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

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. Cancer Res; 72(4); 1013-22. Ó2012 AACR.

Mesenchymal Tumors Can Derive from Ng2/Cspg4-Expressing Pericytes with β-Catenin Modulating the Neoplastic Phenotype

“…Since mice expressing the Ctnnb1 ex3 allele would not form tumors, we analyzed cells from sarcomas induced by a localized injection of an adenovirus expressing cre recombinase into Trp53 flox/flox; ; Kras G12D mice. Sarcoma cells were dissociated and studied as grafts in immunodeficient NOD- scid IL2rγ null mice (Wang et al, 2012). 10,000 cells were implanted subcutaneously along with matrigel.…”

“…Individual cells from ten primary human osteosarcomas or undifferentiated pleomorphic sarcomas were used to establish xenografts in immunodeficient NOD- scid IL2rγ null mice as previously reported (Wang et al, 2012). Similar to the work in murine tumors, mice were treated with lithium (Chen et al, 2007).…”

Recombinant TIMP-1-GPI inhibits growth of fibrosarcoma and enhances tumor sensitivity to doxorubicin

“…Alterations in regulatory pathways and gene networks support the suggestion that SP cells resemble CSCs and may thus effectively model cell types responsible for tumor initiation, relapse, metastasis and chemoresistance [28, 29]. Recently, the importance of these cells in sarcoma, a tumor entity with high rates of relapse and chemoresistance, was demonstrated [30]. …”

Undifferentiated High-Grade Pleomorphic Sarcoma of the Pelvis: Case Report.

“…This finding is demonstrated by the inability of xenograft tumors subjected to pathway blockade to be serially transplanted to new hosts. [6] Diagnostic imaging is required to know the extent of the lesion and assesses the integrity and function of adjacent organs. Surgery is the main curative modality.…”