Nanog signaling in cancer promotes stem-like phenotype and immune evasion
Kyung Hee Noh, … , T.-C. Wu, Tae Woo Kim
Kyung Hee Noh, … , T.-C. Wu, Tae Woo Kim
Published October 24, 2012
Citation Information: J Clin Invest. 2012;122(11):4077-4093. https://doi.org/10.1172/JCI64057.
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Nanog signaling in cancer promotes stem-like phenotype and immune evasion

Abstract

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.

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

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Figure 9

Inhibition of Nanog renders the tumor vulnerable to immune-mediated control.

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Inhibition of Nanog renders the tumor vulnerable to immune-mediated cont...
(A) Diagram of the immune-based therapy regimen in mice implanted with HCT116 colon cancer cells transduced with plasmid encoding a SCT of H2-Db heavy chain linked to β2-microglobulin and the H2-Db–restricted E7 epitope (HCT116/SCT-E7). (B) Tumor growth and (C) survival of mice inoculated with HCT116/SCT-E7 and treated with the indicated reagents (5 mice/group). (D) Tumor mass of mice at 25 days after challenge. (E) Western blot analysis of Nanog, pAkt, Tcl1a, Mcl-1, cyclin A, and p21 expression in mice administered with siGFP or siNanog, with or without adoptive transfer of E7-specific CTLs. β-Actin was included as an internal loading control. Numbers below blots indicate expression as measured by fold change. (F) Flow cytometry analysis of the proliferation index of cells inside the tumor, as measured by the mean fluorescence intensity of Ki67 staining. (G) Flow cytometry analysis of the frequency of CFSE-labeled, E7-specific CTLs in the tumors of mice that received adoptive transfer, together with either siGFP or siNanog. (H) Flow cytometry analysis of the frequency of apoptotic (active caspase-3+) cells in the tumors of siGFP- or siNanog-treated mice, with or without adoptive transfer of E7-specific CTLs. Error bars represent mean ± SD.