Hedgehog and Notch signaling regulate self-renewal of undifferentiated pleomorphic sarcomas.
Journal Article (Journal Article)
Like many solid tumors, sarcomas are heterogeneous and include a small fraction of the so-called side population (SP) cells with stem-like tumor-initiating potential. Here, we report that SP cells from a soft tissue tumor of enigmatic origin termed undifferentiated pleomorphic sarcoma (also known as malignant fibrous histiocytoma or MFH sarcoma) display activation of both the Hedgehog and Notch pathways. Blockade to these pathways in murine xenograft models, this human cancer decreased the proportion of SP cells present and suppressed tumor self-renewal, as illustrated by the striking inability of xenograft tumors subjected to pathway blockade to be serially transplanted to new hosts. In contrast, conventional chemotherapies increased the proportion of SP cells present in tumor xenografts and did not affect their ability to be serially transplanted. SP cells from these tumors displayed an unexpectedly high proliferation rate which was selectively inhibited by Hedgehog and Notch blockade compared with conventional chemotherapies. Together, our findings deepen the concept that Hedgehog and Notch signaling are fundamental drivers of tumor self-renewal, acting in a small population of tumor-initiating cells present in tumors. Furthermore, our results suggest not only novel treatment strategies for deadly recurrent unresectable forms of this soft tumor subtype, but also potential insights into its etiology which has been historically controversial.
Full Text
Duke Authors
Cited Authors
- Wang, CYY; Wei, Q; Han, I; Sato, S; Ghanbari-Azarnier, R; Whetstone, H; Poon, R; Hu, J; Zheng, F; Zhang, P; Wang, W; Wunder, JS; Alman, BA
Published Date
- February 15, 2012
Published In
Volume / Issue
- 72 / 4
Start / End Page
- 1013 - 1022
PubMed ID
- 22232736
Electronic International Standard Serial Number (EISSN)
- 1538-7445
Digital Object Identifier (DOI)
- 10.1158/0008-5472.CAN-11-2531
Language
- eng
Conference Location
- United States