Derivation of sarcomas from mesenchymal stem cells via inactivation of the Wnt pathway Journal Article
| Authors: | Matushansky, I.; Hernando, E.; Socci, N. D.; Mills, J. E.; Matos, T. A.; Edgar, M. A.; Singer, S.; Maki, R. G.; Cordon-Cardo, C. |
| Article Title: | Derivation of sarcomas from mesenchymal stem cells via inactivation of the Wnt pathway |
| 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/β-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. |
| Keywords: | signal transduction; controlled study; protein expression; intercellular signaling peptides and proteins; unclassified drug; human cell; nonhuman; cell proliferation; mouse; animals; mice; gene expression profiling; stress activated protein kinase; animal experiment; animal model; small interfering rna; cell differentiation; tumor cells, cultured; carcinogenesis; cell lineage; cell transformation, neoplastic; sarcoma; nude mouse; mice, nude; recombinant protein; mesenchymal stem cell; malignant fibrous histiocytoma; wnt proteins; beta catenin; wnt protein; protein inhibitor; wnt5a protein; mesenchymal stem cells; jnk mitogen-activated protein kinases; histiocytoma, malignant fibrous; protein dkk1; wnt2 protein |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 117 |
| Issue: | 11 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2007-11-01 |
| Start Page: | 3248 |
| End Page: | 3257 |
| Language: | English |
| DOI: | 10.1172/jci31377 |
| PUBMED: | 17948129 |
| PROVIDER: | scopus |
| PMCID: | PMC2030456 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 60" - "Export Date: 17 November 2011" - "CODEN: JCINA" - "Source: Scopus" |
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