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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Research Article Oncology

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 8

Nanog promotes a stem-like and immune-resistant phenotype in multiple types of human cancer.

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Nanog promotes a stem-like and immune-resistant phenotype in multiple ty...
(A) Western blot analysis of Nanog expression in various human cancer lines. β-Actin was included as an internal loading control. (B) Western blot analysis of expression of Nanog, Tcl1a, pAkt, cyclin A, and Mcl-1 in human cancer cells treated with siGFP or siNanog. β-Actin was included as an internal loading control. (A and B) Numbers below blots indicate expression as measured by fold change. (C) Sphere-forming capacity of human cancer cells treated with siGFP or siNanog in low-density suspension culture (D) Flow cytometry analysis of the frequency of apoptotic (active caspase-3+) cells in human cancer cells treated with siGFP or siNanog after incubation with E7-specific CTLs at a 1:1 ratio for 4 hours (isotype control staining is indicated by solid gray region; anti-active caspase-3 staining is indicated by black lines). Original magnification, ×40. Error bars represent mean ± SD.