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Cancer Stem Cell Research
The Ontario Cancer Institute at Princess Margaret Hospital leads the world in this area of research
Introduction
Most of us can recall the classroom projects in primary school where we learned how plants grow from tiny seeds first by putting down critical roots and then developing stems, leaves and flowers. The magic of growth and transformation!
In later years, as we all tend to lawns and gardens, we come to learn how key the roots of a plant really are—just try to get rid of your weeds without getting the full root!
In the last decade, scientists have come to understand more about human development, and ‘stem cell’ has become a household term. Since the initial discovery of stem cells by Lasker Award winners Dr. James Till and Dr. Ernest McCulloch at the Princess Margaret Hospital (PMH) in the early 1960’s, scientists have learned not only that that there are different kinds of stem cells—embryonic stem cells, adult stem cells, and cord blood stem cells—but that the concept of a stem cell extends to the development of cancer. This idea is quite revolutionary since, until quite recently, doctors have thought of and treated cancerous tumours as if they were a homogeneous ‘mass’. The idea that only certain cells (the cancer stem cells) within the tumour can sustain cancer leads to new ways of thinking about the treatment and eradication of the disease.
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The tap root of a dandelion sustains the plant, and will ‘re-grow’ the weed even if the other parts are destroyed. Cancer stem cells are like the root of a tumour. |
The Ontario Cancer Institute (OCI) at Princess Margaret Hospital continues to lead the world in cancer stem cell research, and this article will provide background information on this area of medical research, the people leading the investigation, and their areas of focus.
Stem Cells and Cancer Stem Cells
So, first of all, what is a stem cell? And how are cancer stem cells different from and similar to ‘normal’ stem cells?
A key property of stem cells is their ability to self-renew—the ability to divide and give rise to another stem cell. While most cells divide equally into two cells, a stem cell can divide into two different cells—one is a new stem cell and the other is called a ‘progenitor’ cell. The progenitor cell does not have the power of self-renewal, but has the ability to change/differentiate into various cell types. Below is an illustration depicting the division of a hematopoeitic stem cell from bone marrow which ultimately creates and maintains the various kinds of blood cells.
When a human egg is fertilized and a fetus develops in the womb, the very first stem cells (referred to as embryonic stem cells), possess the power to differentiate into all the different organs and tissues. Once a human body is fully formed, it seems that embryonic stem cells disappear and are replaced by a small set of adult stem cells within each of the major organs (e.g., intestine, kidney, skin) that are responsible for repair and maintenance of that organ.
Interestingly, a by-product of the stem cell self-renewal process is that the number of stem cells in an organ or tissue remains largely unchanged. One stem cell is lost, but a new one is created. Research indicates that the stem cells responsible for maintaining an organ are able to control their own numbers, possibly by sensing when they have the right number through an exchange of chemicals.
Today, pathologists and other researchers know that tumours contain a variety of cells, including some that resemble the tissue in which the cancer originates. Researchers have also identified that some types of tumours contain specific cells, now called cancer stem cells, which are responsible for sustaining the tumour.
Cancer stem cells share the ability of normal stem cells for self-renewal. However, they seem to have lost control over their own population size. In some tumour types, they also appear to be resistant to most current forms of cancer therapies which may be why cancer often recurs in people who are declared to be ‘cancer free’.
History and Timeline
What did Dr. Dick and his team do in 1994 that got the attention of cancer researchers around the world?
In 1994, Dr. John Dick and his team provided the first proof that cells in a cancer are not equal. Some cells are more lethal than others. They isolated the first cancer stem cell in acute myeloid leukemia.
Dr. Dick’s team developed a way of identifying cancer stem cells in leukemia. They found that a protein, CD34, is present on the surface of the cells. This is what scientists refer to as a ‘marker’ or identifier. Cancerous cells without this CD34 marker were injected into mice, and did not develop into leukemia, while cancer cells with the marker consistently developed leukemia.
Unique identifiers that allow scientists to distinguish a cancer stem cell from other cancer cells is important to unlocking much of the mystery.
How Do Cancer Stem Cells Arise in the First Place?
There are a number of theories on how cancer stem cells are first formed in a human body, but no theory has yet been proven. Do they arise from stem cells or more mature progenitor cells?
There is evidence that progenitor cells (regular cells) may undergo DNA mutations or chemical changes that transform them into cancer stem cells—regaining the ability to self-renew.
There is also evidence that cancerous stem cells evolve through malignant transformation of normal stem cells—losing their ability to carefully manage the pace of self-renewal. This theory is supported by the observation that many of the body’s tissues that are most prone to cancer, like the blood, skin and lining of the gut, are composed of short-lived cells that suffer high wear and tear. Cells are believed to become malignant only after a series of mutations has disabled their genetic control systems. So how could a skin cell, which lives only a few weeks, survive long enough to mutate multiple times? There is evidence accumulating that the mutations leading to a cancerous cell would build up in the self-renewing group of stem cells that maintains the skin or blood.
Why is the Discovery of Cancer Stem Cells Important?
The discovery of cancer stem cells holds much promise. For starters, it provides a logical explanation for why cancer often recurs, even when treatments such as surgery, radiation and chemotherapy seem to shrink or eliminate tumours.
As scientists focus on cancer stem cells, they are seeing that these particular cells are naturally resistant to the standard therapies used today to treat cancer—radiation and chemotherapy.
Armed with the knowledge of the existence of cancer stem cells, scientists have studied the drug Gleevec which is prescribed to cancer patients with chronic myeloid leukemia. They believe that Gleevec kills everything except the stem cell. As soon as ‘progenitor’ cells emerge from the stem cell, they are killed by the drug if the patient takes it every day. This suggests that a patient must stay on Gleevec forever as it does not kill the ‘root’ of the cancer.
The new knowledge associated with cancer stem cells has injected more optimism and creativity into the battle with cancer. Rather than being locked into thinking of tumours as a homogenous mass of cells and focused on shrinking the size of tumours, scientists and doctors now know the situation is more complex than that.
The next generation of drugs needs to target the elusive culprits that sustain the tumour—the cancer stem cells. As scientists study these cells and gain a clear understanding of their behaviour and what makes them unique, strategies to defeat them can be developed.
For example, a test study is planned for a drug developed by Merck & Co. originally to treat Alzheimer’s disease. It did not work on Alzheimer’s, but in laboratory studies, it has been found to kill breast cancer stem cells. Thirty women with advanced breast cancer have agreed to test this drug.
What are the Early Strategies for Defeating Cancer Stem Cells?
Cancer stem cells appear to be very mobile, and can move from their original home to other parts of the body. Eradicating them before they spread and spawn more cancer stem cells would be the easiest way to arrest the disease early.
Because cancer stem cells are much more active than normal stem cells, they may be more dependent on certain cellular processes. Developing drugs that block those processes could be an effective strategy.
Blocking a cancer stem cell’s source of nutrition might be another effective strategy for drug development. Normal stem cells tap into many different blood supplies for the oxygen and fuel they need to survive. However, cancerous stem cells seem to focus in on one source and depend on that source for everything they need. Exploring that dependency, and then figuring out how to cut off the source would provide another way to tackle malignancies.
Another strategy is to encourage cancer stem cells to differentiate. Scientists believe that differentiation would limit a cancer stem cell’s ability to form new tumours.
‘Divide and Conquer’: Dr. John Dick’s Team of Cancer Stem Cell Warriors
One of the most impressive things about the cancer stem cell research project led by Dr. John Dick is the cross-institutional collaboration that has been achieved. Dr. Dick’s team of principal investigators includes top scientists from the Ontario Cancer Institute at The Princess Margaret, as well as the Hospital for Sick Children (HSC), Toronto General Hospital and McMaster University.
In this project, the scientists are not only sharing their knowledge with one another, but dividing up the necessary work among the institutions in a way that takes advantage of resident expertise and research funding. They have collectively organized the project to fast track the work and to maximize the chance of success.
Because cancer stem cells look and behave differently depending on what kind of tumour they are sustaining (e.g., lung, breast, colon), much of the research needs to be conducted on multiple ‘fronts’—ideally conducted by the scientists most familiar with the various types of cancer. That is why Dr. Dick’s team is organized by cancer ‘site’ with a lead scientist heading each area where cancer stem cells have been identified.
Dr. John Dick (right) leads a team of world-class researchers working across Ontario and focused on cancer stem cells. (l to r) Drs. Ben Neel (OCI/PMH), Tom Waddell (TGRI/TGH), Peter Dirks (HSC) and John Hassell (McMaster) meet regularly to discuss progress and strategies for research in this promising new area of cancer stem cells.
What Areas of Cancer Stem Cell Research are the Focus at the Ontario Cancer Institute?
Early experiments indicating that only cancer stem cells can sustain and grow a tumour offer sufficient encouragement to invest further in this area of research. OCI is in a world-leading position in cancer stem cell research and will continue to recruit the people, develop the infrastructure, and build local and international relationships in the scientific community to maintain this position.
As with most cancer research, the ultimate goal of the Cancer Stem Cell (CSC) Program at the OCI is to improve the lives of those living with cancer. The researchers do this by developing improved diagnostic tools, plus treatment and therapies that are easy to administer and non-toxic for the patient.
Hundreds…maybe hundreds of thousands of experiments, tests, and trials need to be completed to get to those tools and treatments, and the team is organizing their work into the following areas:
- identifying and isolating cancer stem cells
- defining the characteristics of cancer stem cells, and
- determining the prognostic, diagnostic and therapeutic value of cancer stem cells
Identifying and isolating cancer stem cells
While cancer stem cells have been discovered in at least six different types of cancer, scientists want to develop more efficient ways to identify and isolate the cancer stem cells within a tumour. The ability to effectively filter out and create ‘pure’ cancer stem cell populations is a fundamental need for the many experiments the team has planned.
The team maintains ‘live cell banks’ of cancer samples that can be studied and used to test new drugs and therapies.
Defining the characteristics of cancer stem cells
In parallel with identifying cancer stem cells and further purifying these populations of cells, our researchers are working to further understand and document the intricate biology and behaviour of cancer stem cells. They are studying the genes and proteins that are involved in cancer stem cell functioning using state-of-the-art technologies, one of which is a new instrument developed as part of a Genome Canada program that is designed to study many different proteins in a single cell.
A central component of the cancer stem cell program is to take advantage of the opportunities that our multidisciplinary and multi-institutional networking approach offers. The primary advantage is the ability to capture a larger sample, increasing the statistical power of the studies that address whether the knowledge of cancer stem cell biology provides enhanced therapeutic, prognostic or diagnostic value compared to the analysis of bulk tumour cells.
Determining the prognostic, diagnostic and therapeutic value of cancer stem cells
Knowledge from the first two areas will serve as a ‘genesis’ to:
- Develop tools that facilitate cancer diagnosis and help predict the extent and severity of the disease. Knowledge of the biology and behaviour of cancer stem cells will hopefully lead to reliable tools for physicians to identify different kinds of cancer and to assess how advanced the disease is
- Devise cancer stem cell-specific therapies
The xenotransplant models (where human cancer cells are transplanted to mice) will provide the basis to acquire high quality pre-clinical data on the effectiveness of unique therapeutic treatments.
As data about cancer stem cells grows and patient samples accumulate, the researchers plan to, and in many cases have already started to, correlate it with clinical data to determine if they can predict the outcome for a patient. The researchers plan to build the infrastructure needed to efficiently collect and record clinical information on patients with solid tumours and with leukemia—information such as tumour grade, staging, subtype and outcome. A database will link the data collected with each sample studied so that clinical data and updated cancer outcomes for each patient will be linked to a specific tumour specimen.
Leading the pack in archiving viable leukemia samples is Dr. Mark Minden at The Princess Margaret. He has been archiving samples from patients at the first stage of the disease and at relapse for the past 10 years. His team has proven capabilities to bank live single cell tumour suspensions for several types of leukemia and blood disorders, including AML, ALL, MDS and CML. He also has clinical databases and an ethical framework in place to link banked tumour cells to clinical data. The clinical databases capture data on molecular analysis of the patient’s leukemia cells, diagnostic information, treatment administered, and outcomes (including side effects of treatment).
The leukemia banks at PMH, HSC and McMaster are also coordinating their efforts to minimize duplication and to benefit from standardized protocols and prior experience.
Developing core resources to support cancer stem cell research province-wide
The more good minds that understand the role of cancer stem cells and the biology behind them, the more potential there is to uncover innovative new approaches, treatments and solutions. The CSC team at the Ontario Cancer Institute at The Princess Margaret is making it a priority to support the cancer stem cell research efforts of other teams in Ontario and across the country. For example, they will provide high quality immune-deficient mice, flow cytometry facilities, cell-based MAb (monoclonal antibody-based) generation, and access to leading-edge equipment and instrumentation.
Biography of the Program Director
Dr. John Dick
John Dick, PhD is a Senior Scientist at Princess Margaret Hospital and Director of the Cancer Stem Cell Program at the Ontario Institute for Cancer Research. Dr. Dick is world-renowned for his work in the development of a human blood stem cell assay using immune-deficient mice, which has transformed the study of stem cells. He led the group that identified colon-cancer initiating cells, providing support for the hierarchical organization of colon cancer. Considered a luminary by his colleagues, he has won numerous awards including the Dameshek Prize (ASH), Noble Prize (NCIC), Michael Smith Award (CIHR), and most recently he shared the Diamond Jubilee Award (NCIC) with Drs. James Till and Ernest McCulloch. He has expertise in stem cells, NOD/SCID mice, gene transfer, transplantation, retroviruses, leukemia, oncogenes, hematopoiesis, and lentivectors.
Glossary
ALL
acute lymphoblastic leukemia
AML
acute myeloid leukemia
CML
chronic myelogenous leukemia
CSC
cancer stem cell
Cytogenetics
the branch of biology linking the study of genetic inheritance with the study of cell structure
Flow Cytometry
the detection and quantification of cellular parameters as cells are carried in a liquid stream through a nozzle that is illuminated by one or more lasers emitting light of defined wavelengths which excite a variety of fluorescent dyes
HSC
Toronto’s Hospital for Sick Children
MDS
myelodysplastic syndrome (a rare blood disorder)
Morphology
the form and structure of organisms
OCI
Ontario Cancer Institute at The Princess Margaret
TGH / TGRI
Toronto General Hospital and Toronto General Research Institute
Xenotransplant
a surgical procedure in which tissue or whole organs are transferred from one species to another species (in the case of the cancer stem cell research at OCI, this is primarily transplanting cells or tissue from a human to a mouse)
Multimedia
A Brief Interview with Dr. John Dick (2 min)
»Video
Dr. John Dick’s Cancer Stem Cell presentation at Princess Margaret Hospital: Behind the Scenes
»Part 1
»Part 2
Further Reading
Scientists Weigh Stem Cells’ Role as Cancer Cause, New York Times, Dec 21, 2007, Gina Kolata.
»View Article
Stem Cells That Kill, Time Magazine, Apr 17, 2006, Alice Park
»View Article
Stem Cells: The Real Culprits in Cancer?, Scientific American, July 2006, Michael F. Clarke and Michael W. Becker.
»View Article
Stem Cells May be Key to Cancer, New York Times, Feb 21, 2006, Nicholas Wade
»View Article
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