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.
View: Text | PDF
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

×

Figure 1

Immune selection enhances the stem-like properties and tumorigenicity of human cancer cells.

Options: View larger image (or click on image) Download as PowerPoint
Immune selection enhances the stem-like properties and tumorigenicity of...
(A) Diagram depicting the process of in vitro immune selection of human cervical cancer cells. (B and C) Flow cytometry analysis of the frequency of apoptotic (active caspase-3+) cells in the P0, P1, P2, and P3 populations (B) after incubation with E7-specific CTLs at a 1:1 ratio for 4 hours (isotype control staining is indicated by solid gray regions; anti-active caspase-3 staining is indicated by the black lines) or (C) after intracellular delivery of granzyme B. (D) Growth rate of P0 versus P3 cells in culture. Cells were harvested at the indicated times and counted after trypan blue staining to exclude dead cells. (E) Western blot analysis of expression of cyclin A and p21 in P0 versus P3 cells. β-Actin was included as an internal loading control. Numbers below blots indicate expression as measured by fold change. (F) Sphere-forming capacity of P0 versus P3 cells in low-density suspension culture. Original magnification, ×40. (G) Tumorigenicity of P0 versus P3 cells inoculated at indicated doses into 5 NOD/SCID mice per group. (H) Tumor burden 12 days after injection of 103 P0 or P3 cells. (I) Flow cytometry analysis of stemness markers in P0, P1, P2, and P3 populations (isotype control staining is indicated by solid gray region; staining for stemness markers is indicated by black lines). Error bars represent mean ± SD.