Deconstructing Stem Cell Tumorigenicity: A Roadmap to Safe Regenerative Medicine

Department of Cell Biology and Human Anatomy & Stem Cell Program, University of California Davis School of Medicine, Sacramento, CA, USA.
Stem Cells (Impact Factor: 6.52). 05/2009; 27(5):1050-6. DOI: 10.1002/stem.37
Source: PubMed


Many of the earliest stem cell studies were conducted on cells isolated from tumors rather than from embryos. Of particular interest was research on embryonic carcinoma cells (EC), a type of stem cell derived from teratocarcinoma. The EC research laid the foundation for the later discovery of and subsequent work on embryonic stem cells (ESC). Both ESC isolated from the mouse (mESC) and then later from humans (hESC) shared not only pluripotency with their EC cousins, but also robust tumorigenicity as each readily form teratoma. Surprisingly, decades after the discovery of mESC, the question of what drives ESC to form tumors remains largely an open one. This gap in the field is particularly serious as stem cell tumorigenicity represents the key obstacle to the safe use of stem cell-based regenerative medicine therapies. Although some adult stem cell therapies appear to be safe, they have only a very narrow range of uses in human disease. Our understanding of the tumorigenicity of human induced pluripotent stem cells (IPSC), perhaps the most promising modality for future patient-specific regenerative medicine therapies, is rudimentary. However, IPSC are predicted to possess tumorigenic potential equal to or greater than that of ESC. Here, the links between pluripotency and tumorigenicity are explored. New methods for more accurately testing the tumorigenic potential of IPSC and of other stem cells applicable to regenerative medicine are proposed. Finally, the most promising emerging approaches for overcoming the challenges of stem cell tumorigenicity are highlighted.

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    • "Stem cell therapy has been proposed as a potential candidate for treating neurological diseases by inducing pluripotent stem cells into differentiated neurons (Alvarez et al. 2010; Yoo et al. 2013); however, many unaddressed risks remain in this context. A high risk of tumorigenesis transformed from the transplantation of differentiated neurons remains an obstacle to the clinical usage of stem cell therapies (Shih et al. 2007; Knoepfler 2009). To seek another approach for cell-based therapies, we suggested the differentiated fibroblasts as an alternative choice (Chen et al. 2012). "
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    • "In addition, the iPSCs and their differentiated stem cells should not form tumors. Compared with currently used animal models for intraspecies stem cell transplantation, the " Mouse Clone Model " is much more advantageous for the following investigations:Not exactly the same with each other genetically and have the potential to induce immune reaction Immunodeficient mouse model[29]Deficient immune system for various reasons Many different strains are available, such as nude-mice strains, etc. Some transplanted stem cells might result in tumors due to the weakened immune system " Mouse Clone Model " Theoretically identical with each other, and exactly the same between transplanted stem cells and mouse recipients In theory, no immune rejection reaction, and cannot form tumor due to the normal immune system Need tedious work and high techniques to generate a clone of mice to investigate the immune rejection of established stem cell lines, including iPSCs and various tissue-specific stem cells, and to select suitable stem cell lines and cloned mice based on the immune rejection data; to investigate the tumor formation of iPSCs and other stem cell lines and to select suitable stem cells and cloned mice that possess low or absent tumorigenicity based on the tumor formation assay[27]; to investigate, after the selection of applicable stem cells and mice, the appropriate stages of different stem cells for their transplantation; and to genetically decipher the mechanisms of immune rejection and tumor formation more precisely. Because the stem cells and the mouse clone are biologically " selves " , this model will provide much stronger and direct evidence for stem cell therapy, and further give instructions for patientspecific iPSC-based therapy clinically. "
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    • "Adult stem cells are present in somatic tissues, e.g., bone marrow or adipose tissue, and play a vital role to repair and replenish dying somatic cells and damaged tissues [27]. Despite their immense potential in tissue engineering applications, ESCs and iPSCs have been found to differentiate into tumor cells [28], severely limiting scopes of their clinical trials in humans. This makes mesenchymal stem cells (a type of adult stem cells) a viable and practical alternative to use in stem cell research, as there is no literature report till date that hMSCs express cancer genes under any circumstances [11] [27]. "
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