Hi Jahal,

Basically, in both types of cells the main mechanism is the activation of the

the human telomerase enzyme (hTERT), that is a responsible DNA polymerase for adding the telomere sequences to the end of the chromosomes that is not only actively express in stem cells but also in cancer cells, allowing the cell immortalization.

The only difference that I can see is how the hTERT is expressed in those cells, for example in cancer cells you can have the degradation of hTERT transcription repressor NFX1-91 but also the overexpression of intermediary proto-oncogene protein Myc and the transcription factor Sp1 that can bind to the promotor sequence of the hTERT and lead to its expression. There are many more mechanims in which hTERT can be actively expressed. Those are some examples

Good Luck!

Actually it is much more complex than just reactivation of the telomerase enzyme; sure that may cause immortality, but the complex pathology of metastasis via cancer stem cell relies on their ability to reactivate stem cell like patterns of gene expression. This allows them to migrate and reestablish a flawed developmental

program, i.e., a tumor at a distant site, eventually causing death.

One should bear in mind that all normal stem cells express telomerase as part of being immortal. It seems likely that most, if not all, cancer stem cells (CSCs) derive from mutations in normal stem cells (since most of the required gene expressions for being a stem cell are already in place), so loss of negative feed-back control leads to CSC creation to yield benign tumors (or teratomata) and further mutations lead to malignancy (spreading ability). In that sense, normal and cancer stem cells share many features in common. This would also fit in with the tissue of origin specificity of most tumors.

LG Lajtha discussed much of this in his classic chapter "Stem Cell Concepts" in "Stem Cells: Their Identification and Characterization, CS Potten ed., Churchill Livingstone, London, 1983. See also my own chapter: "Stem Cells in Planarians" in the same book. Planairians are an interesting system for the study of normal stem cells because they have morphologically identifiable toti-potential stem cells, from which all tissues (including the sexual apparatus and gametes) originate. This is why they have such amazing powers of regeneration.

Diogo Estêvão

Randall Gieni

Christopher Lange

Thanks for your comments.

I think Self Renewal (SR) ability of Normal Stem Cells (NSCs) is a key concept to understand the difference between mechanism of immortality in Cancer Stem Cells (CSCs) vs NSCs. As you know, SR is a key characteristic of stem cells (SCs), but why these immortal cells renew themselves? Because this ability guarantee the maintaining of their repository. For example: genomic insults to their DNA triggers senescence in these cells and finally lead to cell death and without SR these cells disappear after a while!!! Here SR helps to find out that, NSCs undergone senescence too.

Now with this short introduction, the answer of the aforesaid question, is depend on the origin of CSCs.

If we consider "somatic cell de-differentiation" as the origin of CSCs:

When telomeres length reach a threshold, replicative senescence lead to cell death. At this point if the cells already have tumor initiative mutations (i.e., p53 loss), they can bypass cellular senescence and continue to divide until critically shortened telomeres initiate crisis. At this point chromosome end to end fusion lead to extensive cell death (apoptosis), but a very rare cell population (1/100000-10000000) can bypass crisis and become immortal by upregulation or reactivation of telomerase (i.e., by mutations in promoter of hTERT).

If we consider somatic NSCs as the origin of CSCs:

As it is evident, these cells already express telomerase, but at the presence of senescence-inducing conditions, due to tumor initiative mutations (i.e., p53 loss) these cells bypass senescence and become immortal CSCs and with more replications, more mutations may occur.

One should bear in mind that ALT mechanism is also employed by 10–15 % of tumors to maintain telomere length and upregulation or reactivation of telomerase, is not the only mechanism of immortality!!

Article Roles of telomeres and telomerase in cancer, and advances in...

Article Telomeres and telomerase in normal and cancer stem cells

Article ALTernative Telomere Maintenance and Cancer

Some points worth noting: (1) p53 mutations are found in only about 50% of tumors. (2) Most cell replications, a prime source of mutations (copying errors), are done by the Amplifying Transit Cells (ATCs), which therefore accumulate most of the mutations before they become terminally differentiated, fulfil their physiological function, and then die. (3) The mutations a normal stem cell word need to become a CSC are those involved in "quorum sensing" that provide the negative feedback to stop production of cytokines like erythropoietin in the case of hematologic al stem cells for red cell production. This, in turn limits the numbers or proportion of stem cells and their proliferation. The Lajtha chapter I cited previously explains much of this.

Many of Christopher's points are well stated. I come from a slightly different, epigenetic perspective. We have found that BMI-1, originally identified as an oncogene, is highly expressed in cancer stem cells relative to the more differentiated general tumor cells.

BMI-1 is the E3 ubiquitin ligase catayltic subunit of PRC1, which along with PRC2 and DNA methylation are responsible for the aberrant silencing of genes involved in many aspects of cell identity, signalling and proliferation in most cancers (Gieni and Hendzel 2009). It is true that p53 is only mutated at the DNA level in 50% of tumors, however, the Retinoblastoma, Ink/Arf, p53 integrated cell cycle arrest process is made ineffective through either mutation or epimutation; i.e., in this case the aberrant silencing of genes which impact cell cycle arrest and apoptosis, in almost all cancers.

Silencing of non-tissue appropriate genes is the primary way in which cells define and protect identity. In Cancer and regular Stem cells many developmental pathways are bound by both repressive and gene expression activating complexes leaving them in a repressed yet inducible state. As cells differentiate many of the tissue inappropriate genes become permanently silenced allowing terminal differentiation and eventual cell death. Within a tumor most of the cancer cells are carrying out this sort of pathway made inappropriate by the introduction of both mutations and epimutations, however, the rare cancer stem cells remain undifferentiated and more mobile. Our major contribution was to show that ubiquitylation of Histones by BMI-1 is one of the very earliest steps in the DNA Damage Response (DDR) providing the initial ubiquitinylations required for creation of poly ubiquitin chains which activates the DDR cascade of repair factors.

These initial ubiquitinylations are now found to be responsible for the gene silencing that occurs in the genes found both up and down stream of double strand breaks potentially creating the conditions for further aberrant gene silencing events.

One of our major contributions has been to show that the high level of BMI-1 expression in cancer stem cells provides enhanced DDR function, in effect protecting the CSC from the very DNA damaging treatments meant to destroy them. This makes sense in the context of regular stem cells where the protection of DNA sequences is paramount to the stem cell properly carrying out developmental gene expression but is a means of cellular protection in the CSC. Thus shrinkage of a tumor after such therapy is only ultimately effective if the CSC population self-protected from such damage is also eliminated.

BMI-1 is one of a handful of "stemness genes" whose high expression in tumors is shown to define a "death from cancer" phenotype in a large range of cancer types ( Glinsky et al. 2005). Its contribution appears to be at numerous levels including over activation of cellular signalling pathways through silencing of negative regulators, silencing apoptosis and cell cycle arrest related genes, to protection of CSC from DNA damaging therapies.

There is also debate about the origin of CSC. Indeed, epithelial to mesenchymal transition is a normal physiological process of de-differentiation required for many functions, which reactivates "stemness associated genes" within epithelial cells resulting in more "CSC like" gene expression pattern. The process of dedifferentiation of even well differentiated cell types such as fibroblasts back to pleuripotent stem cells, and the many examples in the literature of various combinations of manipulations which can result in re-initiation of a stem cell expression phenotype suggests that the story of the origin of CSC and their self-renewal abilities is still being defined.