Induction of a regenerative microenvironment in skeletal muscle is sufficient to induce embryonal rhabdomyosarcoma in p53-deficient mice

被引:21
作者
Camboni, Marybeth [2 ]
Hammond, Sue [4 ,5 ]
Martin, Laura T. [1 ,3 ]
Martin, Paul T. [1 ,2 ]
机构
[1] Ohio State Univ, Coll Med, Dept Pediat, Columbus, OH 43205 USA
[2] Nationwide Childrens Hosp, Res Inst, Ctr Gene Therapy, Columbus, OH USA
[3] Nationwide Childrens Hosp, Div Hematol Oncol Bone Marrow Transplantat, Columbus, OH USA
[4] Ohio State Univ, Coll Med, Nationwide Childrens Hosp, Div Pathol & Lab Med, Columbus, OH 43205 USA
[5] Ohio State Univ, Coll Med, Dept Pathol, Columbus, OH 43205 USA
关键词
p53; rhabdomyosarcoma; mdx; muscular dystrophy; tumour microenvironment; SARCOGLYCAN-DEFICIENT MICE; ALVEOLAR RHABDOMYOSARCOMA; MUSCULAR-DYSTROPHY; MUTANT MICE; MDX MICE; EXPRESSION; TUMORS; OVEREXPRESSION; MOUSE; CELL;
D O I
10.1002/path.2996
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
We have previously reported that mice with muscular dystrophy, including mdx mice, develop embryonal rhabdomyosarcoma (eRMS) with a low incidence after 1 year of age and that almost all such tumours contain cancer-associated p53 mutations. To further demonstrate the relevance of p53 inactivation, we created p53-deficient mdx mice. Here we demonstrate that loss of one or both p53 (Trp53) alleles accelerates eRMS incidence in the mdx background, such that almost all Trp53(-/-) mdx animals develop eRMS by 5 months of age. To ascertain whether increased tumour incidence was due to the regenerative microenvironment found in dystrophic skeletal muscles, we induced muscle regeneration in Trp53(+/+) and Trp53(-/-) animals using cardiotoxin (Ctx). Wild-type (Trp53(+/+)) animals treated with Ctx, either once every 7 days or once every 14 days from 1 month of age onwards, developed no eRMS; however, all similarly Ctx-treated Trp53(-/-) animals developed eRMS by 5 months of age at the site of injection. Most of these tumours displayed markers of human eRMS, including over-expression of Igf2 and phosphorylated Akt. These data demonstrate that the presence of a regenerative microenvironment in skeletal muscle, coupled with Trp53 deficiency, is sufficient to robustly induce eRMS in young mice. These studies further suggest that consideration should be given to the potential of the muscle microenvironment to support tumourigenesis in regenerative therapies for myopathies. Copyright (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
引用
收藏
页码:40 / 49
页数:10
相关论文
共 44 条
  • [1] Anderson John, 1999, Neoplasia (New York), V1, P340, DOI 10.1038/sj.neo.7900052
  • [2] Medical Progress - Common musculoskeletal tumors of childhood and adolescence
    Arndt, CAS
    Crist, WM
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 1999, 341 (05) : 342 - 352
  • [3] A web-accessible complete transcriptome of normal human and DMD muscle
    Bakay, M
    Zhao, P
    Chen, J
    Hoffman, EP
    [J]. NEUROMUSCULAR DISORDERS, 2002, 12 : S125 - S141
  • [4] REARRANGEMENT OF THE PAX3 PAIRED BOX GENE IN THE PEDIATRIC SOLID TUMOR ALVEOLAR RHABDOMYOSARCOMA
    BARR, FG
    GALILI, N
    HOLICK, J
    BIEGEL, JA
    ROVERA, G
    EMANUEL, BS
    [J]. NATURE GENETICS, 1993, 3 (02) : 113 - 117
  • [5] Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma
    Barr, FG
    [J]. ONCOGENE, 2001, 20 (40) : 5736 - 5746
  • [6] BISCHOFF R, 2004, SATELLITE CELLS MYOL, P66
  • [7] Expression profiling in stably regenerating skeletal muscle of dystrophin-deficient mdx mice
    Boer, JM
    de Meijer, EJ
    Mank, EM
    van Ommen, GB
    den Dunnen, JT
    [J]. NEUROMUSCULAR DISORDERS, 2002, 12 : S118 - S124
  • [8] Dystrophin-deficient mdx mice display a reduced life span and are susceptible to spontaneous rhabdomyosarcoma
    Chamberlain, Jeffrey S.
    Metzger, Joseph
    Reyes, Morayma
    Townsend, DeWayne
    Faulkner, John A.
    [J]. FASEB JOURNAL, 2007, 21 (09) : 2195 - 2204
  • [9] Alveolar rhabdomyosarcoma: Is the cell of origin a mesenchymal stem cell?
    Charytonowicz, Elizabeth
    Cordon-Cardo, Carlos
    Matushansky, Igor
    Ziman, Mel
    [J]. CANCER LETTERS, 2009, 279 (02) : 126 - 136
  • [10] DAVIS RJ, 1994, CANCER RES, V54, P2869