Nobody has yet tested which cells actually contribute to disease in patients.
Therapies must eliminate all cells with the potential to contribute to disease.

Sean Morrison

One of the best lectures that I’ve heard this year so far was Sean Morrison’s talk at University of Pennsylvania. Research in his lab made me think for the first time about complexity of cancer stem cell concept. For me he is an example of how real basic science should be done.

His “cancer stem cells” talk was recently recorded in the Koch Institute Symposium, held on June 19, 2009 at MIT.

He is talking about some very new unpublished data at the end of the lecture. I’d like to bring your attention to one of the last slide, shows that high frequency of tumorigenic cells (serially transplantable) could be observed not only in highly immunocompromised mice (like NOG), but also in fully immunocompetent histocompatible.

link
copyright: MIT Tech TV

****************

also read:
Cancer stem cells - how mouse model can change the concept
Complexity of cancer stem cells
Validity of the cancer stem cell concept under discussion

also watch:
Robert Weinberg - Cancer stem cells and malignant progression
Catriona Jamieson - The molecular evolution of leukemic stem cells
Irving Weissman - Stem Cells: Units in Regeneration, Cancer, and Natural Selection
Owen Witte - A Delicate Balance: Stem Cells, Cancer and the Immune Response

Recently, anti-cancer activity of some well known drugs was discovered, which was shown to rely on targeting of cancer stem cells (CSC). Explanations for some very effective anti-leukemic drug combination were recently found in the laboratories. I’ll give you some examples of “from-bed-to-the-bench” translation coming from leukemia clinic.

Arsenic targets quiescent leukemic stem cell

Ido et al showed that arsenic trioxide specifically targets quiescent leukemia-initiating cells (LIC) in chronic myelogenous leukaemia model. Arsenic trioxide selectively and reversibly decreases PML protein expression on hematopoietic stem cells (HSC) and LIC and causes their impaired quiescence and self-renewal.

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.

Authors consider that this mechanism could be a possible explanation of dramatic ability of arsenic to cure acute promyelocytic leukemia (APL). I’d remind you that arsenic has been used for treatment of leukemia for centuries.

Yet another study provides the same explanation for therapeutic efficacy of arsenic with retinoic acid in treatment of APL. These drugs, which successfully have been used in leukemia clinic, acts through degradation of fusion PML-RARA in LIC blocking their self-renewal.

Except APL, arsenic trioxide is active against Glivec (Imatinib)- resistant CML cells and potentiates its efficacy through other then PML mechanisms.

Interferon wakes up dormant hematopoietic stem cells

Two recent studies provided evidences for one possible mechanisms for manipulation of quiescent hematopoietic stem cells (HSC). The first study came from Andreas Trumpp lab and describes how interferon-alpha stimulates HSC proliferation through exit from quiescent state. Sato et al, found that mice, deficient for one of the components of the IFN pathway, have abnormal proliferation of HSC leading to their rapid functional exhaustion.

So far, we don’t know if we can apply this results for targeting quiescent LIC, but it was proposed as possible explanation of IFN efficacy in combinational therapy of CML.

Persistent CML-initiating cells, or CML stem cells, which are protected from imatinib killing by their quiescent status, are probably responsible for the regrowth of the disease.

Strikingly, a handful of CML patients that were first treated with IFN-alpha and then switched to imatinib treatment—a molecularly targeted therapy directed against BCR-ABL, the fusion protein characteristic of CML - experienced persistent remission…

The emerging possibility to explain the stable remission in the patients previously treated with IFN-alpha could be that the exposure to IFN-alpha induced the CML stem cells to exit quiescence and proliferate such that, upon imatinib treatment, they became vulnerable to imatinib rather than remaining protected.

Zileuton selectively targets CML stem cells

Recently, well-known 5-Lipoxygenase inhibitor - Zileuton alone or in combination with Gleevec, was found unexpectedly effective in eradication of LIC. Zileuton is widely used for asthma treatment, where it mechanistically inhibits the Alox5 gene.

The researchers found that CML did not develop in mice without Alox5 because of impaired function of leukemia stem cells. Also, Alox5 deficiency did not affect normal stem cell function, providing the first clear differentiation between normal and cancer stem cells.

Zileuton is not in clinical trial for leukemia treatment yet, but it was proposed in Chen’s study.

*****
This essay is aimed to show how drug-resistance to one agent (Glivec for instance), discovered in leukemia clinic, could lead to investigation in laboratory and possible explanation by cancer stem cell theory. Targeting of leukemia-initiating cells by additional drugs underlies achieving of successful clinical and cytological remission.

_____________________
citations:
Emmanuelle Passegué & Patricia Ernst. IFN-alpha wakes up sleeping hematopoietic stem cells. Nat Med 2009; 15: 612 - 613
A lethal cancer knocked down by one-two drug punch. GEN June 7.

also read:
Salomon P. Stemming out of a new PML era? Cell Death Differ. 2009 Jun 12
Jonathan D. Licht. Acute Promyelocytic Leukemia — Weapons of Mass Differentiation. NEJM 2009;360:928-930

read more:
Stem Cells, Quiescence and Cancer
Regulation of leukemic stem cells self-renewal and quiescence - the role of p21
Complexity of cancer stem cells

Recently some folks and I were fascinated by a concept based on developing cell capturing and cell trafficking control implantable devices. The concept is based on known receptor-ligand interactions between circulating bone marrow cells or seeded cells and defined factors embedded in the device. This approach may provide a new generation of cell therapies in the future.

Lately, some of these devices entered the commercialization phase and were licensed by companies. I’d like to give you a brief overview of some of these kind of devices.

1. “Jianyi Zhang’s patch”
device-patch: PEGylated fibrinogen, bound with recombinant SDF-1
how it works: Patch implanted in myocardium released SDF-1 - homing factor for hematopoietic (Sca1+/cKit+) cells. Recruited bone marrow progenitor/stem cells to mediate heart muscle and regeneration.
IP: US patent application # 20050118144
phase: experimental
potential application: heart muscle regeneration
publications: Zhang G, et al. Controlled release of stromal cell derived. Factor-1α in situ increases stem cell homing to the infarcted heart. Tissue Eng. 2007;13(8):2063-2071

2. “Michael King’s device”
device: P-selectin–coated microtubes implanted as arteriovenous shunt
how it works: P-selectin triggers mobilization of hematopoietic stem/progenitor cells from bone marrow. Enriched stem cell fraction could be collected and eventually expanded and/or transplanted.
separation of cancer cells - TRAIL-coated device:

…device that filters the blood for cancer and stem cells. When he captures cancer cells, he kills them. When he captures stem cells, he harvests them for later use in tissue engineering, bone marrow transplants…

IP: Michael King’s (U of Rochester) US patents: 20060183223, 20070178084;
Jeffery Karp (MIT), technology exclusively licensed by CellTraffix
phase: experimental-preclinical
potential application: hematology, oncology
publications: Wojciechowski JC, et al. Capture and enrichment of CD34-positive haematopoietic stem and progenitor cells from blood circulation using P-selectin in an implantable device. Br J Haematol. 2008 March; 140(6): 673–681 (OA)

Finally, most intelligent device from new generation:
3. “David Mooney’s device”
devices in work: In situ bioreactive devices (iBD). Examples:

• PLG matrix with mobilized GM-CSF and tumor antigen. G-CSF attracts dendritic cells, which start to expand and present tumor antigen. After release, antigen-presenting dendritic cells migrate to lymphoid organs and activate specific anti-tumor clon of cytotoxic T-cells.
• Alginate scaffold with VEGF and endothelial progenitors. VEGF could attract endogenous endothelial cells or support scaffold-embed ones and stimulate local neovascularization.

IP: David Mooney’s lab at Harvard University US patents; technology licensed by InCytu
phase: experimental-preclinical
potential application: immunotherapy in oncology, tissue regeneration and therapuetic angiogenesis
publications: Ali OA,et al. Infection-mimicking materials to program dendritic cells in situ. Nat Mater. 2009 Feb;8(2):151-8
Silva EA, et al. Material-based deployment enhances efficacy of endothelial progenitor cells. PNAS 2008 Sep 23;105(38):14347-52 (OA)

So, ideally device should be composed of biodegradable material with some mobilized factors and dedicated to recruit desired cell population, modify their qualities and controllably release them for in situ therapy. Development of those devices demonstrates a good example of a multidisciplinary approach, coming from tissue engineering principals. Future development of such devices can provide an absolutely new way of cell-based therapies.

This is the first demonstration of anti-cancer activity in a living organism by cells derived from human embryonic stem cells.

Dan Kaufman (University of Minnesota)

A while ago I wrote about the difficulties on the way to generating functional hematopoietic stem cells from human embryonic stem cells (hESC) and I was even trying to challenge the significance of this research for clinical applications. I’d like to notice that generation of mature blood cells from hESC has been much more successful. Thus functional T-cells, NK cells and erythrocytes were efficiently derived from hESC. But only a few of them have been studied for functionality of derived cells in live organism (in vivo) models, which are very important for estimation of therapeutic potential.

Now Dan Kaufman’s lab from University of Minnesota demonstrate for the first time efficient cancer killing activity in vivo, mediated by immune cells derived from hESC. They generated natural killer (NK) cells using previously published protocol and investigated their anti-cancer activity on the range of tumors in vitro and in mouse leukemia model.

In my opinion this study has 2 most important advantages:
1. They used in vivo mouse model of human leukemia to estimate therapeutic potential of hESC-derived NK cells.
2. The authors compared activity and function of NK cells derived from hESC versus cord blood (CB) derived counterparts. I remember only 1 or 2 studies (correct me if I’m wrong) which were done to functionally compare hESC-derived cell types vs adult stem cell derived counterparts. Surprisingly CB-derived NK cells showed less cytolytic activity versus range of cancer lines in vitro and less anti-tumor activity in mouse model compared to hESC-derived NK!

Remarkably, all mice (13 of 13) treated with hESC-NK cells demonstrated rapid and complete clearance of the primary tumor within two weeks after tumor inoculation. In contrast, mice treated with UCB-NK cells had significantly less anti-tumor activity in vivo, with only 5 out of 13 tumor-free animals treated with UCB-NK cells.

This anti-tumor effect of hESC-derived NK cells (sorted and unsorted) was so strong that there was no cancer recurence observed and it was protective against metastasis.

The author’s explanation of enhanced activity of hESC-derived NK cells is that they are more mature and acquired more activation receptors compare to cord blood, which contain more immature and NK progenitors.

Now, I’d like to notice why if hESC-derived cells will ever reach the clinical endpoint, NK cells will be one of the first candidates:

1 NK cells could be used only for anti-cancer therapies, usually in “nothing to lose” cohort of patients. Allogeneic HLA-mismatched NK cells will be safe and not immunogeneic.

Unfortunately there are not many online sources of reliable information about stem cells. A huge part of information modified by mass media or advertisers.

Today I’ll indicate 3 - relatively new sources that I actively use last year for my own education. I can tell - you can trust these sources. They provide valid information.

1. StemBook

This is a real online book, written by leading scientists in the field. Updated regularly, freely available in pdf format.
For scientists, medical/biology students, physicians.
Who is behind: Harvard Stem Cell Institute
How to contribute - write a chapter!

2. Stem Cell Resources

Excellent educational resource for broad audience.
Who is behind: Bioscience Network (online publisher)
How to contribute: suggest a resource!

3. Stem Cell Gateway

For stem cell research community.
Who is behind: Springer (publisher)
How to contribute: submit your manuscript!

Here I was trying to summarize some approaches used for improvement of engraftment by mostly increasing stem cell number per graft. The top part of the table represents approaches which have a potential to be commercialized.

CB - cord blood; BM - bone marrow; MB - mobilized blood

Let me know if I missed something.

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Lab web-site

also watch:
Cancer Stem Cells: A Discussion
Understanding of cancer - 5 great talks
Owen Witte - A Delicate Balance: Stem Cells, Cancer and the Immune Response

more lectures

With such a diversity of opinion, one might imagine that some hugely controversial or complex data sets have led investigators to propose widely varying interpretations.
Craig Jordan

Lately I was reading a few reviews and commentaries about the validity of cancer stem cell concept and possibility of targeting these cells for therapeutic purposes. I realize that all of controversies and scientific debate caused not only by misunderstanding the concept or difference in assays but also high natural complexity of cancer stem cells (SCS). The more we learn about them the more complex it seems.

Like all good things in science, I suspect that the rigid version of the cancer stem cell model is going to need some tweaking
John Dick (U of Toronto)

Earlier, I divided people who discuss about the validity of the CSC concept into 2 categories:
A. believers (CSC exist and concept is correct)

There is no doubt that there are cancer stem cells… This has tremendous clinical importance; the therapies we currently use don’t target them.
Max Wicha (U of Michigan)

B. non-believers (all points of the concept are questioned and challenged)

It now appears likely that the remainder of the cancer stem cell hypothesis may also fall by the wayside
Joseph Lipsick (Stanford University School of Medicine)

Now, due to the apparent complexity 2 more categories appeared in the list:

C. partial believers - basic scientists:

some cancers follow cancer stem cell concept, some are not. We have to distinguish them
Sean Morrison (U of Michigan)

D. partial believers - clinicians (CSC model is true for some cancers, but there is no point in attempts to target them therapeutically)

Trying to find ways to treat cancer stem cells is like trying to close the barn door after the horse is out
Isaiah Fidler (MD Anderson Cancer Center)

Ok, now I’d like to share some thoughts about what makes CSC so complex.

1. Let’s look at cell-of-origin: Most of us thought before that CSC should arise from normal adult stem cell due to mutations because they are so similar. Now we know that CSC could arise from normal adult stem cell or progenitor or even mature differentiated cells due to mutations. So, mutations happening on any level could create the cancer cells sharing characteristics of normal tissue stem cells.

2. The rarity of CSC was one of the first characteristics that was questioned.
In different kinds of tumors in different kinds of detection assays it appear to be now something between from 0.01% to 50% of tumor mass. Big variation, isn’t it?

3. Detection problem is number one in developing the CSC concept. It’s becoming clear that identification of CSC by surface markers could not work for many cancers that was proposed before.

example 1: acute myelogenous leukemia CSC: proposed detection phenotype Lin-/CD34+/CD38- is not valid today, because leukemia-initiating cells were detected in CD34+/CD38+ and even outside of Lin- progenitor cells (unpublished data).

example 2: Recently validity of bona fide cancer stem cell marker - CD133 was put under question for lung cancer, colon cancer and glioblastoma.

Some doubts about validity of CD24 and CD44 for breast cancer in disease progression context you can find in this review.

In the search of cancer stem cells, the approach of identifying subpopulations of cells from surface marker expression is flawed. It’s much more complicated than taking out a cell with a marker and asking if you can form a tumor.
Kornelia Polyak (Dana Faber Cancer Institute)

4. CSC dynamically change with cancer progression.

Cancer stem cells themselves aren’t a homogeneous entity and they can evolve
John Dick (U of Toronto)

We are just coming to the realization of this point. It was nicely shown in Kornelia Polyak’s group 2007 work.
Can you imagine the situation: you are working in the lab and isolating CSC from the patients biopsy samples by defined phenotype, you inject them into NOG mice and get a tumor. Half of year later you take sample from the same patients with progression of the same cancer, sort CSC out by the same markers, inject them into the mice and… don’t get any tumors!

So CSC are continually evolving, changing genetically and epigenetically, turning off and turning on a different number of different signaling pathways during cancer progression! Moreover, CSC progeny could acquire new genetic mutations and become a new drug-resistant stem-cell-like “tumor seeds” different from the parental population. So how can we catch this moving target?

I summarized some positions of evolution of the cancer stem cell concept in the table:

5. Nearly impossible to target?

Finally, as CSC evolve as cancers progress, their unique characteristics become so blurry that it’s almost impossible to target them precisely. In an attempt to target signaling pathways, which are selectively activated in CSC but not in normal stem cells, we should give to a patient cocktail of drugs in addition to conventional therapy, destroying tumor mass. With this toxicity one might imagine number and scale of side effects that could affect a patient.

But not everything about CSC is so pessimistic. We know many good examples of successful targeting and eradication in tumors where the CSC model could be applied. We still have a lot of ways, other than surface molecules and signaling pathways, to target them. We are still developing a models to validate the concept. We can see clinical relevance and significance of CSC. Field is developing tremendously right now and a model is in the making.

… debating the existence of CSCs or their frequency is not a particularly useful exercise, and the scientific community would be well served to move beyond these issues. Rather, the more pertinent question is whether studying and targeting CSC is important for developing better forms of therapy. The answer to that query seems somewhat less clear.
Craig Jordan (U of Rochester)

*********************

citations:
Craig Jordan. Cancer stem cells: controversial or just misunderstood? Cell Stem Cell 2009;4:203
Karen Rowan. Are cancer stem cells real? After four decades, debate still simmers. J Natl Cancer Inst. 2009;doi:10.1093/jnci/djp083

read more for free:
Breast cancer’s genetic profile calls the cancer stem cell hypothesis into question. (The Scientist)
The cancer stem cell hypothesis: in search of definitions, markers, and relevance. (Lab Invest)
Cancer stem cells: controversies and misconceptions. (The Niche)
Cancer stem cell sightings and slightings. (Nature Reports Stem Cells)
John Dick: careful assays for cancer stem cells. (Nature Reports Stem Cells)
Validity of the cancer stem cell concept under discussion (Hematopoiesis)
Cancer stem cells - how mouse model can change the concept (Hematopoiesis)
Cancer stem cells and CD133 controversies (Hematopoiesis)

Dr. Curt Civin holds the King Fahd Professorial Chair of Pediatric Oncology, is Professor of Pediatrics and Oncology and Director of Pediatric Oncology at the Johns Hopkins Oncology Center. Dr. Civin has utilized the human-mouse chimera assay to quantify the in vivo engraftment of human stem/progenitor cells and leukemia, is advancing the isolation, expansion, and gene transduction of human lymphohematopoietic stem and progenitor cells, and is using gene transduction and in vivo assay techniques to explore the molecular biology of leukemogenesis.

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