Hedgehog and Notch signaling regulate self-renewal of undifferentiated pleomorphic sarcomas.
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.
Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
Chang Ye Yale
CY
Wang
Qingxia
Q
Wei
Ilkyu
I
Han
Shingo
S
Sato
Ronak
R
Ghanbari-Azarnier
Heather
H
Whetstone
Raymond
R
Poon
Jiayi
J
Hu
Feifei
F
Zheng
Phil
P
Zhang
Weishi
W
Wang
Jay S
JS
Wunder
Benjamin A
BA
Alman
D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D020869:Gene Expression Profiling; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051677:Histiocytoma, Malignant Fibrous / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014308:Triparanol / Q000494:pharmacology
D053823:Hedgehog Proteins; D051880:Receptors, Notch; D014308:Triparanol