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Review
. 2019 Jan;76(1):45-65.
doi: 10.1007/s00018-018-2924-7. Epub 2018 Oct 3.

Potential application of cell reprogramming techniques for cancer research

Shigeo Saito  1   2 , Ying-Chu Lin  3 , Yukio Nakamura  4 , Richard Eckner  5 , Kenly Wuputra  6 , Kung-Kai Kuo  7 , Chang-Shen Lin  8   9 , Kazunari K Yokoyama  10   11
Affiliations
Review

Potential application of cell reprogramming techniques for cancer research

Shigeo Saito et al. Cell Mol Life Sci. 2019 Jan.

Abstract

The ability to control the transition from an undifferentiated stem cell to a specific cell fate is one of the key techniques that are required for the application of interventional technologies to regenerative medicine and the treatment of tumors and metastases and of neurodegenerative diseases. Reprogramming technologies, which include somatic cell nuclear transfer, induced pluripotent stem cells, and the direct reprogramming of specific cell lineages, have the potential to alter cell plasticity in translational medicine for cancer treatment. The characterization of cancer stem cells (CSCs), the identification of oncogene and tumor suppressor genes for CSCs, and the epigenetic study of CSCs and their microenvironments are important topics. This review summarizes the application of cell reprogramming technologies to cancer modeling and treatment and discusses possible obstacles, such as genetic and epigenetic alterations in cancer cells, as well as the strategies that can be used to overcome these obstacles to cancer research.

Keywords: Cancer stem cells; Epigenetics; Induced pluripotent stem cells; Organoid culture; Reactive oxygen species; Somatic cell nuclear transfer.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Schematic model of the interaction between reprogramming to pluripotency and tumorigenesis. The reprogramming of somatic cells to pluripotency is performed by overexpressing reprogramming factors (such as OCT4, KLF4, SOX2, c-MYC, NANOG, and miRNAs) and inhibiting tumor suppressor genes (such as those encoding p14ARF, p16Ink4a, p21Cip1, and p53), to reset their fate toward a state of pluripotency, which is a dedifferentiation process that resembles tumor development. Patient-specific or healthy iPSCs are used in cell-based therapy after inducing differentiation to appropriate types of cells, for transplantation into patients. For example, iPCCs were derived by introducing OSKM factors and knocking down vector shTP53 in tumor cells in a manner similar to that described in iPSC protocols. The teratomas that are formed after the transfer of iPCCs to SCID mice are then dissected out, and isolated cells can form putative CSC-like phenotypes. The various malignancy characteristics observed in iPCCs seem to depend on differences in tumor cell types. In contrast, CSCs can be derived by an OCT4-mediated dedifferentiation process in tumor progression, even in somatic cells, via the stable expression of telomerase, the H-Ras V12 mutant, and inhibition of the p53 and retinoblastoma protein (pRB) pathways. CSCs can also be derived directly from tumor cells via the overexpression of OCT4, NANOG, KLF4, and IGFBP3, in a dedifferentiating manner. Putative CSCs and iPCCs are expected to be used in studies of drug screening or cancer-initiation mechanisms in the field of human cancer therapeutics. Hypoxia enhances the reprogramming of somatic cells, and HIFs directly regulate the factors that are needed for self-renewal and multipotency in cancer cells and CSCs. Furthermore, hypoxia increases the production of ROS, which promote cell development and EMT in CSCs via the TGF-β signaling pathway and drive CSCs to produce VEGF, which induces angiogenesis
Fig. 2
Fig. 2
Schematic model of the mechanisms via which epigenesis, p53, and ROS‒hypoxia‒HIFs promote reprogramming efficiently and genome integrity in PSCs. Cancer cells with driver and passenger mutations might be overcome by epigenetic reprogramming and DNA repair to induce the formation of PSCs with correct plasticity. Active chromatin with active histone markers (H3K4me3, H3K79me2, H3Ac, and H3K27Ac) should be repressed by repressive markers (H3K9me3, H3K36me2/3, and H3K27me3) at specific regions by three different reprogramming methods (SCNT, iPSC, and DR). Forced expression of reprogramming factors increases the levels of ROS that are generated in mitochondria, which in turn causes DNA damage and undermines both reprogramming efficiency and the genomic integrity of iPSCs. Antioxidants can promote reprogramming efficiency and safeguard the stability of the genomes of iPSCs by inhibiting ROS production and exerting non-antioxidant functions, including modulating epigenetic modifiers, and histones
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