Nanog signaling in cancer promotes stem-like phenotype and immune evasion
Authors
Kyung Hee Noh ; Bo Wook Kim ; Kwon-Ho Song ; Hanbyoul Cho ; Young-Ho Lee ; Jin Hee Kim ; Joon-Yong Chung ; Jae-Hoon Kim ; Stephen M. Hewitt ; Seung-Yong Seong ; Chih-Ping Mao ; T.-C. Wu ; Tae Woo Kim
Citation
JOURNAL OF CLINICAL INVESTIGATION, Vol.122(11) : 4077-4093, 2012
Adaptation of tumor cells to the host is a major cause of cancer progression, failure of therapy, and ultimately death. Immune selection drives this adaptation in human cancer by enriching tumor cells with a cancer stem cell-like (CSC-like) phenotype that makes them resistant to CTL-mediated apoptosis; however, the mechanisms that mediate CSC maintenance and proliferation are largely unknown. Here, we report that CTL-mediated immune selection drives the evolution of tumor cells toward a CSC-like phenotype and that the CSC-like phenotype arises through the Akt signaling pathway via transcriptional induction of Tcl1a by Nanog. Furthermore, we found that hyperactivation of the Nanog/Tcl1a/Akt signaling axis was conserved across multiple types of human cancer. Inhibition of Nanog in a murine model of colon cancer rendered tumor cells susceptible to immune-mediated clearance and led to successful, long-term control of the disease. Our findings establish a firm link among immune selection, disease progression, and the development of a stem-like tumor phenotype in human cancer and implicate the Nanog/Tcl1a/Akt pathway as a central molecular target in this process.