Reprogramming of gastrointestinal cancer cells

Abstract

Cell reprogramming reverts cells to multipotent, preprogrammed states by re-establishing epigenetic markers. It can also induce considerable malignant phenotype modification. Because key events in cancer relapse and metastasis, including epithelial-mesenchymal transition phenotypes, are regulated primarily by reversible and transient epigenetic modifications rather than the accumulation of irreversible and stable genetic abnormalities, studying dynamic mechanisms regulating these biological processes is important. Transcription factors for induced pluripotent stem cells and non-coding microRNAs allow pluripotent phenotype induction. We present the current knowledge of the possible applications of cell reprogramming in reducing aggressive phenotype expression, which can induce tumor cell hibernation and maintain appropriate phenotypes, thereby minimizing relapse and metastasis after surgical resection of gastrointestinal cancer.

Figure 1

Cellular reprogramming in normal and cancer cells. Cellular reprogramming in normal and cancer cells can be viewed globally as a mechanism of phenotype reversal of parental cells through the modulation of epigenetic status into a more undifferentiated state. Defined transcription factors (Yamanaka cocktail)‐induced reprogramming is involved in the regulation of mesenchymal–epithelial transition (MET), which is controlled by a group of microRNAs (miR) through ZEB1/ZEB2 and TGFβR2. Those miRNAs play a role in global demethylation through AOF1/2 and MECP1/2. In contrast to normal cell reprogramming (upper panel), cancer cell reprogramming (lower panel) remains obscure. The reverse of MET, epithelial–mesenchymal transition (EMT), results in a chemotherapy‐resistant phenotype. Thus, reprogramming is supposed to open the silent chromatin through DNA demethylation and activate histone codes, which would elicit re‐expression of tumor suppressor genes, pushing cancer cells into a more benign phenotype. Further investigation would provide insight into how much of the tumor phenotype could be reversed through the contribution of reversible epigenetic and irreversible genetic changes in cancer. Reprogramming cancer cells might become a promising method for reversing or attenuating malignancy for therapeutic purposes. iPCC, induced pluripotent stem cell‐like cancer cell; iPSC, induced pluripotent stem cell; TGF, transforming growth factor; TSG, tumor suppressor gene.