Cancer cell reprogramming: a promising therapy converting malignancy to benignity

Abstract

In the past decade, remarkable progress has been made in reprogramming terminally differentiated somatic cells and cancer cells into induced pluripotent cells and cancer cells with benign phenotypes. Recent studies have explored various approaches to induce reprogramming from one cell type to another, including lineage-specific transcription factors-, combinatorial small molecules-, microRNAs- and embryonic microenvironment-derived exosome-mediated reprogramming. These reprogramming approaches have been proven to be technically feasible and versatile to enable re-activation of sequestered epigenetic regions, thus driving fate decisions of differentiated cells. One of the significant utilities of cancer cell reprogramming is the therapeutic potential of retrieving normal cell functions from various malignancies. However, there are several major obstacles to overcome in cancer cell reprogramming before clinical translation, including characterization of reprogramming mechanisms, improvement of reprogramming efficiency and safety, and development of delivery methods. Recently, several insights in reprogramming mechanism have been proposed, and determining progress has been achieved to promote reprogramming efficiency and feasibility, allowing it to emerge as a promising therapy against cancer in the near future. This review aims to discuss recent applications in cancer cell reprogramming, with a focus on the clinical significance and limitations of different reprogramming approaches, while summarizing vital roles played by transcription factors, small molecules, microRNAs and exosomes during the reprogramming process.

Keywords: Benign; Cancer cell reprogramming; Cancer stem cell; Exosome; Induced pluripotent stem cell; Malignancy; MicroRNA; Pluripotency; Small molecule; Transcription factor.

Fig. 1

Emerging therapeutic strategies against primary cancer. Researchers and clinicians have explored three mainstay strategies for cancer treatment: regulating the immune responses to cancer cells; reprogramming cancer cells into benign cells; directly eradicating cancer stem cells. Immunotherapy and targeted therapy have better therapeutic performance comparing to conventional chemo-/radio-therapy, but their effects are still suffering from the existence of cancer stem cells and heterogeneity. Cancer cell reprogramming therapy elicits a potential to convert cancer cells into benign cells regardless of cell subtypes. Although cancer cell reprogramming therapy has not entered clinical trials to date, progress still continues

Fig. 2

Epigenetic landscape of cell reprogramming and development. Cells undergo extensive epigenetic modifications from pluripotency to a terminally differentiated state. Cell fates have been identified as flexible and reversible, suggesting that terminally differentiated cells, such as cancer cells, are feasible to be reprogrammed back into a pluripotent stage via re-activation of epigenetic barriers. The induced pluripotent stem cells can further differentiate into benign cells with distinct lineages. Unlike indirect cancer cell reprogramming, direct cancer cell reprogramming allows cells to bypass the pluripotent stage so that they can be directly converted into other types of cells by transcription factors, small molecules, microRNAs or exosome