Stem cell

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Mouse embryonic stem cells with fluorescent marker.

Human Embryonic Stem cell colony on mouse embryonic fibroblast feeder layer.

Stem cells are cells found in most, if not all, multi-cellular organisms. They are
characterized by the ability to renew themselves through mitotic cell division and
differentiating into a diverse range of specialized cell types. Research in the stem cell
field grew out of findings by Canadian scientists Ernest A. McCulloch and James E. Till
in the 1960s.[1][2] The two broad types of mammalian stem cells are: embryonic stem
cells that are found in blastocysts, and adult stem cells that are found in adult tissues. In
a developing embryo, stem cells can differentiate into all of the specialized embryonic
tissues. In adult organisms, stem cells and progenitor cells act as a repair system for the
body, replenishing specialized cells, but also maintain the normal turnover of
regenerative organs, such as blood, skin or intestinal tissues.

As stem cells can be grown and transformed into specialized cells with characteristics
consistent with cells of various tissues such as muscles or nerves through cell culture,
their use in medical therapies has been proposed. In particular, embryonic cell lines,
autologous embryonic stem cells generated through therapeutic cloning, and highly
plastic adult stem cells from the umbilical cord blood or bone marrow are touted as
promising candidates.[3]

Contents
[hide]

• 1 Properties of stem cells

o 1.1 Potency definitions
o 1.2 Identifying stem cells
• 2 Embryonic stem cells
• 3 Adult stem cells
• 4 Lineage
• 5 Treatments
• 6 Controversy surrounding human embryonic stem cell research
• 7 Key stem cell research events
• 8 Stem cell funding & policy debate in the US
• 9 See also
• 10 References

• 11 External links

[edit] Properties of stem cells

The classical definition of a stem cell requires that it possess two properties:

• Self-renewal - the ability to go through numerous cycles of cell division while

maintaining the undifferentiated state.
• Potency - the capacity to differentiate into specialized cell types. In the strictest
sense, this requires stem cells to be either totipotent or pluripotent - to be able to
give rise to any mature cell type, although multipotent or unipotent progenitor
cells are sometimes referred to as stem cells.

[edit] Potency definitions

Pluripotent, embryonic stem cells originate as inner mass cells within a blastocyst. The
stem cells can become any tissue in the body, excluding a placenta. Only the morula's
cells are totipotent, able to become all tissues and a placenta.

Potency specifies the differentiation potential (the potential to differentiate into different
cell types) of the stem cell.

• Totipotent stem cells are produced from the fusion of an egg and sperm cell.
Cells produced by the first few divisions of the fertilized egg are also totipotent.
These cells can differentiate into embryonic and extraembryonic cell types.

• Pluripotent stem cells are the descendants of totipotent cells and can differentiate
into cells derived from any of the three germ layers.

• Multipotent stem cells can produce only cells of a closely related family of cells
(e.g. hematopoietic stem cells differentiate into red blood cells, white blood cells,
platelets, etc.).

• Unipotent cells can produce only one cell type, but have the property of self-
renewal which distinguishes them from non-stem cells (e.g. muscle stem cells).

[edit] Identifying stem cells

The practical definition of a stem cell is the functional definition - the ability to
regenerate tissue over a lifetime. For example, the gold standard test for a bone marrow
or hematopoietic stem cell (HSC) is the ability to transplant one cell and save an
individual without HSCs. In this case, a stem cell must be able to produce new blood
cells and immune cells over a long term, demonstrating potency. It should also be
possible to isolate stem cells from the transplanted individual, which can themselves be
transplanted into another individual without HSCs, demonstrating that the stem cell was
able to self-renew.

Properties of stem cells can be illustrated in vitro, using methods such as clonogenic
assays, where single cells are characterized by their ability to differentiate and self-
renew.[4][5] As well, stem cells can be isolated based on a distinctive set of cell surface
markers. However, in vitro culture conditions can alter the behavior of cells, making it
unclear whether the cells will behave in a similar manner in vivo. Considerable debate
exists whether some proposed adult cell populations are truly stem cells.

[edit] Embryonic stem cells

Main article: Embryonic stem cell

Embryonic stem cell lines (ES cell lines) are cultures of cells derived from the epiblast
tissue of the inner cell mass (ICM) of a blastocyst or earlier morula stage embryos.[6] A
blastocyst is an early stage embryo—approximately four to five days old in humans and
consisting of 50–150 cells. ES cells are pluripotent and give rise during development to
all derivatives of the three primary germ layers: ectoderm, endoderm and mesoderm. In
other words, they can develop into each of the more than 200 cell types of the adult body
when given sufficient and necessary stimulation for a specific cell type. They do not
contribute to the extra-embryonic membranes or the placenta.

Nearly all research to date has taken place using mouse embryonic stem cells (mES) or
human embryonic stem cells (hES). Both have the essential stem cell characteristics, yet
they require very different environments in order to maintain an undifferentiated state.
Mouse ES cells are grown on a layer of gelatin and require the presence of Leukemia
Inhibitory Factor (LIF).[7] Human ES cells are grown on a feeder layer of mouse
embryonic fibroblasts (MEFs) and require the presence of basic Fibroblast Growth Factor
(bFGF or FGF-2).[8] Without optimal culture conditions or genetic manipulation,[9]
embryonic stem cells will rapidly differentiate.

A human embryonic stem cell is also defined by the presence of several transcription
factors and cell surface proteins. The transcription factors Oct-4, Nanog, and SOX2 form
the core regulatory network that ensures the suppression of genes that lead to
differentiation and the maintenance of pluripotency.[10] The cell surface antigens most
commonly used to identify hES cells are the glycolipids SSEA3 and SSEA4 and the
keratan sulfate antigens Tra-1-60 and Tra-1-81. The molecular definition of a stem cell
includes many more proteins and continues to be a topic of research.[11]

After nearly ten years of research[12], there are no approved treatments or human trials
using embryonic stem cells. ES cells, being totipotent cells, require specific signals for
correct differentiation - if injected directly into another body, ES cells will differentiate
into many different types of cells, causing a teratoma. Differentiating ES cells into usable
cells while avoiding transplant rejection are just a few of the hurdles that embryonic stem
cell researchers still face.[13] Many nations currently have moratoria on either ES cell
research or the production of new ES cell lines. Because of their combined abilities of
unlimited expansion and pluripotency, embryonic stem cells remain a theoretically
potential source for regenerative medicine and tissue replacement after injury or disease.

[edit] Adult stem cells

Main article: Adult stem cell

Stem cell division and differentiation. A - stem cell; B - progenitor cell; C -

differentiated cell; 1 - symmetric stem cell division; 2 - asymmetric stem cell division; 3 -
progenitor division; 4 - terminal differentiation

The term adult stem cell refers to any cell which is found in a developed organism that
has two properties: the ability to divide and create another cell like itself and also divide
and create a cell more differentiated than itself. Also known as somatic (from Greek
Σωματικóς, "of the body") stem cells and germline (giving rise to gametes) stem cells,
they can be found in children, as well as adults.[14]

Pluripotent adult stem cells are rare and generally small in number but can be found in a
number of tissues including umbilical cord blood.[15] A great deal of adult stem cell
research has focused on clarifying their capacity to divide or self-renew indefinitely and
their differentiation potential.[16] In mice, pluripotent stem cells are directly generated
from adult fibroblast cultures.[17]

Most adult stem cells are lineage-restricted (multipotent) and are generally referred to by
their tissue origin (mesenchymal stem cell, adipose-derived stem cell, endothelial stem
cell, etc.).[18][19]

Adult stem cell treatments have been successfully used for many years to treat leukemia
and related bone/blood cancers through bone marrow transplants.[20] Adult stem cells are
also used in veterinary medicine to treat tendon and ligament injuries in horses.[21] The
use of adult stem cells in research and therapy is not as controversial as embryonic stem
cells, because the production of adult stem cells does not require the destruction of an
embryo. Additionally, because in some instances adult stem cells can be obtained from
the intended recipient, (an autograft) the risk of rejection is essentially non-existent in
these situations. Consequently, more US government funding is being provided for adult
stem cell research.[22]

[edit] Lineage
Main article: Stem cell line

To ensure self-renewal, stem cells undergo two types of cell division (see Stem cell
division and differentiation diagram). Symmetric division gives rise to two identical
daughter cells both endowed with stem cell properties. Asymmetric division, on the other
hand, produces only one stem cell and a progenitor cell with limited self-renewal
potential. Progenitors can go through several rounds of cell division before terminally
differentiating into a mature cell. It is possible that the molecular distinction between
symmetric and asymmetric divisions lies in differential segregation of cell membrane
proteins (such as receptors) between the daughter cells.[23]

An alternative theory is that stem cells remain undifferentiated due to environmental cues
in their particular niche. Stem cells differentiate when they leave that niche or no longer
receive those signals. Studies in Drosophila germarium have identified the signals dpp
and adherins junctions that prevent germarium stem cells from differentiating.[24][25]

Main article: Induced Pluripotent Stem Cell

The signals that lead to reprogramming of cells to an embryonic-like state are also being
investigated. These signal pathways include several transcription factors including the
oncogene c-Myc. Initial studies indicate that transformation of mice cells with a
combination of these anti-differentiation signals can reverse differentiation and may
allow adult cells to become pluripotent.[26] However, the need to transform these cells
with an oncogene may prevent the use of this approach in therapy.

[edit] Treatments
Main article: Stem cell treatments

Medical researchers believe that stem cell therapy has the potential to dramatically
change the treatment of human disease. A number of adult stem cell therapies already
exist, particularly bone marrow transplants that are used to treat leukemia.[27] In the
future, medical researchers anticipate being able to use technologies derived from stem
cell research to treat a wider variety of diseases including cancer, Parkinson's disease,
spinal cord injuries, Amyotrophic lateral sclerosis and muscle damage, amongst a number
of other impairments and conditions.[28][29] However, there still exists a great deal of social
and scientific uncertainty surrounding stem cell research, which could possibly be
overcome through public debate and future research, and further education of the public.

Stem cells, however, are already used extensively in research, and some scientists do not
see cell therapy as the first goal of the research, but see the investigation of stem cells as
a goal worthy in itself.[30]

[edit] Controversy surrounding human embryonic stem

cell research
Main article: Stem cell controversy

There exists a widespread controversy over human embryonic stem cell research that
emanates from the techniques used in the creation and usage of stem cells. Human
embryonic stem cell research is controversial because, with the present state of
technology, starting a stem cell line requires the destruction of a human embryo and/or
therapeutic cloning. However, recently, it has been shown in principle that adult stem cell
lines can be manipulated to generate embryonic-like stem cell lines using a single-cell
biopsy similar to that used in preimplantation genetic diagnosis that may allow stem cell
creation without embryonic destruction.[31] It is not the entire field of stem cell research,
but the specific field of human embryonic stem cell research that is at the centre of an
ethical debate.

Opponents of the research argue that embryonic stem cell technologies are a slippery
slope to reproductive cloning and can fundamentally devalue human life. Those in the
pro-life movement argue that a human embryo is a human life and is therefore entitled to
protection.

Contrarily, supporters of embryonic stem cell research argue that such research should be
pursued because the resultant treatments could have significant medical potential. It is
also noted that excess embryos created for in vitro fertilization could be donated with
consent and used for the research.

The ensuing debate has prompted authorities around the world to seek regulatory
frameworks and highlighted the fact that stem cell research represents a social and ethical
challenge.

[edit] Key stem cell research events

• 1960s - Joseph Altman and Gopal Das present scientific evidence of adult
neurogenesis, ongoing stem cell activity in the brain; their reports contradict
Cajal's "no new neurons" dogma and are largely ignored.
• 1963 - McCulloch and Till illustrate the presence of self-renewing cells in mouse
bone marrow.
• 1968 - Bone marrow transplant between two siblings successfully treats SCID.
• 1978 - Haematopoietic stem cells are discovered in human cord blood.
• 1981 - Mouse embryonic stem cells are derived from the inner cell mass by
scientists Martin Evans, Matthew Kaufman, and Gail R. Martin. Gail Martin is
attributed for coining the term "Embryonic Stem Cell".
• 1992 - Neural stem cells are cultured in vitro as neurospheres.
• 1997 - Leukemia is shown to originate from a haematopoietic stem cell, the first
direct evidence for cancer stem cells.
• 1998 - James Thomson and coworkers derive the first human embryonic stem cell
line at the University of Wisconsin-Madison.
• 2000s - Several reports of adult stem cell plasticity are published.
• 2001 - Scientists at Advanced Cell Technology clone first early (four- to six-cell
stage) human embryos for the purpose of generating embryonic stem cells.[32]
• 2003 - Dr. Songtao Shi of NIH discovers new source of adult stem cells in
children's primary teeth.[33]
• 2004-2005 - Korean researcher Hwang Woo-Suk claims to have created several
human embryonic stem cell lines from unfertilised human oocytes. The lines were
later shown to be fabricated.
• 2005 - Researchers at Kingston University in England claim to have discovered a
third category of stem cell, dubbed cord-blood-derived embryonic-like stem cells
(CBEs), derived from umbilical cord blood. The group claims these cells are able
to differentiate into more types of tissue than adult stem cells.
• August 2006 - Rat Induced pluripotent stem cells: the journal Cell publishes
Kazutoshi Takahashi and Shinya Yamanaka, "Induction of Pluripotent Stem Cells
from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors".
• October 2006 - Scientists in England create the first ever artificial liver cells
using umbilical cord blood stem cells.[34][35]
• January 2007 - Scientists at Wake Forest University led by Dr. Anthony Atala
and Harvard University report discovery of a new type of stem cell in amniotic
fluid.[5] This may potentially provide an alternative to embryonic stem cells for
use in research and therapy.[36]
 • June 2007 - Research reported by three different groups shows that normal skin
cells can be reprogrammed to an embryonic state in mice.[37] In the same month,
scientist Shoukhrat Mitalipov reports the first successful creation of a primate
stem cell line through somatic cell nuclear transfer[38]
• October 2007 - Mario Capecchi, Martin Evans, and Oliver Smithies win the 2007
Nobel Prize for Physiology or Medicine for their work on embryonic stem cells
from mice using gene targeting strategies producing genetically engineered mice
(known as knockout mice) for gene research.[39]
• November 2007 - Human Induced pluripotent stem cells: Two similar papers
released by their respective journals prior to formal publication: in Cell by
Kazutoshi Takahashi and Shinya Yamanaka, "Induction of Pluripotent Stem Cells
from Adult Human Fibroblasts by Defined Factors", and in Science by Junying
Yu, et al., from the research group of James Thomson, "Induced Pluripotent Stem
Cell Lines Derived from Human Somatic Cells": pluripotent stem cells generated
from mature human fibroblasts. It is possible now to produce a stem cell from
almost any other human cell instead of using embryos as needed previously, albeit
the risk of tumorigenesis due to c-myc and retroviral gene transfer remains to be
determined.
• January 2008 - Human embryonic stem cell lines were generated without
destruction of the embryo[40]
• January 2008 - Development of human cloned blastocysts following somatic cell
nuclear transfer with adult fibroblasts[41]
• February 2008 - Generation of Pluripotent Stem Cells from Adult Mouse Liver
and Stomach: these iPS cells seem to be more similar to embryonic stem cells
than the previous developed iPS cells and not tumorigenic, moreover genes that
are required for iPS cells do not need to be inserted into specific sites, which
encourages the development of non-viral reprogramming techniques. [42][43]

[edit] Stem cell funding & policy debate in the US

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• 1993 - As per the National Institutes of Health Revitalization Act, Congress and
President Bill Clinton give the NIH direct authority to fund human embryo
research for the first time.[44]
• 1995 - The U.S. Congress enacts into law an appropriations bill attached to which
is the Dickey Amendment which prohibited federally appropriated funds to be
used for research where human embryos would be either created or destroyed.
This predates the creation of the first human embryonic stem cell lines.
 • 1999 - After the creation of the first human embryonic stem cell lines in 1998 by
James Thomson of the University of Wisconsin, Harriet Rabb, the top lawyer at
the Department of Health and Human Services, releases a legal opinion that
would set the course for Clinton Administration policy. Federal funds, obviously,
could not be used to derive stem cell lines (because derivation involves embryo
destruction). However, she concludes that because human embryonic stem cells
"are not a human embryo within the statutory definition," the Dickey-Wicker
Amendment does not apply to them. The NIH was therefore free to give federal
funding to experiments involving the cells themselves. President Clinton strongly
endorses the new guidelines, noting that human embryonic stem cell research
promised "potentially staggering benefits." And with the guidelines in place, the
NIH begins accepting grant proposals from scientists.[45]
• 02 November, 2004 - California voters approve Proposition 71, which provides
$3 billion in state funds over ten years to human embryonic stem cell research.
• 2001-2006 - U.S. President George W. Bush signs an executive order which
restricts federally-funded stem cell research on embryonic stem cells to the
already derived cell lines. He supports federal funding for embryonic stem cell
research on the already existing lines of approximately $100 million and $250
million for research on adult and animal stem cells.
• 5 May, 2006 - Senator Rick Santorum introduces bill number S. 2754, or the
Alternative Pluripotent Stem Cell Therapies Enhancement Act, into the U.S.
Senate.
• 18 July, 2006 - The U.S. Senate passes the Stem Cell Research Enhancement Act
H.R. 810 and votes down Senator Santorum's S. 2754.
• 19 July, 2006 - President George W. Bush vetoes H.R. 810 (Stem Cell Research
Enhancement Act), a bill that would have reversed the Gingrich-era
appropriations amendment which made it illegal for federal money to be used for
research where stem cells are derived from the destruction of an embryo.
• 07 November, 2006 - The people of the U.S. state of Missouri passed
Amendment 2, which allows usage of any stem cell research and therapy allowed
under federal law, but prohibits human reproductive cloning.[46]
• 16 February, 2007 – The California Institute for Regenerative Medicine became
the biggest financial backer of human embryonic stem cell research in the United
States when they awarded nearly $45 million in research grants.[47]

[edit] See also

Cancer stem cell

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Cancer stem cells (CSCs) are a sub-population of cancer cells (found within tumors or
hematological cancers) that possess characteristics normally associated with stem cells.
These cells are believed to be tumorigenic (tumor-forming), in contrast to the bulk of
cancer cells, which are thought to be non-tumorigenic. CSCs have stem cell properties
such as self-renewal and the ability to differentiate into multiple cell types. A theory
suggests such cells persist in tumors as a distinct population and cause relapse and
metastasis by giving rise to new tumours. Development of specific therapies targeted at
cancer stem cells holds hope for improvement of survival and quality of life of cancer
patients, especially for sufferers of metastatic disease.

Stem cell specific and conventional cancer therapies

Existing cancer treatments were mostly developed on animal models, where therapies
able to promote tumor shrinkage were deemed effective. However, animals could not
provide a complete model of human disease. In particular, in mice, whose life spans do
not exceed two years, tumor relapse is exceptionally difficult to study.

The efficacy of cancer treatments are, in the initial stages of testing, often measured by
the amount of tumour mass they kill off. As cancer stem cells would form a very small
proportion of the tumour, this may not necessarily select for drugs that act specifically on
the stem cells. The theory suggests that conventional chemotherapies kill differentiated or
differentiating cells, which form the bulk of the tumor but are unable to generate new
cells. A population of cancer stem cells, which gave rise to it, could remain untouched
and cause a relapse of the disease.

Contents
[hide]

• 1 Evidence for cancer stem cells

o 1.1 Importance of stem cells
o 1.2 Mechanistic and mathematical models
• 2 Where do cancer stem cells come from?
• 3 Implications for cancer treatment
• 4 Cancer stem cell pathways
o 4.1 Bmi-1
o 4.2 Notch
o 4.3 Sonic hedgehog and Wnt
• 5 External links

• 6 References

[edit] Evidence for cancer stem cells

Opponents of the paradigm do not deny the existence of cancer stem cells as such. Cancer
cells must be capable of continuous proliferation and self-renewal in order to retain the
many mutations required for carcinogenesis, and to sustain the growth of a tumor since
differentiated cells cannot divide indefinitely (constrained by the Hayflick Limit).
However, it is debated whether such cells represent a minority. If most cells of the tumor
are endowed with stem cell properties there is no incentive to focusing on a specific
subpopulation. There is also debate on the cell of origin of these cancer stem cells -
whether they originate from stem cells that have lost the ability to regulate proliferation,
or from more differentiated population of progenitor cells that have acquired abilities to
self-renew (which is related to the issue of stem cell plasticity).

The first conclusive evidence for cancer stem cells was published in 1997 in Nature
Medicine. Bonnet and Dick[1] isolated a subpopulation of leukaemic cells that express a
specific surface marker CD34, but lacks the CD38 marker. The authors established that
the CD34+/CD38- subpopulation is capable of initiating tumors in NOD/SCID mice that
is histologically similar to the donor. (Matsui, 2004)

In cancer research experiments, tumor cells are sometimes injected into an experimental
animal to establish a tumor. Disease progression is then followed in time and novel drugs
can be tested for their ability to inhibit it. However, efficient tumor formation requires
thousands or tens of thousands of cells to be introduced. Classically, this has been
explained by poor methodology (i.e. the tumor cells lose their viability during transfer) or
the critical importance of the microenvironment, the particular biochemical surroundings
of the injected cells. Supporters of the cancer stem cell paradigm argue that only a small
fraction of the injected cells, the cancer stem cells, have the potential to generate a tumor.
In human acute myeloid leukemia the frequency of these cells is less than 1 in 10,000.[1]

Further evidence comes from histology, the study of tissue structure of tumors. Many
tumors are very heterogeneous and contain multiple cell types native to the host organ.
Heterogeneity is commonly retained by tumor metastases. This implies that the cell that
produced them had the capacity to generate multiple cell types. In other words, it
possessed multidifferentiative potential, a classical hallmark of stem cells.[1]

The existence of leukaemic stem cells prompted further research into other types of
cancer. Cancer stem cells have recently been identified in several solid tumours,
including:

• Breast cancer[2]
• Brain cancer[3]
• Colon cancers[4]
• Pancreatic cancer[5]
• Ovarian cancer[6]

[edit] Importance of stem cells

Not only is finding the source of cancer cells necessary for successful treatments, but if
current treatments of cancer do not properly destroy enough cancer stem cells, the tumor
will reappear. Including the possibility that the treatment of for instance, chemotherapy,
will leave only chemotherapy-resistant cancer stem cells, then the ensuing tumor will
most likely also be resistant to chemotherapy. If the cancer tumor is detected early
enough, enough of the tumor can be killed off and marginalized with traditional
treatment. But as the tumor size increases, it becomes more and more difficult to remove
the tumor without conferring resistance and leaving enough behind for the tumor to
reappear.

Some treatments with chemotherapy, such as paclitaxel in ovarian cancer (a cancer

usually discovered in late stages), may actually serve to promote certain cancer growth
(55-75% relapse <2 years[7]). It potentially does this by destroying only the cancer cells
susceptible to the drug (targeting those that are CD44-positive, a trait which has been
associated with increased survival time in some ovarian cancers), and allowing the cells
which are unaffected by paclitaxel (CD44-negative) to regrow, even after a reduction in
over a third of the total tumor size.[6] There are studies, though, which show how
paclitaxel can be used in combination with other ligands to affect the CD44-positive
cells.[8] While paclitaxel alone, as of late, does not cure the cancer, it is effective at
extending the survival time of the patients.[7]

[edit] Mechanistic and mathematical models

Once the pathways to cancer are hypothesized, it is possible to develop predictive

mathematical biology models,[9] e.g., based on the cell compartment method. For
instance, the growths of the abnormal cells from their normal counterparts can be denoted
with specific mutation probabilities. Such a model has been employed to predict that
repeated insult to mature cells increases the formation of abnormal progeny, and hence
the risk of cancer.[10] Considerable work needs to be done, however, before the clinical
efficacy of such models is established.

[edit] Where do cancer stem cells come from?

This is still an area of ongoing research. Logically, the smallest change (and hence the
most likely mutation) to produce a cancer stem cell would be a mutation from a normal
stem cell. Also, in tissues with a high rate of cell turnover (such as the skin or GI
epithelium, where cancers are common), it can be argued that stem cells are the only cells
that live long enough to acquire enough genetic abnormalities to become cancerous.
However it is still possible that more differentiated cancer cells (in which the genome is
less stable) could acquire properties of 'stemness'.

It is likely that in a tumour there are several lines of stem cells, with new ones being
created and others dying off as a tumour grows and adapts to its surroundings.[11] Hence,
tumour stem cells can constitute a 'moving target', making them even harder to treat.
[edit] Implications for cancer treatment
The existence of cancer stem cells have several implications in terms of future cancer
treatment and therapies. These include disease identification, selective drug targets,
prevention of metastasis, and development of new strategies in fighting cancer.

Normal somatic stem cells are naturally resistant to chemotherapeutic agents - they have
various pumps (such as MDR) that pump out drugs, DNA repair proteins and they also
have a slow rate of cell turnover (chemotherapeutic agents naturally target rapidly
replicating cells). Cancer stem cells, being the mutated counterparts of normal stem cells,
may also have similar functions which allows them to survive therapy. These surviving
cancer stem cells then repopulates the tumour, causing relapse. By selectively targeting
cancer stem cells, it would be possible to treat patients with aggressive, non-resectable
tumours, as well as preventing the tumour from metastasizing. The hypothesis implies
that if the cancer stem cells are eliminated, the cancer would simply regress due to
differentiation and cell death.

There has also been a lot of research into finding specific markers that may distinguish
cancer stem cells from the bulk of the tumour (as well as from normal stem cells), with
some success.[12] Proteomic and genomic signatures of tumours are also being
investigated. Success in these area would enable faster identification of tumour subtypes
as well as personalized medicine in cancer treatments by using the right combination of
drugs and/or treatments to efficiently eliminate the tumour.

[edit] Cancer stem cell pathways

A normal stem cell may be transformed into a cancer stem cell through disregulation of
the proliferation and differentiation pathways controlling it. Scientists working on cancer
stem cells hope to design new drugs targeting these cellular mechanisms. The first
findings in this area were made using haematopoietic stem cells (HSCs) and their
transformed counterparts in leukemia, the disease whose stem cell origin is most strongly
established. However, these pathways appear to be shared by stem cells of all organs.

[edit] Bmi-1

The Polycomb group transcriptional repressor Bmi-1 was discovered as a common

oncogene activated in lymphoma[13] and later shown to specifically regulate HSCs.[14] The
role of Bmi-1 has also been illustrated in neural stem cells.[15] The pathway appears to be
active in cancer stem cells of pediatric brain tumors.[16]

[edit] Notch

The Notch pathway has been known to developmental biologists for decades. Its role in
control of stem cell proliferation has now been demonstrated for several cell types
including haematopoietic, neural and mammary[17] stem cells. Components of the Notch
pathway have been proposed to act as oncogenes in mammary[18] and other tumors.

[edit] Sonic hedgehog and Wnt

These developmental pathways are also strongly implicated as stem cell regulators.[19]
Both Sonic hedgehog(SHH) and Wnt pathways are commonly hyperactivated in tumors
and are required to sustain tumor growth. However, the Gli transcription factors that are
regulated by SHH take their name from gliomas, where they are commonly expressed at
high levels. A degree of crosstalk exists between the two pathways and their activation
commonly goes hand-in-hand.[20] This is a trend rather than a rule. For instance, in colon
cancer hedgehog signalling appears to antagonise Wnt.[21]

Sonic hedgehog blockers are available, such as cyclopamine. There is also a new water
soluble cyclopamine that may be more effective in cancer treatment. There is also
DMAPT, a water soluble derivative of parthenolide that targets AML (leukemia) stem
cells, and possibly other cancer stem cells as in myeloma or prostate cancer. A clinical
trial of DMAPT is to start in England in late 2007 or 2008. Furthermore, GRN163L was
recently started in trials to target myeloma stem cells. If it is possible to eliminate the
cancer stem cell, than a potential cure may be achieved if there are no more cancer stem
cells to repopulate a cancer.