Hedgehog and Notch Signaling Regulate Self-Renewal of Undifferentiated Pleomorphic Sarcomas

Chang Ye Yale Wang,Jay S Wunder,Benjamin A Alman,Phil Zhang,Ilkyu Han,Raymond Poon,Weishi Wang,Jiayi Hu,Heather Whetstone,Qingxia Wei,Ronak Ghanbari- Azarnier,Shingo Sato,Feifei Zheng

doi:10.1158/0008-5472.can-11-2531

Abstract

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.

Highlights

Cytologic heterogeneity is common in neoplasia [1]
The Hh and notch signaling pathways are activated in side population (SP) cells from undifferentiated pleomorphic sarcomas
To examine whether there are genes that are differentially regulated in SP cells in undifferentiated pleomorphic sarcomas, we compared gene expression profiles between SP and non-SP cell populations from 10 primary tumors

Summary

Introduction

Cytologic heterogeneity is common in neoplasia [1]. The various cellular subpopulations differ in their morphologic, biochemical, genetic, and karyotypic characteristics [2]. Subpopulations of cells with an enhanced capacity to initiate tumors when transplanted into immunodeficient mice are termed tumor-initiating cells and are thought to be responsible for self-renewal of the neoplasm. These tumor-initiating cells have the ability to recapitulate the original morphology of primary tumors upon serial transplantation in mice and have been identified in a variety of tumor types [3,4,5,6,7,8]. Sarcomas are composed of a heterogeneous population of cells with mes-.

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