Mouse mesenchymal stem cells expressing PAX-FKHR form alveolar rhabdomyosarcomas by cooperating with secondary mutations.
Alveolar rhabdomyosarcomas (ARMS) are highly malignant soft-tissue sarcomas that arise in children, adolescents, and young adults. Although formation and expression of the PAX-FKHR fusion genes is thought to be the initiating event in this cancer, the role of PAX-FKHR in the neoplastic process remains largely unknown in a progenitor cell that is undefined. We hypothesize that PAX-FKHR determine the ARMS progenitor to the skeletal muscle lineage, which when coupled to the inactivation and/or activation of critical cell signaling pathways leads to the formation of ARMS. Because a number of studies have proposed that mesenchymal stem cells (MSC) are the progenitor for several of the sarcomas, we tested this hypothesis in MSCs. We show that PAX-FKHR induce skeletal myogenesis in MSCs by transactivating MyoD and myogenin. Despite exhibiting enhanced growth in vitro, the PAX-FKHR-expressing populations do not form colonies in soft agar or tumors in mice. Expression of dominant-negative p53, or the SV40 early region, elicits tumor formation in some of the PAX-FKHR-expressing populations. Additional activation of the Ras signaling pathway leads to highly malignant tumor formation for all of the populations. The PAX-FKHR-expressing tumors were shown to have histologic, immunohistochemical, and gene expression profiles similar to human ARMS. Our results show the critical role played by PAX-FKHR in determining the molecular, myogenic, and histologic phenotype of ARMS. More importantly, we identify MSCs as a progenitor that can give rise to ARMS.
Ren
Yue-Xin
YX
Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, CA 90027, USA.
Finckenstein
Friedrich Graf
FG
Abdueva
Diana A
DA
Shahbazian
Violette
V
Chung
Brile
B
Weinberg
Kenneth I
KI
Triche
Timothy J
TJ
Shimada
Hiroyuki
H
Anderson
Michael J
MJ
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics*; D000957:Antigens, Viral, Tumor / Q000235:genetics; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002648:Child; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D024510:Muscle Development / Q000502:physiology; D018482:Muscle, Skeletal; D009154:Mutation / Q000235:genetics*; D018008:Myogenin / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D000072041:PAX3 Transcription Factor; D051763:PAX7 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D051761:Paired Box Transcription Factors / Q000235:genetics* / Q000378:metabolism; D018232:Rhabdomyosarcoma, Alveolar / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D000952:Antigens, Polyomavirus Transforming; D000957:Antigens, Viral, Tumor; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D018008:Myogenin; D015514:Oncogene Proteins, Fusion; D000072041:PAX3 Transcription Factor; D051763:PAX7 Transcription Factor; D051761:Paired Box Transcription Factors; C497322:Pax7 protein, mouse; D016159:Tumor Suppressor Protein p53; C068686:Pax3 protein, mouse