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 pO(2)-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.

Hypoxia-resistant profile implies vulnerability of cancer stem cells to physiological agents, which suggests new therapeutic targets

“…Anaplastic tumors are constantly developing successful strategies to survive in hypoxia, this being an exclusive prerogative essential for maintaining their stemness 2 . The prerogative is coupled to a biochemical marker that was discovered by Warburg as long ago as 1925, opening the way to explore cancer cell metabolism.…”

Stemness-Related Transcriptional Factors and Homing Gene Expression Profiles in Hepatic Differentiation and Cancer

“…Carcinogenesis is a multistep process that transforms differentiated tissues into an immature cell population (1). This neoplastic progression in cancer cells causes an accumulation of genetic and epigenetic alterations by multiple DNA mutations and clonal selection.…”

“…They play critical roles in maintaining the pluripotency and self-renewal (stemness) characteristics of human embryonic stem cells (ESCs) (5) and contribute to the reprogramming of adult somatic cells into an ESC-like state (4). Their gene expression has been reported in cancer stem cell niche and tumor cells in higher levels than in nontumor tissues (1). Overexpression of OCT3/4, SOX2 and NANOG has been detected in several cancers, including breast (6), head immature undifferentiated phenotypes and to acquire novel molecular signatures (2).…”

Reversible Mitochondrial DNA Accumulation in Nuclei of Pluripotent Stem Cells

“…Although various reasons for the low reprogramming efficiency have been discussed [20,21], one possibility is that frequent nuclear DNA damage during reprogramming lowers the reprogramming efficiency [20,21,[24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41]. The effect of the oncogenes c-Myc and Klf4 may contribute to this observation [42,43]. Despite these significant changes in the genomic DNA, nuclear trafficking and/or amplification of mtDNA has never been considered as a potential player in the process of reprogramming.…”