I have recently (1 July, 2013) completed a review of recent stem cell developments that touches upon these issues surrounding iPSCs, and will therefore share with you an admittedly brief distillation of some of my findings as they related to your excellent query:
The Heart of Induced Pluripotent Stem Cells (iPSCs)
IPSCs or induced pluripotent stem cells are cells that were originally from adult tissues, but have been “reprogrammed” to be pluripotent stem cells (stem cells able to become all the adult cells of the body), generally via forcing the expression in adult cells of proteins essential to the ESC identity, through transduction of these adult cells with a retrovirus vector containing the DNA for the key proteins, although non-retroviral approached have also been shown possible, and thus functioning with near-identity to human embryonic stem cells (hESCs), hence effectively after reprogramming constituting an embryonic stem cell (ESC) state [1,2]. These iPSCs were first created with mouse cells in 2006 [3], and later with human cells in 2007 [4]. And of course, like human embryonic stem cells (hESCs), iPSCs proliferate near-indefinitely which along with their pluripotency, makes them highly attractive in regenerative medicine.
The Shinya Yamanaka team that was one of the first to create human iPSCs demonstrated that in cells without the p53 tumor suppressor, iPSC generation was increased by up to 20% [5], and this was confirmed in other studies where it was observed that cells with non-functional p53 mutants or p53 pathway mutations also xhibited increased reprogramming efficiencies [6,7].
These findings, of decreasing p53 activity greatly inducing iPSC derivation, collectively would appear to imply that virtually any human cell harbors a highly enhanced potential to initiate a cancer via the loss of p53 activity, an implication that if fully confirmed stands against and in contradiction to the cancer stem cell hypothesis that holds that only and specifically rare stem cells can gain mutations over time to give rise to cancers [8], and - as I have independently argued in these forums - this entails that a rather high and "common" (not rare) number of cells hold intrinsic tumorigenic potential, tumorigenicity, than dictated the cancer stem cell hypothesis; here we have the prospect that a p53 mutation in any cell - not just stem cells - dramatically enlarges as cell's potential for initiating a cancer.
However, some caution is required here, because we could too casually as some investigators (Shi Liu and others) conceive of iPSCs as essentially “man-made cancer stem cells [9,10] when in fact there are important differences: so although it is true that iPSCs can induce teratoma tumors when injected into animal hosts and also express certain embryonic proteins enabling them,, like tumor cells, to differentiate into multiple cell types, nonetheless in stark contrast, iPSCs, being gestated in controlled laboratory settings, display tumorigenic potential only when they are undifferentiated, but to have therapeutic applicability, iPSCs, like all cells, must be carefully differentiated to some target adult cell type, so that iPSCs must lose their multipotency that means loss also of their tumorigenic potential.
New Developments: Shaking Up the Old Complacency
However I will mention two new scientific and in particular translational breakthroughs that refine and extend our understanding of these issues in important ways.
First, researchers in China and at the Baylor College of Medicine [11] have recently examined via RT-PCR the association between induced pluripotent stem cell (iPS)-related genes and the biological behavior of human colorectal cancer (CRC) cells, finding (1) an overlap between iPS-related genes and CSCs in CRC, and more specifically, that the transcript levels of the iPS-related genes OCT4, SOX2, and especially NANOG are strikingly high in CSCs-enriched human CRC tumor cells, suggesting that RNA interference of NANOG (a member of the homeobox family of DNA binding transcription factors that is expressed in embryonic stem cells (ESCs) and is thought to be a key factor in maintaining pluripotency), could short-circuit or "truncate" the aggressiveness of CRC cells by (1) suppressing proliferation, invasion, tumorigenicity and by (2) increasing their sensitivity to chemotherapies like 5-FU. This development supports the view of overlapping, but non-coextensive, phenomenon, namely of iPSCs and CSCs (cancer stems cells) as distinct but significantly overlapping processes and mechanisms with the potential to leverage some shared elements like the NANOG transcription factor to significantly degrade the aggressiveness of CSC-enriched colorectal cancer (CRC) cells, in a fashion that I regard as holding some parallel with epigenetic phenomenon, of silencing certain entities (like NANOG) that appear to fuel to tumorigenicity and aggressiveness of tumor cells, while possibly also enhancing selective chemosensitivity (in their study, to 5-FU-based therapies).
The second "watershed" development has been that Japanese researchers at the Institute for Frontier Medical Sciences at Kyoto University [12] for the first time have isolated and characterized so-called induced pluripotent cancer stem-like cells (iCSCs) - in essence self-renewing pluripotent cell clones - which exhibit defining properties of cancer stem cells, namely self-renewal and tumorigenicity in vivo. It is hoped that this new type of stem-like cells may provide a model for carcinogenesis with high goodness-of-fit. Starting with unstable induced epithelial stem cell (iESC) lines, the researchers derived stable iCSC lines. But again I would not we have structurally and architecturally overlap but not identity: although iCSCs share with iPSCs the expression of pluripotent marker genes, they lack REX1 and LIN28 expression, while again in contrast, exhibiting the expression of somatic marker genes EMP1 and PPARγ. In addition the pluripotent markers CDH1 and SSEA4 were weakly expressed in both iESCs and iCSCs, but these were highly expressed in iPSCs, and - still another contrast - TRA-1-60 expression was observed in iPSCs, but not in either iESCs nor iCSCs.
Summary and Forward Perspective
It is clear therefore from the above that despite certain important overlaps and shared phenomena, we must hold distinct these entities of:
(1) induced pluripotent stem cells (iPSCs),
(2) induced pluripotent cancer stem-like cells (iCSCs), and
(3) "classical" (non-induced) cancer stem cells (CSCs).
We must also attend to the conceptual inconsistencies between the cancer stem cell (CSC) hypothesis on the one hand and the operation and functionality induced pluripotent stem cells (iPSCs) on the other, and - I would suggest - possibly view the newly developed induced pluripotent cancer stem-like cells (iCSCs) as in some sense potentially playing a bridging role between these two conceptually divergent perspectives. I perceive the just published findings of UK researchers [13], in using Herpesvirus saimiri (HSV)-based vectors to reprogram a Ewing's Sarcoma family tumor cell line (A673) to produce stem cell-like colonies, as provisionally enhancing the potential reach of induced pluripotent cancer stem-like cells (iCSCs) approach. At this juncture therefore we have overlapping but still appreciably conceptually dueling approaches for accounting for the processes of carcinogenesis and tumorigenesis at the stem cell level, and I would argue we therefore need to tease out the different predictions these distinct models are making about key phenomena that may be testable in a preclinical, clinical and translational context, to help guide further research in the most productive direction for real-world gains in the human therapeutic arena.
References
1. Takahashi K, Tanabe K, Ohnuki M., et al. Induction of Pluripotent Stem Cells from Adult Human Fibroblasts. Cell. 2007. 131: 1-12.
2. Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells. Science. 2007. 318(5858): 1917-1920.
3. Takahashi K, Yamanaka S. Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell. 2006. 126: 663–676.
4. Takahashi K, Tanabe K, Ohnuki M., et al. Induction of Pluripotent Stem Cells from Adult Human Fibroblasts. Cell. 2007. 131: 1-12.
5. Hong H, Takahashi K, Ichisaka T, et al. Suppression of induced pluripotent stem cell generation by the p53-p21 pathway. Nature 27 2009 August 460, 1132-1135.
6. Utikal J, Polo JM, Stadtfeld M, et al. Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature. 2009. 460: 1145-1148.
7. Li H, Collado M, Villasante A, et al. The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature. 2009. 460: 1136-1139.
8. Kawamura T, Suzuki J, Wang YV, et al. Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature. 2009. 460: 1140-1144.
9. Liu, S. V. iPS Cells: A More Critical Review. Stem Cells and Development. 2008A. 17: 391-397.
10. Liu S. Endorsing a more cautious approach for iPSC research and development. Logical Biology 10 (2):49-51, 2010.
11. Shi Z, Bai R, Fu ZX, Zhu YL, Wang RF, Zheng S. Induced pluripotent stem cell-related genes influence biological behavior and 5-fluorouracil sensitivity of colorectal cancer cells. J Zhejiang Univ Sci B 2012; 13(1):11-9.
12. Nagata S, Hirano K, Kanemori M, Sun LT, Tada T. Self-renewal and pluripotency acquired through somatic reprogramming to human cancer stem cells. PLoS One 2012; 7(11):e48699.
13. Brown HF, Unger C, Whitehouse A. Potential of Herpesvirus Saimiri-Based Vectors To Reprogram a Somatic Ewing's Sarcoma Family Tumor Cell Line. J Virol 2013; 87(12):7127-39.
I have recently (1 July, 2013) completed a review of recent stem cell developments that touches upon these issues surrounding iPSCs, and will therefore share with you an admittedly brief distillation of some of my findings as they related to your excellent query:
The Heart of Induced Pluripotent Stem Cells (iPSCs)
IPSCs or induced pluripotent stem cells are cells that were originally from adult tissues, but have been “reprogrammed” to be pluripotent stem cells (stem cells able to become all the adult cells of the body), generally via forcing the expression in adult cells of proteins essential to the ESC identity, through transduction of these adult cells with a retrovirus vector containing the DNA for the key proteins, although non-retroviral approached have also been shown possible, and thus functioning with near-identity to human embryonic stem cells (hESCs), hence effectively after reprogramming constituting an embryonic stem cell (ESC) state [1,2]. These iPSCs were first created with mouse cells in 2006 [3], and later with human cells in 2007 [4]. And of course, like human embryonic stem cells (hESCs), iPSCs proliferate near-indefinitely which along with their pluripotency, makes them highly attractive in regenerative medicine.
The Shinya Yamanaka team that was one of the first to create human iPSCs demonstrated that in cells without the p53 tumor suppressor, iPSC generation was increased by up to 20% [5], and this was confirmed in other studies where it was observed that cells with non-functional p53 mutants or p53 pathway mutations also xhibited increased reprogramming efficiencies [6,7].
These findings, of decreasing p53 activity greatly inducing iPSC derivation, collectively would appear to imply that virtually any human cell harbors a highly enhanced potential to initiate a cancer via the loss of p53 activity, an implication that if fully confirmed stands against and in contradiction to the cancer stem cell hypothesis that holds that only and specifically rare stem cells can gain mutations over time to give rise to cancers [8], and - as I have independently argued in these forums - this entails that a rather high and "common" (not rare) number of cells hold intrinsic tumorigenic potential, tumorigenicity, than dictated the cancer stem cell hypothesis; here we have the prospect that a p53 mutation in any cell - not just stem cells - dramatically enlarges as cell's potential for initiating a cancer.
However, some caution is required here, because we could too casually as some investigators (Shi Liu and others) conceive of iPSCs as essentially “man-made cancer stem cells [9,10] when in fact there are important differences: so although it is true that iPSCs can induce teratoma tumors when injected into animal hosts and also express certain embryonic proteins enabling them,, like tumor cells, to differentiate into multiple cell types, nonetheless in stark contrast, iPSCs, being gestated in controlled laboratory settings, display tumorigenic potential only when they are undifferentiated, but to have therapeutic applicability, iPSCs, like all cells, must be carefully differentiated to some target adult cell type, so that iPSCs must lose their multipotency that means loss also of their tumorigenic potential.
New Developments: Shaking Up the Old Complacency
However I will mention two new scientific and in particular translational breakthroughs that refine and extend our understanding of these issues in important ways.
First, researchers in China and at the Baylor College of Medicine [11] have recently examined via RT-PCR the association between induced pluripotent stem cell (iPS)-related genes and the biological behavior of human colorectal cancer (CRC) cells, finding (1) an overlap between iPS-related genes and CSCs in CRC, and more specifically, that the transcript levels of the iPS-related genes OCT4, SOX2, and especially NANOG are strikingly high in CSCs-enriched human CRC tumor cells, suggesting that RNA interference of NANOG (a member of the homeobox family of DNA binding transcription factors that is expressed in embryonic stem cells (ESCs) and is thought to be a key factor in maintaining pluripotency), could short-circuit or "truncate" the aggressiveness of CRC cells by (1) suppressing proliferation, invasion, tumorigenicity and by (2) increasing their sensitivity to chemotherapies like 5-FU. This development supports the view of overlapping, but non-coextensive, phenomenon, namely of iPSCs and CSCs (cancer stems cells) as distinct but significantly overlapping processes and mechanisms with the potential to leverage some shared elements like the NANOG transcription factor to significantly degrade the aggressiveness of CSC-enriched colorectal cancer (CRC) cells, in a fashion that I regard as holding some parallel with epigenetic phenomenon, of silencing certain entities (like NANOG) that appear to fuel to tumorigenicity and aggressiveness of tumor cells, while possibly also enhancing selective chemosensitivity (in their study, to 5-FU-based therapies).
The second "watershed" development has been that Japanese researchers at the Institute for Frontier Medical Sciences at Kyoto University [12] for the first time have isolated and characterized so-called induced pluripotent cancer stem-like cells (iCSCs) - in essence self-renewing pluripotent cell clones - which exhibit defining properties of cancer stem cells, namely self-renewal and tumorigenicity in vivo. It is hoped that this new type of stem-like cells may provide a model for carcinogenesis with high goodness-of-fit. Starting with unstable induced epithelial stem cell (iESC) lines, the researchers derived stable iCSC lines. But again I would not we have structurally and architecturally overlap but not identity: although iCSCs share with iPSCs the expression of pluripotent marker genes, they lack REX1 and LIN28 expression, while again in contrast, exhibiting the expression of somatic marker genes EMP1 and PPARγ. In addition the pluripotent markers CDH1 and SSEA4 were weakly expressed in both iESCs and iCSCs, but these were highly expressed in iPSCs, and - still another contrast - TRA-1-60 expression was observed in iPSCs, but not in either iESCs nor iCSCs.
Summary and Forward Perspective
It is clear therefore from the above that despite certain important overlaps and shared phenomena, we must hold distinct these entities of:
(1) induced pluripotent stem cells (iPSCs),
(2) induced pluripotent cancer stem-like cells (iCSCs), and
(3) "classical" (non-induced) cancer stem cells (CSCs).
We must also attend to the conceptual inconsistencies between the cancer stem cell (CSC) hypothesis on the one hand and the operation and functionality induced pluripotent stem cells (iPSCs) on the other, and - I would suggest - possibly view the newly developed induced pluripotent cancer stem-like cells (iCSCs) as in some sense potentially playing a bridging role between these two conceptually divergent perspectives. I perceive the just published findings of UK researchers [13], in using Herpesvirus saimiri (HSV)-based vectors to reprogram a Ewing's Sarcoma family tumor cell line (A673) to produce stem cell-like colonies, as provisionally enhancing the potential reach of induced pluripotent cancer stem-like cells (iCSCs) approach. At this juncture therefore we have overlapping but still appreciably conceptually dueling approaches for accounting for the processes of carcinogenesis and tumorigenesis at the stem cell level, and I would argue we therefore need to tease out the different predictions these distinct models are making about key phenomena that may be testable in a preclinical, clinical and translational context, to help guide further research in the most productive direction for real-world gains in the human therapeutic arena.
References
1. Takahashi K, Tanabe K, Ohnuki M., et al. Induction of Pluripotent Stem Cells from Adult Human Fibroblasts. Cell. 2007. 131: 1-12.
2. Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells. Science. 2007. 318(5858): 1917-1920.
3. Takahashi K, Yamanaka S. Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell. 2006. 126: 663–676.
4. Takahashi K, Tanabe K, Ohnuki M., et al. Induction of Pluripotent Stem Cells from Adult Human Fibroblasts. Cell. 2007. 131: 1-12.
5. Hong H, Takahashi K, Ichisaka T, et al. Suppression of induced pluripotent stem cell generation by the p53-p21 pathway. Nature 27 2009 August 460, 1132-1135.
6. Utikal J, Polo JM, Stadtfeld M, et al. Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature. 2009. 460: 1145-1148.
7. Li H, Collado M, Villasante A, et al. The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature. 2009. 460: 1136-1139.
8. Kawamura T, Suzuki J, Wang YV, et al. Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature. 2009. 460: 1140-1144.
9. Liu, S. V. iPS Cells: A More Critical Review. Stem Cells and Development. 2008A. 17: 391-397.
10. Liu S. Endorsing a more cautious approach for iPSC research and development. Logical Biology 10 (2):49-51, 2010.
11. Shi Z, Bai R, Fu ZX, Zhu YL, Wang RF, Zheng S. Induced pluripotent stem cell-related genes influence biological behavior and 5-fluorouracil sensitivity of colorectal cancer cells. J Zhejiang Univ Sci B 2012; 13(1):11-9.
12. Nagata S, Hirano K, Kanemori M, Sun LT, Tada T. Self-renewal and pluripotency acquired through somatic reprogramming to human cancer stem cells. PLoS One 2012; 7(11):e48699.
13. Brown HF, Unger C, Whitehouse A. Potential of Herpesvirus Saimiri-Based Vectors To Reprogram a Somatic Ewing's Sarcoma Family Tumor Cell Line. J Virol 2013; 87(12):7127-39.
Cancer stem cells” (CSCs), being defined as those cells within a tumor that have properties of stem cells: self-renewal and the ability for differentiation into multiple cell types that occur in tumors.
Cancer stem cells reprogramming as an emerging tool in modeling cancer. The normal development denotes a passage from a pluripotent (zygote) to a “less potent state” (terminal differentiated adult tissues). During this process, adult stem cells (ASCs) in adult tissues suffer multiple tumorigenic “hits” that lead to the generation of “aberrantly reprogrammed” cancer cells, forced to be maintained in an intermediate degree of cellular differentiation. Induced pluripotency is now being employed on cancer cell lines or patients’ tumors (named induced pluripotent cancer stem cells or iPCSCs).
iPCSCs cells epigenetically and transcriptionally resemble the ESC state and the cancer genome seems to be repressed in a pluripotent state. In some cases the iPCSCs may exhibit early stage phenotypes corresponding to partial expression of the reprogrammed cancer genome, constituting in this way a live cell model to study cancer progression. Moreover, these iPCSCs have the ability to re-differentiate back to the original or a different terminal differentiated cell lineage, losing along this process their tumorigenic and metastatic properties (find out more here: https://ptglab.com/news/blog/cancer-stem-cells-as-a-key-to-cure-cancer/)
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