Elsir T, Edqvist PH, Carlson J, Ribom D, Bergqvist M, Ekman S, Popova SN, Alafuzoff I, Ponten F, Nistér M, Smits A
Int. J. Cancer 134 (5) 1123-1131 [2014-03-01; online 2013-09-16]
Recent studies suggest that the regulatory networks controlling the functions of stem cells during development may be abnormally active in human cancers. An embryonic stem cell (ESC) gene signature was found to correlate with a more undifferentiated phenotype of several human cancer types including gliomas, and associated with poor prognosis in breast cancer. In the present study, we used tissue microarrays of 80 low-grade (WHO Grade II) and 98 high-grade human gliomas (WHO Grades III and IV) to investigate the presence of the ESC-related proteins Nanog, Klf4, Oct4, Sox2 and c-Myc by immunohistochemistry. While similar patterns of co-expressed proteins between low- and high-grade gliomas were present, we found up-regulated protein levels of Nanog, Klf4, Oct4 and Sox2 in high-grade gliomas. Survival analysis by Kaplan-Meier analysis revealed a significant shorter survival in the subgroups of low-grade astrocytomas (n = 42) with high levels of Nanog protein (p = 0.0067) and of Klf4 protein (p = 0.0368), in high-grade astrocytomas (n = 85) with high levels of Nanog (p = 0.0042), Klf4 (p = 0.0447), and c-Myc (p = 0.0078) and in glioblastomas only (n = 71) with high levels of Nanog (p = 0.0422) and of c-Myc (p = 0.0256). In the multivariate model, Nanog was identified as an independent prognostic factor in the subgroups of low-grade astrocytomas (p = 0.0039), high-grade astrocytomas (p = 0.0124) and glioblastomas only (p = 0.0544), together with established clinical variables in these tumors. These findings provide further evidence for the joint regulatory pathways of ESC-related proteins in gliomas and identify Nanog as one of the key players in determining clinical outcome of human astrocytomas.