Derivation of sarcomas from mesenchymal stem cells via inactivation of the Wnt pathway

Matushansky, I., Hernando, E., Socci, N. D., Mills, J. E., Matos, T. A., Edgar, M. A., Singer, S., Maki, R. G., Cordon-Cardo, C. (November 2007) Derivation of sarcomas from mesenchymal stem cells via inactivation of the Wnt pathway. J Clin Invest, 117 (11). pp. 3248-57. ISSN 0021-9738 (Print)0021-9738 (Linking)

URL: https://www.ncbi.nlm.nih.gov/pubmed/17948129
DOI: 10.1172/JCI31377

Abstract

Malignant fibrous histiocytoma (MFH), now termed high-grade undifferentiated pleomorphic sarcoma, is a commonly diagnosed mesenchymal tumor, yet both the underlying molecular mechanisms of tumorigenesis and cell of origin remain unidentified. We present evidence demonstrating that human mesenchymal stem cells (hMSCs) are the progenitors of MFH. DKK1, a Wnt inhibitor and mediator of hMSC proliferation, is overexpressed in MFH. Using recombinant proteins, antibody depletion, and siRNA knockdown strategies of specific Wnt elements, we show that DKK1 inhibits hMSC commitment to differentiation via Wnt2/beta-catenin canonical signaling and that Wnt5a/JNK noncanonical signaling regulates a viability checkpoint independent of Dkk1. Finally, we illustrate that hMSCs can be transformed via inhibition of Wnt signaling to form MFH-like tumors in nude mice, and conversely, MFH cells in which Wnt signaling is appropriately reestablished can differentiate along mature connective tissue lineages. Our results provide mechanistic insights regarding the cell of origin of MFH, establish what we believe is a novel tumor suppressor role for Wnt signaling, and identify a potential therapeutic differentiation strategy for sarcomas.

Item Type: Paper
Uncontrolled Keywords: Animals Cell Differentiation/physiology Cell Lineage Cell Transformation, Neoplastic Gene Expression Profiling *Histiocytoma, Malignant Fibrous/metabolism/pathology Humans Intercellular Signaling Peptides and Proteins/genetics/metabolism JNK Mitogen-Activated Protein Kinases/metabolism Mesenchymal Stromal Cells/cytology/*physiology Mice Mice, Nude Signal Transduction/*physiology Tumor Cells, Cultured Wnt Proteins/genetics/*metabolism beta Catenin/metabolism
Subjects: organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell differentiation
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression
diseases & disorders > cancer > cancer types > sarcoma
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > Wnt
CSHL Authors:
Communities: CSHL labs > Maki lab
Depositing User: Matt Covey
Date: November 2007
Date Deposited: 26 Oct 2016 19:31
Last Modified: 26 Oct 2016 19:31
PMCID: PMC2030456
Related URLs:
URI: http://repository.cshl.edu/id/eprint/33677

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