Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Lung inflammatory injury and tissue repair (Jul 2023)
    • Immune Environment in Glioblastoma (Feb 2023)
    • Korsmeyer Award 25th Anniversary Collection (Jan 2023)
    • Aging (Jul 2022)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Research letters
    • Letters to the editor
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Research letters
  • Letters to the editor
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
Derivation of sarcomas from mesenchymal stem cells via inactivation of the Wnt pathway
Igor Matushansky, … , Robert G. Maki, Carlos Cordon-Cardo
Igor Matushansky, … , Robert G. Maki, Carlos Cordon-Cardo
Published October 18, 2007
Citation Information: J Clin Invest. 2007;117(11):3248-3257. https://doi.org/10.1172/JCI31377.
View: Text | PDF
Research Article Oncology

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

  • Text
  • PDF
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.

Authors

Igor Matushansky, Eva Hernando, Nicholas D. Socci, Joslyn E. Mills, Tulio A. Matos, Mark A. Edgar, Samuel Singer, Robert G. Maki, Carlos Cordon-Cardo

×

Figure 1

MFH associated with hMSCs.

Options: View larger image (or click on image) Download as PowerPoint
MFH associated with hMSCs.
(A) Unsupervised hierarchical clustering of a...
(A) Unsupervised hierarchical clustering of a panel of STS (described in detail in ref. 9) using a stem cell gene list (Supplemental Table 1). (B) Immunohistochemical staining of differentiation-associated proteins on the indicated tumor specimens from a tissue microarray. A single stain representative of 10 tissue samples each of MFH, LS, and leiomyosarcomas (LMS), and of 6 tissue samples each of fibrosarcomas (FS) are shown. Original magnification, ×200.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts