Possible Strategies to Reduce the Tumorigenic Risk of Reprogrammed Normal and Cancer Cells

Abstract

The reprogramming of somatic cells to pluripotent stem cells has immense potential for use in regenerating or redeveloping tissues for transplantation, and the future application of this method is one of the most important research topics in regenerative medicine. These cells are generated from normal cells, adult stem cells, or neoplastic cancer cells. They express embryonic stem cell markers, such as OCT4, SOX2, and NANOG, and can differentiate into all tissue types in adults, both in vitro and in vivo. However, tumorigenicity, immunogenicity, and heterogeneity of cell populations may hamper the use of this method in medical therapeutics. The risk of cancer formation is dependent on mutations of these stemness genes during the transformation of pluripotent stem cells to cancer cells and on the alteration of the microenvironments of stem cell niches at genetic and epigenetic levels. Recent reports have shown that the generation of induced pluripotent stem cells (iPSCs) derived from human fibroblasts could be induced using chemicals, which is a safe, easy, and clinical-grade manufacturing strategy for modifying the cell fate of human cells required for regeneration therapies. This strategy is one of the future routes for the clinical application of reprogramming therapy. Therefore, this review highlights the recent progress in research focused on decreasing the tumorigenic risk of iPSCs or iPSC-derived organoids and increasing the safety of iPSC cell preparation and their application for therapeutic benefits.

Keywords: induced pluripotent stem cells; organoids; regenerative medicine; reprogramming; therapeutic application; tumorigenic risk.

Figure 1

Methodologies of generating iPSCs and excluding tumorigenic iPSCs for therapeutic applications. Normal somatic cells are reprogrammed to iPSCs by the forced expression of stemness factors such as OCT4, KLF4, SOX2, c-MYC, NANOG, and LIN28 in cells. Supplementation of vitamin C, survivin inhibitor YM 155, CDK inhibitor etoposide, or purvalanol in iPSC cultures and RapaCasp9-G- and RapaCasp9-A-expressing gene-modified T cells were also generated. For the clinical transplantation safety of differentiated derivatives, tumor formation must be investigated using immunocompetent animals before clinical trials. Epigenetic regulators, such as AZA, valproic acid, and tranylcypromine, and cell signaling inhibitors, such as CHIR 99021 and Y27632, can be used as a substitute for genetic reprogramming factors to generate iPSCs. However, the tumorigenic risk of these chemical modulators in reprogramming requires further investigation.

Figure 2

Cancer cell reprogramming procedures that generate iPCSCs with (1) high or (2) low tumorigenic potential. Tumorigenesis of iPCSCs is evaluated using cell transfer to animal models. Cancer cell reprogramming using forced expression of stemness factors and chemical molecules, such as anticancer drugs and cell signaling inhibitors, is useful to induce epigenetic alterations and change the tumorigenic state of the cancer cells. The degree of malignancy of iPCSCs in xenografts appears to depend on the cell of origin of the cancer. CSCs can maintain the quiescent state in cell division, which may be a signal for drug resistance to cancer treatments. The arrows indicate the cell fate conversion and the correlated features.

Figure 3

Possible strategies for reducing the tumorigenic risk in cell reprogramming. The methods to reduce tumorigenic risk are listed in five representative groups. Recently, chemical reprogramming has been described as the most powerful therapeutic invention method. This scheme is modified based on Zhong et al. [164], Copyright © The Author(s) 2022. Published by Oxford University Press on behalf of the West China School of Medicine & West China Hospital of Sichuan University.