reporter gene by wild-type MYOGENIN, but not MYOGENIN with the S160/164A mutations. Functionally, GSK3β repressed muscle creatine kinase (MCK) promoter activity, an effect which was reversed by the S160/164A mutated MYOGENIN. Importantly, GSK3β inhibition or exogenous expression of the S160/164A mutated MYOGENIN in ARMS reduced the anchorage independent growth of RH30 cells in colony-formation assays. Thus, sustained GSK3β activity represses a critical regulatory step in the myogenic cascade, contributing to the undifferentiated, proliferative phenotype in alveolar rhabdomyosarcoma (ARMS).
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Stein R, Frees S, Schröder A, Russo A, Gutjahr P, Faber J, Thüroff JW. Radical surgery and different types of urinary diversion in patients with rhabdomyosarcoma of bladder or prostate--a single institution experience. J Pediatr Urol 2013; 9:932-9. [PMID: 23385048 DOI: 10.1016/j.jpurol.2013.01.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2012] [Accepted: 01/03/2013] [Indexed: 12/11/2022]
Abstract
PURPOSE In a retrospective study we analyzed the outcome of patients treated for rhabdomyosarcoma (RMS) of the bladder/prostate with special attention to radical surgery. METHODS In 25 patients with genitourinary RMS (15 bladder/10 prostate) the median age at diagnosis was 4 years [1-18], and 8 patients had a stage II RMS, 12 stage III and 5 stage IV. In 19/25 (12 bladder/7 prostate), radical surgery and urinary diversion were performed. Urinary diversion comprised 2 continent anal diversions, 11 continent cutaneous diversions, 4 colon conduits and 2 urethral diversions (2 + 3 years of age). In the younger child with urethral diversion, a cutaneous appendix stoma was additionally constructed in case of inability to void spontaneously. RESULTS 4/19 patients who underwent radical surgery died of metastatic RMS; 1 patient with neurofibromatosis died of a secondary tumor. After median follow-up of 132 months (14-420), 14 patients currently have no evidence of disease. 8/14 patients who survived developed 17 complications requiring operative revision. All patients with a continent diversion are continent. The patients with orthotopic bladder substitution are continent day & night and void spontaneously. CONCLUSION For RMS confined to the bladder or bladder neck, radical cystoprostatectomy and orthotopic bladder substitution are an option. Urethral diversion using the ileocecal segment (Mainz-pouch I) offers the advantage of utilizing the appendix as an additional continent cutaneous stoma, which enables parents to evacuate residual urine in young boys, until able to empty the pouch completely themselves. For all other patients with vital tumor after primary chemotherapy, cutaneous urinary diversion is an option. Long-term complication rates in this complex group of patients are acceptable.
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Affiliation(s)
- Raimund Stein
- Division of Pediatric Urology, Department of Urology, University of Mainz, Medical School, Mainz, Germany.
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41
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Zhao B, Yang C, Yang S, Gao Y, Wang J. Construction of conditional lentivirus-mediated shRNA vector targeting the human Mirk gene and identification of RNAi efficiency in rhabdomyosarcoma RD cells. Int J Oncol 2013; 43:1253-9. [PMID: 23913162 DOI: 10.3892/ijo.2013.2048] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Accepted: 07/23/2013] [Indexed: 11/05/2022] Open
Abstract
Rhabdomyosarcoma is the most common malignant soft tissue tumor in children. It has been demonstrated that Mirk as an activated protein kinase is overexpressed in rhabdomyosarcoma cells, which may be correlated with tumorigenesis. The aim of the present study was to explore the possibility of Mirk gene as a therapeutic target for the treatment of rhabdomyosarcoma, and the use of RNA interference in a temporally and spatially restricted manner to study the function of the target gene would be highly beneficial. To address this problem, a conditional lentivirus-mediated short hairpin RNA targeting human Mirk gene was constructed and employed to reduce endogenous Mirk expression in the rhabdomyosarcoma RD cell line in vitro. The expression of Mirk shRNA in RD cells transduced with this recombinant vector could be tracked with the expression of red fluorescent protein by the administration of doxycycline. A stable transgenic RD line was generated by transducing RD lines with the packaging viral particles. Quantitative PCR and western blot analysis indicated that the mRNA and protein levels of Mirk in the transgenic RD cells were significantly lower compared to those in the controls. In addition, the increasing apoptosis of RD cells induced by silencing of the Mirk gene was also observed. Overall, the results demonstrated that this recombinant vector-based RNAi expression system is an efficient approach to knockdown Mirk gene expression in the rhabdomyosarcoma RD cell line, which could, thereby, provide both a protocol to study the role of Mirk gene in tumor cells and a safer gene therapy in the clinic.
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Affiliation(s)
- Boming Zhao
- Department of Orthopaedic Surgery, The No. 1 People's Hospital of Jingzhou, Jingzhou, P.R. China
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42
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Chadalapaka G, Jutooru I, Sreevalsan S, Pathi S, Kim K, Chen C, Crose L, Linardic C, Safe S. Inhibition of rhabdomyosarcoma cell and tumor growth by targeting specificity protein (Sp) transcription factors. Int J Cancer 2013; 132:795-806. [PMID: 22815231 PMCID: PMC3527649 DOI: 10.1002/ijc.27730] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2011] [Accepted: 06/08/2012] [Indexed: 12/30/2022]
Abstract
Specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 are highly expressed in rhabdomyosarcoma (RMS) cells. In tissue arrays of RMS tumor cores from 71 patients, 80% of RMS patients expressed high levels of Sp1 protein, whereas low expression of Sp1 was detected in normal muscle tissue. The non-steroidal anti-inflammatory drug (NSAID) tolfenamic acid (TA) inhibited growth and migration of RD and RH30 RMS cell lines and also inhibited tumor growth in vivo using a mouse xenograft (RH30 cells) model. The effects of TA were accompanied by downregulation of Sp1, Sp3, Sp4 and Sp-regulated genes in RMS cells and tumors, and the role of Sp protein downregulation in mediating inhibition of RD and RH30 cell growth and migration was confirmed by individual and combined knockdown of Sp1, Sp3 and Sp4 proteins by RNA interference. TA treatment and Sp knockdown in RD and RH30 cells also showed that four genes that are emerging as individual drug targets for treating RMS, namely c-MET, insulin-like growth factor receptor (IGFR), PDGFRα and CXCR4, are also Sp-regulated genes. These results suggest that NSAIDs such as TA may have potential clinical efficacy in drug combinations for treating RMS patients.
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Affiliation(s)
- Gayathri Chadalapaka
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX
| | - Indira Jutooru
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX
| | - Sandeep Sreevalsan
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX
| | - Satya Pathi
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX
| | - Kyounghyun Kim
- Institute for Biosciences and Technology, Texas A&M Health Science Center, Houston, TX
| | - Candy Chen
- Department of Pediatrics, Duke University Medical Center, Durham, NC
| | - Lisa Crose
- Department of Pediatrics, Duke University Medical Center, Durham, NC
| | - Corinne Linardic
- Department of Pediatrics, Duke University Medical Center, Durham, NC
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC
| | - Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX
- Institute for Biosciences and Technology, Texas A&M Health Science Center, Houston, TX
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43
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¹⁸F-FDG-PET/CT in initial staging and assessment of early response to chemotherapy of pediatric rhabdomyosarcomas. Nucl Med Commun 2013; 33:1089-95. [PMID: 22929116 DOI: 10.1097/mnm.0b013e328356741f] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE The objective of this retrospective study was to compare positron emission tomography/computed tomography using fluorine-18-fluorodeoxyglucose (18F-FDG-PET/CT) and conventional imaging modalities (CIM) in initial staging and early assessment of response to chemotherapy in children and young adults treated for rhabdomyosarcoma (RMS). PATIENTS AND METHODS At initial staging, 23 patients (9 months to 21 years) with histologically proven RMS underwent 18F-FDG-PET/CT in addition to CIM (MRI of the primary site, whole-body CT, and bone scintigraphy). After three courses of chemotherapy, 13 patients underwent 18F-FDG-PET/CT in addition to CIM. RECIST criteria and visual analysis of 18F-FDG uptake were used for assessment of response. The standard of reference was determined by an interdisciplinary tumor board on the basis of imaging material, histopathology, and follow-up data (median = 5 years). RESULTS 18F-FDG-PET/CT sensitivity was superior to that of CIM for determination of lymph node involvement (100 vs. 75%) and detection of metastases (100 vs. 66%). 18F-FDG-PET/CT results changed therapeutic management in 13% of cases. After three courses of chemotherapy 18F-FDG-PET/CT was able to detect 92% of objective responses compared with 84% by CIM. The rate of complete response was 69% with 18F-FDG-PET/CT compared with 8% with CIM. CONCLUSION This study confirms that 18F-FDG-PET/CT reveals important additional information at initial staging of pediatric RMS, which suggests a superior prognostic value of 18F-FDG-PET/CT in early response to chemotherapy assessment.
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Price RL, Bingmer K, Harkins L, Iwenofu OH, Kwon CH, Cook C, Pelloski C, Chiocca EA. Cytomegalovirus infection leads to pleomorphic rhabdomyosarcomas in Trp53+/- mice. Cancer Res 2012; 72:5669-74. [PMID: 23002204 DOI: 10.1158/0008-5472.can-12-2425] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cytomegalovirus (CMV) has been detected in several human cancers, but it has not proven to be oncogenic. However, recent studies have suggested mechanisms through which cytomegalovirus may modulate the tumor environment, encouraging its study as a positive modifier of tumorigenesis. In this study, we investigated the effects of cytomegalovirus infection in Trp53 heterozygous mice. Animals were infected with murine cytomegalovirus (MCMV) after birth at 2 days (P2) or 4 weeks of age and then monitored for tumor formation. Mice injected at 2 days of age developed tumors at a high frequency (43%) by 9 months of age. In contrast, only 3% of mock-infected or mice infected at 4 weeks developed tumors. The majority of tumors from P2 MCMV-infected mice were pleomorphic rhabdomyosarcomas (RMS) harboring MCMV DNA, RNA, and protein. An examination of clinical cases revealed that human RMS (embryonal, alveolar, and pleomorphic) harbored human cytomegalovirus IE1 and pp65 protein as well as viral RNA. Taken together, our findings offer support for the hypothesis that cytomegalovirus contributes to the development of pleomorphic RMS in the context of Trp53 mutation, a situation that occurs with high frequency in human RMS.
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Affiliation(s)
- Richard L Price
- Department of Neurological Surgery, Dardinger Neuro-oncology Center, Solid Tumor Program at the James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, Ohio, USA
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45
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Eapen SA, Netherton SJ, Sarker KP, Deng L, Chan A, Riabowol K, Bonni S. Identification of a novel function for the chromatin remodeling protein ING2 in muscle differentiation. PLoS One 2012; 7:e40684. [PMID: 22808232 PMCID: PMC3395697 DOI: 10.1371/journal.pone.0040684] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2012] [Accepted: 06/13/2012] [Indexed: 11/18/2022] Open
Abstract
The inhibitor of growth (ING) family of zinc-finger plant homeodomain (PHD)-containing chromatin remodeling protein controls gene expression and has been implicated in the regulation of cell proliferation and death. However, the role of ING proteins in cell differentiation remains largely unexplored. Here, we identify an essential function for ING2 in muscle differentiation. We find that knockdown of ING2 by RNA interference (RNAi) blocks the differentiation of C2C12 cells into myotubes, suggesting that ING2 regulates the myogenic differentiation program. We also characterize a mechanism by which ING2 drives muscle differentiation. In structure-function analyses, we find that the leucine zipper motif of ING2 contributes to ING2-dependent muscle differentiation. By contrast, the PHD domain, which recognizes the histone H3K4me3 epigenetic mark, inhibits the ability of ING2 to induce muscle differentiation. We also find that the Sin3A-HDAC1 chromatin remodeling complex, which interacts with ING2, plays a critical role in ING2-dependent muscle differentiation. These findings define a novel function for ING2 in muscle differentiation and bear significant implications for our understanding of the role of the ING protein family in cell differentiation and tumor suppression.
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Affiliation(s)
- Shawn A. Eapen
- Southern Alberta Cancer Research Institute, Departments of Biochemistry and Molecular Biology and Oncology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Stuart J. Netherton
- Southern Alberta Cancer Research Institute, Departments of Biochemistry and Molecular Biology and Oncology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Krishna P. Sarker
- Southern Alberta Cancer Research Institute, Departments of Biochemistry and Molecular Biology and Oncology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Lili Deng
- Southern Alberta Cancer Research Institute, Departments of Biochemistry and Molecular Biology and Oncology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Angela Chan
- Southern Alberta Cancer Research Institute, Departments of Biochemistry and Molecular Biology and Oncology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Karl Riabowol
- Southern Alberta Cancer Research Institute, Departments of Biochemistry and Molecular Biology and Oncology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Shirin Bonni
- Southern Alberta Cancer Research Institute, Departments of Biochemistry and Molecular Biology and Oncology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
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Kang Z, Sun SY, Cao L. Activating Death Receptor DR5 as a Therapeutic Strategy for Rhabdomyosarcoma. ISRN ONCOLOGY 2012; 2012:395952. [PMID: 22577581 PMCID: PMC3345273 DOI: 10.5402/2012/395952] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2012] [Accepted: 01/24/2012] [Indexed: 11/23/2022]
Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. It is believed to arise from skeletal muscle progenitors, preserving the expression of genes critical for embryonic myogenic development such as MYOD1 and myogenin. RMS is classified as embryonal, which is more common in younger children, or alveolar, which is more prevalent in elder children and adults. Despite aggressive management including surgery, radiation, and chemotherapy, the outcome for children with metastatic RMS is dismal, and the prognosis has remained unchanged for decades. Apoptosis is a highly regulated process critical for embryonic development and tissue and organ homeostasis. Like other types of cancers, RMS develops by evading intrinsic apoptosis via mutations in the p53 tumor suppressor gene. However, the ability to induce apoptosis via the death receptor-dependent extrinsic pathway remains largely intact in tumors with p53 mutations. This paper focuses on activating extrinsic apoptosis as a therapeutic strategy for RMS by targeting the death receptor DR5 with a recombinant TRAIL ligand or agonistic antibodies directed against DR5.
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Affiliation(s)
- Zhigang Kang
- Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
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Mahoney SE, Yao Z, Keyes CC, Tapscott SJ, Diede SJ. Genome-wide DNA methylation studies suggest distinct DNA methylation patterns in pediatric embryonal and alveolar rhabdomyosarcomas. Epigenetics 2012; 7:400-8. [PMID: 22419069 DOI: 10.4161/epi.19463] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Rhabdomyosarcoma is the most common soft-tissue sarcoma in children. While cytogenetic abnormalities have been well characterized in this disease, aberrant epigenetic events such as DNA hypermethylation have not been described in genome-wide studies. We have analyzed the methylation status of 25,500 promoters in normal skeletal muscle, and in cell lines and tumor samples of embryonal and alveolar rhabdomyosarcoma from pediatric patients. We identified over 1,900 CpG islands that are hypermethylated in rhabdomyosarcomas relative to skeletal muscle. Genes involved in tissue development, differentiation, and oncogenesis such as DNAJA4, HES5, IRX1, BMP8A, GATA4, GATA6, ALX3, and P4HTM were hypermethylated in both RMS cell lines and primary samples, implicating aberrant DNA methylation in the pathogenesis of rhabdomyosarcoma. Furthermore, cluster analysis revealed embryonal and alveolar subtypes had distinct DNA methylation patterns, with the alveolar subtype being enriched in DNA hypermethylation of polycomb target genes. These results suggest that DNA methylation signatures may aid in the diagnosis and risk stratification of pediatric rhabdomyosarcoma and help identify new targets for therapy.
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Affiliation(s)
- Sarah E Mahoney
- Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
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48
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A set of imprinted genes required for normal body growth also promotes growth of rhabdomyosarcoma cells. Pediatr Res 2012; 71:32-8. [PMID: 22289848 PMCID: PMC3420822 DOI: 10.1038/pr.2011.6] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
INTRODUCTION In many normal tissues, proliferation rates decline postnatally, causing somatic growth to slow. Previous evidence suggests that this decline is due, in part, to decline in the expression of growth-promoting imprinted genes including Mest, Plagl1, Peg3, Dlk1, and Igf2. Embryonal cancers are composed of cells that maintain embryonic characteristics and proliferate rapidly in childhood. We hypothesized that the abnormal persistent rapid proliferation in embryonal cancers occurs in part because of abnormal persistent high expression of growth-promoting imprinted genes. RESULTS Analysis of microarray data showed elevated expression of MEST, PLAGL1, PEG3, DLK1, and IGF2 in various embryonal cancers, especially rhabdomyosarcoma, as compared to nonembryonal cancers and normal tissues. Similarly, mRNA expression, assessed by real-time PCR, of MEST, PEG3, and IGF2 in rhabdomyosarcoma cell lines was increased as compared to nonembryonal cancer cell lines. Furthermore, siRNA-mediated knockdown of MEST, PLAGL1, PEG3, and IGF2 expression inhibited proliferation in Rh30 rhabdomyosarcoma cells. DISCUSSION These findings suggest that the normal postnatal downregulation of growth-promoting imprinted genes fails to occur in some embryonal cancers, particularly rhabdomyosarcoma, and contributes to the persistent rapid proliferation of rhabdomyosarcoma cells and, more generally, that failure of the mechanisms responsible for normal somatic growth deceleration can promote tumorigenesis.
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Lee MH, Jothi M, Gudkov AV, Mal AK. Histone methyltransferase KMT1A restrains entry of alveolar rhabdomyosarcoma cells into a myogenic differentiated state. Cancer Res 2011; 71:3921-31. [PMID: 21493592 PMCID: PMC3107367 DOI: 10.1158/0008-5472.can-10-3358] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Alveolar rhabdomyosarcoma (ARMS) is an aggressive pediatric muscle cancer, which arrested during the process of skeletal muscle differentiation. In muscle myoblast cells, ectopic expression of the histone H3 lysine 9 (H3K9) methytransferase KMT1A blocks differentiation by repressing a myogenic gene expression program. In this study, we tested the hypothesis that activation of a KMT1A-mediated program of transcriptional repression prevents ARMS cells from differentiating. We investigated whether KMT1A represses the expression of differentiation-associated genes in ARMS cells, thereby blocking muscle differentiation. Our results show that expression of KMT1A is induced in human ARMS cancer cell lines when cultured under differentiation-permissible conditions. shRNA-mediated knockdown of KMT1A decreased anchorage dependent and independent cell proliferation and tumor xenograft growth, increased expression of differentiation-associated genes, and promoted the appearance of a terminally differentiated-like phenotype. Finally, shRNA-directed KMT1A knockdown restored the impaired transcriptional activity of the myogenic regulator MyoD. Together, our results suggested that high levels of KMT1A in ARMS cells under differentiation conditions impairs MyoD function, thereby arresting myogenic differentiation in these tumor cells. Thus, targeting KMT1A may be a novel strategy for the treatment of this disease.
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MESH Headings
- Animals
- Cell Differentiation/physiology
- Cell Growth Processes/physiology
- Cell Line, Tumor
- Child
- Gene Expression Regulation, Neoplastic
- Gene Knockdown Techniques
- Histone Methyltransferases
- Histone-Lysine N-Methyltransferase/biosynthesis
- Histone-Lysine N-Methyltransferase/deficiency
- Histone-Lysine N-Methyltransferase/genetics
- Humans
- Mice
- MyoD Protein/metabolism
- Myogenin/genetics
- Promoter Regions, Genetic
- RNA, Small Interfering/administration & dosage
- RNA, Small Interfering/genetics
- Rhabdomyosarcoma, Alveolar/enzymology
- Rhabdomyosarcoma, Alveolar/genetics
- Rhabdomyosarcoma, Alveolar/pathology
- Transduction, Genetic
- Transplantation, Heterologous
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Affiliation(s)
- Min-Hyung Lee
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York
| | - Mathivanan Jothi
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York
| | - Andrei V. Gudkov
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York
| | - Asoke K. Mal
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York
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50
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Kang Z, Chen JJ, Yu Y, Li B, Sun SY, Zhang B, Cao L. Drozitumab, a human antibody to death receptor 5, has potent antitumor activity against rhabdomyosarcoma with the expression of caspase-8 predictive of response. Clin Cancer Res 2011; 17:3181-92. [PMID: 21385927 PMCID: PMC3096734 DOI: 10.1158/1078-0432.ccr-10-2874] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Rhabdomyosarcoma (RMS) is a common pediatric soft-tissue tumor. In this study, we evaluated the efficacy and selectivity of drozitumab, a death receptor DR5-targeted therapeutic antibody, in RMS preclinical models. EXPERIMENTAL DESIGN A panel of 11 RMS cell lines was used for in vitro studies. The molecular marker predictive of response to drozitumab was interrogated. Selected RMS cell lines were injected into the gastrocnemius muscle of mice for in vivo assessment of the potency and selectivity of drozitumab. RESULTS We report that DR5, but not DR4, persisted at high levels and on the surface of all RMS cell lines. DR5 antibody drozitumab was effective in vitro against the majority of RMS cell lines. There was a strong correlation between caspase-8 expression and the sensitivity to drozitumab, which induced the rapid assembly of the death-induced signaling complex and the cleavage of caspase-8 only in sensitive cells. More importantly, caspase-8 catalytic activity was both necessary and sufficient for mediating the sensitivity to drozitumab. Furthermore, drozitumab had potent antitumor activity against established RMS xenografts with a specificity predicted from the in vitro analysis and with tumor-free status in half of the treated mice. CONCLUSION Our study provides the first preclinical evaluation of the potency and selectivity of a death receptor antibody in RMS. Drozitumab is effective, in vitro, against the majority of RMS cell lines that express caspase-8 and, in vivo, may provide long-term control of RMS.
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MESH Headings
- Animals
- Antibodies, Monoclonal/pharmacology
- Antibodies, Monoclonal/therapeutic use
- Antibodies, Monoclonal, Humanized
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Biomarkers, Pharmacological/analysis
- Biomarkers, Pharmacological/metabolism
- Biomarkers, Tumor/analysis
- Biomarkers, Tumor/metabolism
- Caspase 8/genetics
- Caspase 8/metabolism
- Cell Line, Tumor
- Female
- Humans
- Mice
- Mice, Inbred C57BL
- Prognosis
- Receptors, TNF-Related Apoptosis-Inducing Ligand/antagonists & inhibitors
- Receptors, TNF-Related Apoptosis-Inducing Ligand/immunology
- Rhabdomyosarcoma/diagnosis
- Rhabdomyosarcoma/drug therapy
- Rhabdomyosarcoma/genetics
- Rhabdomyosarcoma/metabolism
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Zhigang Kang
- Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
- Laboratroy of Proteomics and Analytical Technologies, SAIC-Frederick Inc, National Cancer Institute-Frederick, Frederick, Maryland
| | - Jun-Jie Chen
- Division of Therapeutic Proteins, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, Maryland
| | - Yunkai Yu
- Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
- Laboratroy of Proteomics and Analytical Technologies, SAIC-Frederick Inc, National Cancer Institute-Frederick, Frederick, Maryland
| | - Bo Li
- Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia
| | - Shi-Yong Sun
- Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia
| | - Baolin Zhang
- Division of Therapeutic Proteins, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, Maryland
| | - Liang Cao
- Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
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