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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Apoptosis / genetics
-
Apoptosis / immunology
-
CD8-Positive T-Lymphocytes / immunology
-
CD8-Positive T-Lymphocytes / metabolism
-
CD8-Positive T-Lymphocytes / pathology
-
Cell Line, Tumor
-
Cell Proliferation
-
Colonic Neoplasms / genetics
-
Colonic Neoplasms / immunology*
-
Colonic Neoplasms / metabolism
-
Colonic Neoplasms / pathology
-
Female
-
Homeodomain Proteins / genetics
-
Homeodomain Proteins / immunology*
-
Homeodomain Proteins / metabolism
-
Mice
-
Mice, Inbred NOD
-
Mice, SCID
-
Nanog Homeobox Protein
-
Neoplasm Transplantation
-
Neoplastic Stem Cells / immunology
-
Neoplastic Stem Cells / metabolism*
-
Proto-Oncogene Proteins / genetics
-
Proto-Oncogene Proteins / immunology
-
Proto-Oncogene Proteins / metabolism
-
Proto-Oncogene Proteins c-akt / genetics
-
Proto-Oncogene Proteins c-akt / immunology
-
Proto-Oncogene Proteins c-akt / metabolism
-
Signal Transduction / genetics
-
Signal Transduction / immunology*
-
Transcription, Genetic / genetics
-
Transcription, Genetic / immunology
-
Transplantation, Heterologous
-
Tumor Escape*
Substances
-
Homeodomain Proteins
-
NANOG protein, human
-
Nanog Homeobox Protein
-
Proto-Oncogene Proteins
-
TCL1A protein, human
-
Proto-Oncogene Proteins c-akt