Retinoic acid fails to induce cell cycle arrest with myogenic differentiation in rhabdomyosarcoma

被引:13
作者
Al-Tahan, Alaa [1 ]
Sarkis, Omar [1 ]
Harajly, Mohamad [1 ]
Kebbe Baghdadi, Omar [1 ]
Zibara, Kazem [2 ]
Boulos, Fouad [3 ]
Dighe, Dipti [4 ]
Kregel, Steven [4 ]
Bazarbachi, Ali [5 ]
El-Sabban, Marwan [6 ]
Skapek, Stephen X. [4 ]
Saab, Raya [1 ]
机构
[1] Amer Univ Beirut, Dept Pediat, Beirut 11072020, Lebanon
[2] Lebanese Univ, Beirut, Lebanon
[3] Amer Univ Beirut, Dept Pathol & Lab Med, Beirut 11072020, Lebanon
[4] Univ Chicago, Div Pediat Hematol Oncol, Chicago, IL 60637 USA
[5] Amer Univ Beirut, Dept Internal Med, Beirut 11072020, Lebanon
[6] Amer Univ Beirut, Dept Anat Cell Biol & Physiol Sci, Beirut 11072020, Lebanon
关键词
differentiation; minimal residual disease; retinoic acid; rhabdomyosarcoma; therapy; xenograft; SKELETAL-MUSCLE DIFFERENTIATION; DEPENDENT KINASE 4/6; GENE-EXPRESSION; RETINOBLASTOMA PROTEIN; GROWTH; LINES; INHIBITION; CHILDHOOD; PRB; UTILITY;
D O I
10.1002/pbc.23246
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Current treatment strategies do not cure most children with recurrent or high-risk disease, underlying the need for novel therapeutic approaches. Retinoic acid has been shown to induce differentiation in a variety of cells including skeletal myoblasts and neuroblasts. In the setting of minimal residual disease, retinoic acid improves survival in neuroblastoma, another poorly differentiated childhood tumor. Whether such an approach is useful for rhabdomyosarcoma has not yet been investigated. Several in vitro studies have demonstrated an appreciable effect of retinoic acid on human RMS cellular proliferation and differentiation.Procedure. We assessed the efficacy of ATRA on rhabdomyosarcoma, in vitro and in vivo, using cell lines and xenografts. Results. ATRA slowed RMS cell proliferation, and promoted a more differentiated myogenic phenotype in both alveolar and embryonal RMS cell lines. Treatment of cultured murine myoblasts with retinoids increased Myogenin expression, but did not induce cell cycle arrest. Despite the favorable in vitro effects, ATRA failed to delay relapse of minimal residual disease using human RMS xenografts in immuno-suppressed NOD-SCID (NSG) mice. Interestingly, tumors that recurred after ATRA treatment showed evidence of enhanced muscle differentiation. Conclusion. Our results indicate that ATRA could increase the expression of some genes associated with muscle differentiation in rhabdomyosarcoma cells, but there was no benefit of single-agent therapy in an MRD model, likely because cell cycle arrest was uncoupled from the pro-differentiation effects of retinoids. Pediatr Blood Cancer 2012; 58: 877-884. (C) 2011 Wiley Periodicals, Inc.
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收藏
页码:877 / 884
页数:8
相关论文
共 43 条
[1]   Myogenin expression, cell cycle withdrawal, and phenotypic differentiation are temporally separable events that precede cell fusion upon myogenesis [J].
Andres, V ;
Walsh, K .
JOURNAL OF CELL BIOLOGY, 1996, 132 (04) :657-666
[2]   Differentiation of rhabdomyosarcoma cell lines using retinoic acid [J].
Barlow, Jason W. ;
Wiley, Joe C. ;
Mous, Marieke ;
Narendran, Aru ;
Gee, Matthew F. W. ;
Goldberg, Michael ;
Sexsmith, Elizabeth ;
Malkin, David .
PEDIATRIC BLOOD & CANCER, 2006, 47 (06) :773-784
[3]  
Berner JM, 1996, GENE CHROMOSOME CANC, V17, P254, DOI 10.1002/(SICI)1098-2264(199612)17:4<254::AID-GCC7>3.0.CO
[4]  
2-2
[5]   Rhabdomyosarcoma: New windows of opportunity [J].
Breitfeld, PP ;
Meyer, WH .
ONCOLOGIST, 2005, 10 (07) :518-527
[6]   COMPARATIVE-STUDIES BETWEEN A NEW HUMAN RHABDOMYOSARCOMA CELL-LINE, JR-1 AND ITS TUMOR OF ORIGIN [J].
CLAYTON, J ;
PINCOTT, JR ;
VANDENBERGHE, JA ;
KEMSHEAD, JT .
BRITISH JOURNAL OF CANCER, 1986, 54 (01) :83-90
[7]  
CROUCH GD, 1991, CANCER RES, V51, P4882
[8]   Identification of a PAX-FKHR gene expression signature that defines molecular classes and determines the prognosis of alveolar rhabdomyosarcomas [J].
Davicioni, Elai ;
Finckenstein, Friedrich Graf ;
Shahbazian, Violette ;
Buckley, Jonathan D. ;
Triche, Timothy J. ;
Anderson, Michael J. .
CANCER RESEARCH, 2006, 66 (14) :6936-6946
[9]   Molecular Classification of Rhabdomyosarcoma-Genotypic and Phenotypic Determinants of Diagnosis A Report from the Children's Oncology Group [J].
Davicioni, Elai ;
Anderson, Michael J. ;
Finckenstein, Friedrich Graf ;
Lynch, James C. ;
Qualman, Stephen J. ;
Shimada, Hiroyuki ;
Schofield, Deborah E. ;
Buckley, Jonathan D. ;
Meyer, William H. ;
Sorensen, Poul H. B. ;
Triche, Timothy J. .
AMERICAN JOURNAL OF PATHOLOGY, 2009, 174 (02) :550-564
[10]  
DIAS P, 1990, AM J PATHOL, V137, P1283