Stem Cells, Quiescence and Cancer

by Alexey Bersenev on June 5, 2008 · 7 comments

in cancer stem cell, Journal club, quiescence

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Blogging on Peer-Reviewed ResearchHematopoietic stem cells (HSC) are able to self-renew and give rise to all the blood cell types. Almost all of self-renewing HSC are so-call long-term (LT-HSC), which are capable of reconstituting lethaly-irradiated mice for a long time, unlike short-term HSC, which keep mice alive for the first 2-3 months and give a lot of progenitors. Most LT-HSC are non- or very slow-dividing cells and reside within bone marrow niches in a dormant condition. The ability to maintain this non-dividing condition, or in other terms, stay in the G-0 phase of cell cycle, is called quiescence.

Scheme of cell cycle phases and place of quiescence:

Because it has been proposed that cancer stem cells (CSC) have the same qualities as normal stem cells, the vast majority of them also should stay quiescent and able to self-renew. Because majority of anti-cancer drugs target actively-dividing (cycling) cells, quiescent CSC stayed alive and caused relapses and progression of disease. It would be cool to target CSC precisely based on their unique qualities and eradicate cancer. Quiescence could be the new potential target for anticancer therapy.

Now, according to a recent international study, published online in Nature journal, we can get a solution for targeting quiescence of CSC.

The authors describe a gene – PML, which regulates HSC function through maintenance of quiescence. When researchers serially transplanted bone marrow cells with leukemic oncogene, cells from mice with lack of PML were not able to generate leukemia on 3rd round because the self-renewal and quiescence of leukemia-initiating cells (LIC) were impaired.

Based on these results, the authors used the well-known anti-leukemic drug arsenic trioxide, which selectively and reversibly decreases PML expression on HSC and causes their impaired quiescence. This drug had a remarkable inhibitory effect on LIC maintanance. Arsenic trioxide-induced cycling increased LIC-killing effect of another anti-leukemic drug – Ara-C, which induces apoptosis of dividing cells. The combination of both drugs was able to inhibit leukemogenesis in secondary BMT unlike Ara-C treatment only. Even more, only by combining these two drugs leads to complete cure (ei LIC eradication) of disease in half of recipient mice.

I’d like to pointed out few important conclusions which came up and are confirmed in this study:
* There is a concept that quiescence of CSC may be one of the mechanisms underlying their chemoresistance;
* We can eliminate quiescent LIC for treatment through manipulation of genes-regulators of normal HSC function. Seems like we have only one tool for playing with quiescence so far – to induce cells to enter cell cycle;
* What happened with normal HSC? They also should be affected by these drugs. The answer is that – YES, normal HSC are also affected, but as the authors show, LIC are more sensitive to induction of cell cycle entry by arsenic trioxide, and the amount of quiescent HSC is quite enough to sustain normal hematopoiesis.
* Authors showed exactly the same effect of arsenic trioxide on LIC and HSC (through downregulation of PML) for human chronic myeloid leukemia compared with normal volunteer samples. So, this study could be considered like a preclinical one and arsenic trioxide could be recommended as a component of complex antil-leukemic chemotherapy, targeted towards quiescent leukemia-initiating cells.

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Nature AOP 11 May 2008; doi:10.1038/nature07016
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{ 5 comments… read them below or add one }

Smith September 15, 2008 at 10:42 am

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Reynald December 16, 2008 at 11:58 pm

I think recent data when taken together would tend to counter the assertion that CSCs are quiescent. Based on the work by Mani in weinberg’s lab and numerous observations it seems pretty clear that in the case of solid cancers, CSCs and the EMT are the same thing. In that case it has been shown that the EMT phenotype is in fact proliferative. Although this is simply informed speculation.

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Alex December 17, 2008 at 3:57 am

Yes cancer stem cells (CSC) should be quiescent because they are “altered adult stem cells”. That’s why so hard to kill them, that’s why they are almost undistinguished from normal adult stem cells.
EMT is the phenomenon of transition from normal tissue stem or progenitor to CSC, so it’s not CSC themself – it is a transition process. That’s why it’s proliferative. What is speculation?

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Lei February 10, 2009 at 9:44 pm

I’m always fascinated by cancer. It’s a population of cells with self-sufficient survival and uncontrollable proliferation. This population is highly heterogenous so that doctors can hardly cure cancer with a single drug.
Several biological processes are involved in the onset of cancer, so-called tumorigensis or carcinogenesis. Some are reasonable, such as overdose DNA damage, genomic instability-caused silence of tumor suppressor genes and/or constitutive activation of oncogenes. And cancer itself is well-developed “organ”(if you want one) with self-renewal ability. You are right, that’s how cancer stem cell works. Even cell cycle inhibitor helps to keep cancer stem cell from DNA damage and carry over the “stemness”(Viale, et al., 2009). On top that, single cell xenotransplantation on a mordified mouse model found cancer stem cells constitute a large portion of total cancer population, say 27%, in some cancer types (Quintana et al., 2008).
Cancer cells are all ambitious guys, they travel with the guidance of some cell surface markers, such as chemokines, for example, CXCR4 and RANTES(S Gelmini et al., 2008). They have fun in the body, and once they find their “niche”, they stay there either hibernating or colonizing.Well, now let’s see what advantage cancer has, absence of growth restriction, stimulation of growth, free-roaming and self-repair. But that’s not all.
It’s not surprising even a bad guy has some friends. So does cancer. But it’s hard for me to accept the idea that tissue stem cells, such as adipose stem cell(Fabian Muehlberg et al.2009), actually help cancer cell disseminate just on-site. Are those stromal cells retarded or something? Are they sure they really need that kind of neighbors? Or these bad guys send out friendly information to these stromal cells?
2009 is Darwin’s year. If evolution theory is true, how would you like to fit this phenomenon into it? Cancer cells are more biologically evoluted? Because virologists already claimed that HIV is much more advanced than Ebola virus. HIV allows its hosts live longer so that it can take the advantage to spread, while Ebola kills its hosts right away. So, how about cancer?
I wanna be a devoted researcher for cancer, it’s my personal interest and passion. But, when you start a war and you find all odds are against you, will you still fight? Do you call the courage silly or brave?
BTW, My hubby reminded me that I take cancer’s advantage and get grant money from it. After all, several of my family members suffered and finally died of cancer relapse or cancer metastasis. Most of people will agree that it’s fair for me to get back something from it. I mean a career. Isn’t that too mean?

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James September 18, 2009 at 3:56 pm

Yes, the work is excellent. but I wonder how they can tell the cell is alive or not when cells stay in dormancy.

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