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Overactivation of Ras signaling pathway in CD133+ MPNST cells

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Abstract

Cancer stem cells (CSCs) are believed to be the regenerative pool of cells responsible for repopulating tumors. Gaining knowledge about the signaling characteristics of CSCs is important for understanding the biology of tumors and developing novel anti-cancer therapies. We have identified a subpopulation of cells positive for CD133 (a CSC marker) from human primary malignant peripheral nerve sheath tumor (MPNST) cells which were absent in non-malignant Schwann cells. CD133 was also found to be expressed in human tissue samples and mouse MPNST cells. CD133+ cells were capable of forming spheres in non-adherent/serum-free conditions. The activation levels of Ras and its downstream effectors such as ERK, JNK, PI3K, p38K, and RalA were significantly increased in this population. Moreover, the CD133+ cells showed enhanced invasiveness which was linked to the increased expression of β-Catenin and Snail, two important proteins involved in the epithelial to mesenchymal transition, and Paxilin, a focal adhesion protein. Among other important characteristics of the CD133+ population, endoplasmic reticulum stress marker IRE1α was decreased, implying the potential sensitivity of CD133+ to the accumulation of unfolded proteins. Apoptotic indicators seemed to be unchanged in CD133+ cells when compared to the wild (unsorted) cells. Finally, in order to test the possibility of targeting CD133+ MPNST cells with Ras pathway pharmacological inhibitors, we exposed these cells to an ERK inhibitor. The wild population was more sensitive to inhibition of proliferation by this inhibitor as compared with the CD133+ cells supporting previous studies observing enhanced chemoresistance of these cells.

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Acknowledgments

We wish to acknowledge the efforts of the dedicated staff of the Children Tumor Foundation (CTF) in helping neurofibromatosis patients and supporting related research. We would like to express our gratitude to Dr. George H. DeVries for access to MPNST cells. In addition, we recognize Professor A. Guha for the MPNST cell-lines T530 and T532. We also wish to acknowledge Sarah Ann Martin for providing scientific editorial services for this manuscript, Fernald Stanton for assistance with microscopy, and Richard Hastings for assistance with flow cytometry.

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Authors and Affiliations

  1. KUMC—Molecular Medicine Laboratory, Department of Medicine, The University of Kansas Medical Center, 3901-Rainbow Blvd, 1000 Hixon-Mail Stop: 4037, Kansas city, KS, 66160, USA

    Emma Borrego-Diaz, Kaoru Terai, Kristina Lialyte, Amanda L. Wise, Tuba Esfandyari, Fariba Behbod, Sarah Taylor & Faris Farassati

  2. University Hospital Eppendorf, Hamburg, Germany

    Victor F. Mautner & Melanie Spyra

  3. University of Texas Southwestern Medical Center, Dallas, TX, USA

    Luis F. Parada

  4. Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff, UK

    Meena Upadhyaya

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  1. Emma Borrego-Diaz
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Correspondence to Faris Farassati.

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Kaoru Terai and Kristina Lialyte have contributed equally to this work.

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Borrego-Diaz, E., Terai, K., Lialyte, K. et al. Overactivation of Ras signaling pathway in CD133+ MPNST cells. J Neurooncol 108, 423–434 (2012). https://doi.org/10.1007/s11060-012-0852-1

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