TY - JOUR
T1 - c-Met signaling induces a reprogramming network and supports the glioblastoma stem-like phenotype
AU - Li, Yunqing
AU - Li, Angela
AU - Glas, Martin
AU - Lal, Bachchu
AU - Ying, Mingyao
AU - Sang, Yingying
AU - Xia, Shuli
AU - Trageser, Daniel
AU - Guerrero-Cázares, Hugo
AU - Eberhart, Charles G.
AU - Quiñones-Hinojosa, Alfredo
AU - Scheffler, Bjorn
AU - Laterra, John
PY - 2011/6/14
Y1 - 2011/6/14
N2 - The tyrosine kinase c-Met promotes the formation and malignant progression of multiple cancers. It is well known that c-Met hyperactivation increases tumorigenicity and tumor cell resistance to DNA damaging agents, properties associated with tumor-initiating stem cells. However, a link between c-Met signaling and the formation and/or maintenance of neoplastic stemcells has not been previously identified. Here, we show that c-Met is activated and functional in glioblastoma (GBM) neurospheres enriched for glioblastoma tumorinitiating stem cells and that c-Met expression/function correlates with stem cell marker expression and the neoplastic stem cell phenotype in glioblastoma neurospheres and clinical glioblastoma specimens. c-Met activation was found to induce the expression of reprogramming transcription factors (RFs) known to support embryonic stem cells and induce differentiated cells to form pluripotent stem(iPS) cells, and c-Met activation counteracted the effects of forced differentiation in glioblastoma neurospheres. Expression of the reprogramming transcription factor Nanog by glioblastomacells is shown to mediate the ability of c-Met to induce the stem cell characteristics of neurosphere formation and neurosphere cell self-renewal. These findings show that c-Met enhances the population of glioblastoma stemcells (GBM SCs) via a mechanism requiring Nanog and potentially other c-Met - responsive reprogramming transcription factors.
AB - The tyrosine kinase c-Met promotes the formation and malignant progression of multiple cancers. It is well known that c-Met hyperactivation increases tumorigenicity and tumor cell resistance to DNA damaging agents, properties associated with tumor-initiating stem cells. However, a link between c-Met signaling and the formation and/or maintenance of neoplastic stemcells has not been previously identified. Here, we show that c-Met is activated and functional in glioblastoma (GBM) neurospheres enriched for glioblastoma tumorinitiating stem cells and that c-Met expression/function correlates with stem cell marker expression and the neoplastic stem cell phenotype in glioblastoma neurospheres and clinical glioblastoma specimens. c-Met activation was found to induce the expression of reprogramming transcription factors (RFs) known to support embryonic stem cells and induce differentiated cells to form pluripotent stem(iPS) cells, and c-Met activation counteracted the effects of forced differentiation in glioblastoma neurospheres. Expression of the reprogramming transcription factor Nanog by glioblastomacells is shown to mediate the ability of c-Met to induce the stem cell characteristics of neurosphere formation and neurosphere cell self-renewal. These findings show that c-Met enhances the population of glioblastoma stemcells (GBM SCs) via a mechanism requiring Nanog and potentially other c-Met - responsive reprogramming transcription factors.
KW - Cancer stem cell
KW - Hepatocyte growth factor
KW - Klf4
KW - Oct4
KW - Sox2
UR - http://www.scopus.com/inward/record.url?scp=79959971880&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79959971880&partnerID=8YFLogxK
U2 - 10.1073/pnas.1016912108
DO - 10.1073/pnas.1016912108
M3 - Article
C2 - 21628563
AN - SCOPUS:79959971880
SN - 0027-8424
VL - 108
SP - 9951
EP - 9956
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 24
ER -