TY - JOUR
T1 - Overactivation of Ras signaling pathway in CD133+ MPNST cells
AU - Borrego-Diaz, Emma
AU - Terai, Kaoru
AU - Lialyte, Kristina
AU - Wise, Amanda L.
AU - Esfandyari, Tuba
AU - Behbod, Fariba
AU - Mautner, Victor F.
AU - Spyra, Melanie
AU - Taylor, Sarah
AU - Parada, Luis F.
AU - Upadhyaya, Meena
AU - Farassati, Faris
PY - 2012/7
Y1 - 2012/7
N2 - 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 b-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 IRE1a 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.
AB - 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 b-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 IRE1a 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.
KW - CD133
KW - Cancer stem cells
KW - Malignant peripheral nerve sheath tumor
KW - Ral
KW - Ras
KW - Tumor-initiating cells
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U2 - 10.1007/s11060-012-0852-1
DO - 10.1007/s11060-012-0852-1
M3 - Article
C2 - 22484909
AN - SCOPUS:84864060471
SN - 0167-594X
VL - 108
SP - 423
EP - 434
JO - Journal of Neuro-Oncology
JF - Journal of Neuro-Oncology
IS - 3
ER -