All Things Stem Cell

Recently, many papers have come out that highlight connections between cancer and induced pluripotent stem cells (iPSCs), the latter of which was discussed previously. These papers hold many implications for not only iPSCs, but for our understanding of cancer as well. Additionally, these papers should not at all be thought of as invalidating the importance of iPSCs for studying and treating future therapies, but they should help us better understand what iPSCs are and how to use them appropriately.

The most recent and most publicized link between iPSCs and cancer is p53. p53, also known as protein 53 (53 referring to its molecular mass), is a well-studied protein whose normal function is important in preventing cancer. Though p53 has many different roles, they are quite related. In essence, the job of p53 is to make sure the cell does not accumulate DNA damage, or DNA mutations, which could eventually make the cell cancerous. When a cell has its DNA damaged, often from external stresses, p53 stops the normal cell cycle to fix the DNA damage. If the damage is too great to repair, p53 can prevent the cell from dividing, which would create more damaged cells; p53 initiates programmed cell death, or apoptosis. The potential tumor cell dies. Overall, p53 functions as a “tumor suppressor” to prevent abnormal cells from occurring and multiplying into a cancer (Vazquez et al., 2008). Consequently, it has been found that p53 is mutated in approximately 50% of all human tumors, and other tumors may have mutations in the pathway regulating p53 activity (Vazquez et al., 2008). p53 is therefore well-studied as an oncogene, or a gene that when not functioning normally can contribute to a normal cell becoming cancerous.

So what does p53 have to do with iPSCs? One recently discovered connection is with the generation of iPSCs. Recently, many research groups discovered that when p53 is deleted from, or damaged in, their cells, they could more easily become iPSCs (Hong et al., 2009; Kawamura et al., 2009; Utikal et al., 2009; Li et al., 2009; Zhao et al., 2008). As posted earlier, iPSCs are cells that were originally from adult tissues, but have been “reprogrammed” to be pluripotent stem cells, or stem cells able to become all the adult cells of the body, looking and functioning nearly identical to human embryonic stem cells (hESCs) (Takahashi et al., 2007; Yu et al., 2007).

To create iPSCs, adult cells are exposed to “reprogramming factors,” or transcription factors, thought to be important for pluripotency. Researchers have tested different groups of reprogramming factors, and originally four different factors were found to work best. However, the process is rather inefficient; only a very small percentage of cells exposed to the set of factors actually becomes reprogrammed. Shinya Yamanaka’s group, one of the two that first created human iPSCs, found that iPSC generation increased by up to 20% in cells without p53 (Hong et al., 2009). Other groups have reported similar results; cells with non-functional p53 mutants, or mutations in the p53 pathway, had increased reprogramming efficiencies (Utikal et al., 2009; Li et al., 2009), some even with fewer reprogramming factors than are usually needed (Kawamura et al., 2009). Some researchers speculate that p53 is acting to protect the cells from the DNA damage that the reprogramming factors can cause, as p53 is turned on immediately after the factors are introduced (Kawamura et al., 2009). For a more detailed review of these papers, check out (Dolgin, 2009). Overall, these many separate recent reports clearly show the importance of p53 in creating iPSCs. As a side note, a very interesting remaining question is how exactly these cells become pluripotent after bypassing p53 activity.

What are the implications of the fact that decreasing p53 activity greatly increases iPSC derivation? It could imply that just about any cell in the human body has a greatly increased potential to initiate a cancer by losing p53 activity. Interestingly, this actually runs counter to the cancer stem cell hypothesis, which theorizes that not just any cell, but specifically a rare stem cell, may gain mutations over time and give rise to some cancers (see Figure)(Kawamura et al., 2009). This is a somewhat frightening prospect, suggesting that a far greater number of cells have tumorigenic potential than believed by the stem cell hypothesis, though it may help scientists better understand how cancer develops and consequently how it can be successfully fought.

The cancer stem cell hypothesis (top) theorizes that a (rare) mutated stem cell may gain mutations over time and give rise to cancer. Running counter to this (bottom), some evidence suggests that a mutation in p53, causing it to no longer function, in any given cell (including, but not only, stem cells) may greatly increase the cell’s potential to initiate a cancer.

p53 is not the only cancer-related factor important for the creation of iPSCs; most of the reprogramming factors have actually been suggested to be oncogenes and implicated in the generation of different cancers. C-Myc is a widely-used iPSC reprogramming factor (Takahashi et al., 2008) and is also responsible for the regulation of a very large number of different genes within the cell, including controlling cell proliferation. When c-Myc is over-expressed, or expressed at higher levels than normal, it can cause cancer, and high levels of c-Myc have been detected in many different tumor types (Hermeking, 2003). Other studies have shown that all the other reprogramming factors may also be oncogenes, with one exception (Lin28, which has been shown to not even be required for iPSC generation) (Liu, 2008A). But is this really that surprising? The reprogramming factors are genes expressed in embryonic, pluripotent tissues that are thought to be involved in making the tissue pluripotent. The cells that create cancerous tumors are most likely multipotent, being able to become multiple different cell types, because tumors are heterogenous tissues. Consequently, it is not that surprising that researchers have found connections between these embryonic reprogramming factors, and other embryonic-specific genes, and the creation of tumors and cancer stem cells (Wong et al., 2008; Gunaratne, 2009).

While such reports have caused some researchers to label iPSCs as “man-made cancer stem cells” (Liu, 2008B), it is important to keep in mind the distinct differences between iPSCs and cancer. iPSCs indeed, by definition, can create teratoma tumors when injected into animals and express many embryonic proteins which allow them to differentiate into multiple cell types just like tumors can. However, unlike cancer, iPSCs are grown in laboratories under controlled settings and it is only when they are undifferentiated that they have these tumorigenic potentials. To be used in therapies all cells must be carefully differentiated to the desired, adult cell type. iPSCs must lose their multipotency and consequently their tumorigenic potential. Researchers are currently working on many ways to make iPSCs safer for therapeutic use: using p53 to select for iPSCs that have no introduced DNA damage (Kawamura et al., 2009), optimizing the purification of differentiated populations, improving transient expression of the reprogramming genes, and more. Aside from therapies and regenerative medicine, iPSCs have great potential for creating cellular disease models, creating cell lines from reprogrammed diseased tissue to allow for greater study in laboratories; cancer cells cannot do this in the same fashion. Despite their similarities, iPSCs have the ability to offer scientists many important research opportunities that studying cancer by itself does not.

Understanding the connections between iPSCs and cancer has great potential for improving our treatment of cancer. Because iPSCs are reprogrammed adult cells, it may be possible to think of tumors as reprogrammed adult cells as well. Since iPSCs can be differentiated into specific, desired cell types, some researchers think it may also be possible to differentiate tumors into non-malignant cell types. However, the human body is a much more complicated environment than cells in a controlled laboratory setting (Blelloch et al., 2004; Yang et al., 2008). To potentially improve our abilities to treat cancer, it will take a great open-mindedness and understanding of not only the behavior of these cells in the laboratory, but also of their possible similarities to cancer initiation as it occurs in an organism.

References

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Dolgin, E. Immortality improves cell reprogramming: Knocking out genes with a role in cancer prevention helps produce stem cells. Nature News. 2009.
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Gunaratne, P. H. Embryonic Stem Cell MicroRNAs: Defining Factors in Induced Pluripotent (iPS) and Cancer (CSC) Stem Cells? Curr Stem Cell Res Ther. 2009.
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Hermeking, H. The MYC Oncogene as a Cancer Drug Target. Current Cancer Drug Targets. 2003. 3(3): 163-175.
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