Temozolomide resistant human brain tumor stem cells are susceptible to recombinant vesicular stomatitis virus and double-deleted Vaccinia virus in vitro

2017 ◽  
Vol 95 ◽  
pp. 1201-1208 ◽  
Author(s):  
Bin Jiang ◽  
Xueqing Lun ◽  
Xiaoguang Hao ◽  
Yihua Wang ◽  
Xin Yin ◽  
...  
2008 ◽  
Vol 283 (16) ◽  
pp. 10958-10966 ◽  
Author(s):  
Akio Soeda ◽  
Akihito Inagaki ◽  
Naoki Oka ◽  
Yuka Ikegame ◽  
Hitomi Aoki ◽  
...  

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Katharine V Jensen ◽  
Xiaoguang Hao ◽  
Ahmed Aman ◽  
H Artee Luchman ◽  
Samuel Weiss

Abstract Background The EGFR pathway is frequently mutated in glioblastoma (GBM). However, to date, EGFR therapies have not demonstrated efficacy in clinical trials. Poor brain penetration of conventional inhibitors, lack of patient stratification for EGFR status, and mechanisms of resistance are likely responsible for the failure of EGFR-targeted therapy. We aimed to address these elements in a large panel of molecularly diverse patient-derived GBM brain tumor stem cells (BTSCs). Methods In vitro growth inhibition and on-target efficacy of afatinib, pacritinib, or a combination were assessed by cell viability, neurosphere formation, cytotoxicity, limiting dilution assays, and western blotting. In vivo efficacy was assessed with mass spectrometry, immunohistochemistry, magnetic resonance imaging, and intracranial xenograft models. Results We show that afatinib and pacritinib decreased BTSC growth and sphere-forming capacity in vitro. Combinations of the 2 drugs were synergistic and abrogated the activation of STAT3 signaling observed upon EGFR inhibition in vitro and in vivo. We further demonstrate that the brain-penetrant EGFR inhibitor, afatinib, improved survival in EGFRvIII mt orthotopic xenograft models. However, upregulation of the oncogenic STAT3 signaling pathway was observed following afatinib treatment. Combined inhibition with 2 clinically relevant drugs, afatinib and pacritinib, synergistically decreased BTSC viability and abrogated this compensatory mechanism of resistance to EGFR inhibition. A significant decrease in tumor burden in vivo was observed with the combinatorial treatment. Conclusions These data demonstrate that brain-penetrant combinatorial therapies targeting the EGFR and STAT3 signaling pathways hold therapeutic promise for GBM.


2008 ◽  
Vol 24 (3-4) ◽  
pp. E25 ◽  
Author(s):  
Zhigang Xie ◽  
Lawrence S. Chin

✓ The results of studies conducted in the past several years have suggested that malignant brain tumors may harbor a small fraction of tumor-initiating cells that are likely to cause tumor recurrence. These cells are known as brain tumor stem cells (BTSCs) because of their multilineage potential and their ability to self-renew in vitro and to recapitulate original tumors in vivo. The understanding of BTSCs has been greatly advanced by knowledge of neural progenitor/stem cells (NPSCs), which are multipotent and self-renewing precursor cells for neurons and glia. In this article, the authors summarize evidence that genetic mutations that deregulate asymmetric cell division by affecting cell polarity, spindle orientation, or cell fate determinants may result in the conversion of NPSCs to BTSCs. In addition, they review evidence that BTSCs and normal NPSCs may reside in similar vascularized microenvironments, where similar evolutionarily conserved signaling pathways control their proliferation. Finally, they discuss preliminary evidence that mechanisms of BTSC-associated infiltrativeness may be similar to those underlying the migration of NPSCs and neurons.


2010 ◽  
Vol 12 (12) ◽  
pp. 1220-1230 ◽  
Author(s):  
Einar Osland Vik-Mo ◽  
Cecilie Sandberg ◽  
Havard Olstorn ◽  
Mercy Varghese ◽  
Petter Brandal ◽  
...  

2008 ◽  
Vol 32 (3) ◽  
pp. S26-S26
Author(s):  
Jia Sheng Fang ◽  
Yong Wen Deng ◽  
Ming Chu Li ◽  
Feng Hua Chen ◽  
Ming Lu ◽  
...  

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1635
Author(s):  
Charles Chesnelong ◽  
Xiaoguang Hao ◽  
Orsolya Cseh ◽  
Alice Yijun Wang ◽  
H. Artee Luchman ◽  
...  

In glioblastoma (GBM), brain tumor stem cells (BTSCs) encompass heterogenous populations of multipotent, self-renewing, and tumorigenic cells, which have been proposed to be at the root of therapeutic resistance and recurrence. While the functional significance of BTSC heterogeneity remains to be fully determined, we previously distinguished relatively quiescent stem-like precursor state from the more aggressive progenitor-like precursor state. In the present study, we hypothesized that progenitor-like BTSCs arise from stem-like precursors through a mesenchymal transition and drive post-treatment recurrence. We first demonstrate that progenitor-like BTSCs display a more mesenchymal transcriptomic profile. Moreover, we show that both mesenchymal GBMs and progenitor-like BTSCs are characterized by over-activated STAT3/EMT pathways and that SLUG is the primary epithelial to mesenchymal transition (EMT) transcription factor directly regulated by STAT3 in BTSCs. SLUG overexpression in BTSCs enhances invasiveness, promotes inflammation, and shortens survival. Importantly, SLUG overexpression in a quiescent stem-like BTSC line enhances tumorigenesis. Finally, we report that recurrence is associated with SLUG-induced transcriptional changes in both BTSCs and GBM patient samples. Collectively, our findings show that a STAT3-driven precursor state transition, mediated by SLUG, may prime BTSCs to initiate more aggressive mesenchymal recurrence. Targeting the STAT3/SLUG pathway may maintain BTSCs in a quiescent stem-like precursor state, delaying recurrence and improving survival in GBM.


Author(s):  
Mathieu Seyfrid ◽  
David Bobrowski ◽  
David Bakhshinyan ◽  
Nazanin Tatari ◽  
Chitra Venugopal ◽  
...  

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