The involvement of a Nanog, Klf4 and c-Myc transcriptional circuitry in the intertwining between neoplastic progression and reprogramming

Abstract

One undisputed milestone of traditional oncology is neoplastic progression, which consists of a progressive selection of dedifferentiated cells driven by a chance sequence of genetic mutations. Recently it has been demonstrated that the overexpression of well-defined transcription factors reprograms somatic cells to the pluripotent stem status. The demonstration raises crucial questions as to whether and to what extent this reprogramming contributes to tumorigenesis, and whether the epigenetic changes involved in it are reversible. Here, we show for the first time that a tumor produced in vivo by a chemical carcinogen is the product of the interaction between neoplastic progression and reprogramming. The experimental model employed the prototype of ascites tumors, the Yoshida AH130 hepatoma and other neoplasias, including human melanoma. AH130 hepatoma was started in the liver by the carcinogen o-aminoazotoluene. This compound binds to and abolishes the p53 protein, producing a genomic instability that promotes both the neoplastic progression and the hepatoma reprogramming. Eventually this tumor contained 100% CD133⁺ elements and pO₂-dependent percentages of the three embryonic transcription factors Nanog, Klf4 and c-Myc. Once transferred into aerobic cultures, the minor cellular fraction expressing this triad generates various types of adherent cells, which are progressively substituted by non-tumorigenic elements committed to fibromuscular, neuronal and glial differentiation. This reprogramming appears to be accomplished stepwise, with the assembly of the triad into a sophisticated transcriptional, oxygen-dependent circuitry, in which Nanog and Klf4 antagonistically regulate c-Myc, and hence, cell hypoxia survival and cell cycle activation.

Keywords: :

• neoplastic progression
• tumor reprogramming
• p53 lack
• embryonic transcription factors
• cancer metabolism
• pO₂ and cell cycle

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed

Acknowledgments

The authors are indebted to Professor Paolo Romagnoli, Department of Anatomy and Histology of the University of Florence, for the electron microscopic figures. We are grateful Prof. P. Boyde, University of Cambridge, UK, for his help in the revision of the manuscript. This paper is dedicated to the memory of Prof. E. Ciaranfi and Prof. A. Fonnesu, who directly from Warburg’s and Krebs’s laboratories transmitted to us the intellectual commitment and the rigorous experimental skill required for studying cancer development. This work was supported by grants from Ente Cassa di Risparmio di Firenze, Istituto Toscano Tumori (ITT), Associazione Italiana per la Ricerca sul Cancro (AIRC), Regione Toscana and Ministero della Salute.