There has been a great deal of work on stem cells (see our White Paper). We may
think of such cells as being part of the embryo, and in the placenta at birth.
They are thought of as the universal cell generator. Theoretically the stem
cell should become whatever cell type we may want it to be. In a more narrow
sense there may be a variety of localized stem cells, namely cells which
replenish local cells which are worn away such as on the skin or in the colon.
It is not the mature cells which do the reproducing but it is the few stem
cells which reside in say the basal layer of the skin which reproduce and
create off spring which are just plain old keratinocytes.
In this note we examine in some detail the prostate stem
cell, and in turn we generate the ability to consider the cancer stem cell
issue in broader detail. We have discussed this issue in our draft volume on
Prostate Cancer Genomics, and this is an additive section as that volume
progresses.
The focus is on stem cells. It does not address the pathways
which are different or activated. That in itself is a critical question. Namely
what differentiates a stem cell from a mature non stem like cell when we
examine the pathways? Thus when looking at PCa we see that pathway changes are
then most likely pathway changes in the stem cell alone, yet if the
agglomeration of stem cells is such that the non-stem constituents reflect the
genetic makeup of the stem cell, then we would expect some parity in pathway
dynamics. This will be an issue we examine in a later report.
The cancer stem cell theory has been developed over the past
decade or so. For many years the theory was that cancer was clonal, namely one
single cell was at fault and its progeny were the direct result of that
genetically modified parent, a single parent, and that as the cancer evolved
there may be increased genetic defects but again all were from a single parent.
Cancer stems cells are a construct which predicates the
development of mature cells in a cell line as coming from a set of stem cells,
akin to the blood cells arising from the bone. In contrast to the linear model
of Vogelstein, say in the colon, the epithelial cell of the colon wall has some
genetic disruption, and after multiple disruptions this epithelial cell becomes
cancerous, dividing without bounds and failing to remain where is was supposed
to. Typically an adenoma develops which after the final genetic hit becomes an
adenocarcinoma.
For example, we have examined the prostate cancer cell, and
in so doing have used a non CSC model, namely it is a basal or luminal cell
which becomes genetically changed. If however we are wrong and there is an
equivalent prostate cancer stem cell, as some have conjectured, then management
of cancer of the prostate is quite a different thing. As we have expressed
before, if one has diffuse HGPIN in the prostate and then after several high
density prostate biopsies it disappears, is that inferentially valid for a
prostate CSC?
The cancer stem cell construct is fundamentally different.
It is not a mature cell which takes the genetic hits but the stem cell. The
malignant stem cell acts almost as a force at a distance, and can impact other
cells as the stem cell itself can reproduce, albeit at a somewhat slower rate
than what it may influence.
Arguably if one can remove the stem cell then one removes
any future malignancy, even to the extent of having other cells enter apoptosis
for failure of having an active stem cell.
As Weinberg notes, there is the theory of clonal development
of cancer which states that the cancer cells are pluripotent and have developed
from a single source and that they have the capability of reproducing and do so
in an autonomous manner[1]. Then there is the theory
of the cancer stem cell, the theory which states that there is the equivalent
of a stem cell as we know in blood cells, which have the capability but that
the majority of malignant cells do not necessarily have that capacity.
The NCI presents an excellent summary of Cancer stem cell,
CSC, research[2]:
The theory of the
cancer stem cell (CSC) has generated as much excitement and optimism as perhaps
any area of cancer research over the last decade. Biologically, the theory
goes, these cells are distinct from the other cells that form the bulk of a
tumor in that they can self-perpetuate and produce progenitor cells, the way
that traditional stem cells do. The progenitors’ job is then to repopulate
tumor cells eradicated by treatments such as chemotherapy or radiation.
But for all the
attention and fanfare CSC research has received, the findings reported to date
are far from clear-cut, investigators acknowledge. For example, most of the
studies that have identified human CSCs have used mouse xenograft assays and
cells from only a small number of human tumor samples, making it difficult to
draw firm conclusions. In addition, other researchers haven’t always been
able to replicate initially reported findings. And while these tumor-initiating
cells, as they are also called, have been described as being a rare class,
several studies have found that the number of cells that can form tumors in
these mouse experiments is actually quite large, suggesting that perhaps CSCs
aren’t such a privileged breed.
As we shall discuss
herein, the CSC does not yet have a steady state definition or description.
Furthermore it is also difficult to tag and identify. In the above definition,
there is the issue of what makes the stem cell different and how many are there
and how do we identify it. The CSC is in one sense the single cell which can
regenerate a full cancer growth. But does that mean in vivo or in vitro or
both? Murine models have been used extensively but there are serious questions
regarding their extensibility.
We shall discuss some
of these issues in this report. Now the NCI goes on to say:
In other words, the
idea of just what cancer stem cells are, and their role in different cancers,
appears to be changing.
“The [stem cell] model
has not been adequately tested in most cancers,” said Dr. Sean Morrison, who
directs the Center for Stem Cell Biology at the University of Michigan. “I
think that there are some cancers that do clearly follow a cancer stem cell
model…But it will be more complicated than what’s been presented so far.”
They continue by noting a significant conclusion of the CSC
theory, the fact that the CSC is the controlling cell, not just any cell.
Specifically they state:
Unlike the random or
“stochastic” model dominant in cancer research, which holds that nearly any
cancer cell has the potential to form a tumor, the cancer stem cell model is
one of a hierarchical organization, with the pluripotent cancer stem cell
sitting ready and able to amass all of the components of the original tumor.
It’s also thought,
with some experimental evidence to support it, that CSC pluripotency allows
these cells to adapt and to resist chemotherapy, radiation therapy, and even
current molecularly targeted therapies. If true, then these treatments may not
harm the most lethal tumor cells, those that can lead to a recurrence with the
production of a new set of progenitors.
Despite numerous
studies published in the last 16 years that identified CSCs for different
cancers—including colon, brain, pancreatic, and breast cancer—the consensus
among researchers seems to be that the evidence is strongest for the first
cancer in which a population of tumor-initiating cells was discovered, acute
myeloid leukemia (AML), as well as for other blood cancers.
The above has substantial positive and negative impact. A
single stem cell may control everything, for a while. If however it undergoes
mitosis then we may have many stem cells. Or we may keep a single one. For
example if a stem cell in mitosis reproduces a single stem cell plus a non-stem
cancer cell, then we maintain single CSCs, while we multiply the malignant non
CSC cells. However, if the CSC in mitosis just multiples itself for a while,
then we end up with a collection of very powerful and spreadable bombs of CSCs.
The NCI also continues:
“The reason why
it’s so much stronger for hematologic malignancies are because hematopoiesis
research goes back 40 or 50 years and it’s very stem cell-based,” said Dr. Jean
Wang, a stem cell researcher at the University of Toronto. “Whereas in solid
tumors, there’s less of a foundation for identifying the normal cellular
hierarchies and for [cell-surface] markers that identify different populations
of cells like stem cells and progenitors.”
The above comment has some merit but one must also recognize
that the hematopoietic cells are fundamentally generated in a specific
location, the bone, and there may very well be no such locations specificity
for the many other cells we are considering. Nevertheless, we continue:
Even so, Dr. Wang believes the existence of CSCs is
pretty well demonstrated for breast and brain cancers. But, she cautioned, “I
don’t know if it applies to all cancers. In a lot [of cancers] it does seem to
apply. But most of the markers we have right now are still very rough.”
Despite the evidence for CSC-like cells in a growing
number of cancers, the theory clearly has its skeptics, who point to problems
such as shortcomings in the mouse xenograft assay and the variable specificity
of the cell-surface markers used to demarcate a CSC from a non-CSC.
“I still feel that it’s a concept yet to be proven,” said
Dr. Barbara Vonderhaar, who, along with colleagues in NCI’s Center for Cancer
Research, recently published a study identifying a population of CSC-like cells
in estrogen receptor-negative breast cancer. “It’s certainly a good idea, but
it’s only a hypothesis at this point. We still don’t have definitive proof that
cancer stem cells exist.”
The CSC concept is “a work in transition,” said Dr.
William Matsui, from the Johns Hopkins School of Medicine, whose lab studies
the role of stem cells in hematologic cancers. “To me, as a clinical person,
the ideal model is one where you can find something that is going to work in
humans. We’re far from that.”
The existence of CSCs in PCa has been examined and as with
many cancers is still open for discussion. However as we shall discuss later
the CSC model does have certain interesting uses in the progression and
metastasis of cancer.
For example:
Cell Proliferation: If we assume that the CSC is the
dominant cell that proliferates and all others do not, albeit being cancer
cells themselves, then the growth of PCa in terms of cells is complex but one
can then more easily explain indolent PCa.
Metastasis: We know that metastasis occurred by lymphatic and
hematological means. However PCa cells, non-CSC PCa cells may break loose and
yet not result in classic metastasis. The issue then is one where it may be
necessary for the CSC to move by these means.
Many other such issues will arise and we discuss the CSC
idea here and we return to it later in the work.
Now we can view the stem cells as shown below. There is a
stem cell which can give rise to a new stem cell of ultimately a Post Mitotic
Differentiated Cancer Cell. The PMDC cannot replicate, whereas the stem cell
can. For metastasis it is thus necessary to send out a few stem cells, not PMDC
cells.
The first issue is a definition of a stem cell. We may
understand stem cell from the hematopoietic stem cells found in the bone which
give rise to a variety of blood cells and other types of cells. In fact almost
all cells in the body which require some form of replenishment have such stem
cells. Consider the skin. The basal layer has stem cells to generate the
keratinocytes. In fact it may be argued that melanocytes have their own stem
cells as well.
Cells are reproducing via the cell cycle as we show below
and discuss in Appendix B. With a stem cell, it is only that cell which does
the mitotic division; all other cells are just mature functioning cells subject
to normal cell death or apoptosis.
The question is however, which cells. Which cells are the
stem cells? Are all cells reproducing or just some select class of cells. The
concept of stem cells makes the issue one of a small select group of cells.
These are the stem cells.
As Alberts et al state (pp 1417-1421):
Humans renew the outer layers of their epidermis a
thousand times over in the course of a lifetime. In the basal layer, there have
to be cells that can remain undifferentiated and carry on dividing for this
whole period, continually throwing off descendants that commit to
differentiation, leave the basal layer, and are eventually discarded.
The process can be maintained only if the basal cell
population is self-renewing. It must therefore contain some cells that generate
a mixture of progeny, including daughters that remain undifferentiated like
their parent, as well as daughters that differentiate. Cells with this property
are called stem cells.
They have so important a role in such a variety of
tissues that it is useful to have a formal definition. The defining properties
of a stem cell are as follows:
1. It is not itself terminally differentiated (that is,
it is not at the end of a pathway of differentiation).
2. It can divide without limit (or at least for the
lifetime of the animal).
3. When it divides, each daughter has a choice: it can
either remain a stem cell, or it can embark on a course that commits it to
terminal differentiation.
Stem cells are required wherever there is a recurring
need to replace differentiated cells that cannot themselves divide. The stem
cell itself has to be able to divide—that is part of the definition—but it
should be noted that it does not necessarily have to divide rapidly; in fact,
stem cells usually divide at a relatively slow rate.
We present below a simplified example of a specialized stem
cell. The stem cell is the only one of its kind to divide. The mature cells do
not generally divide; they are just functional and proceed to mature. The stem
cell always produces at least one of its own kinds, another stem cell, and then
one of the mature like cells. Note the initial stem cell. In this example we
allow it to divide and produce one stem cell and one maturing cell. Thus at
some point this process just keeps the number of stem cells constant but can
produce an ever growing number of maturing cells.
Now when we examine the above we can see that if the stem
cell divides once every hour, and the life of a mature cell is say 24 hours,
then we have a growth effect. We must have a cell stability of one
replenishment per one destroyed. During a growth state however, the stem cells
are reproducing quickly and cells are added. The stem cell responds to surface
stimulants to enter into cell cycle production.
As Tang et al state:
Normal adult stem cells (SC) have several fundamental
properties: they are generally very rare, can self-renew, have tremendous
proliferative potential but normally (i.e., in their niches) are quiescent, and
can differentiate along one or several different cell lineages.
The most defining property of a SC is its ability to
self-renew while being able to differentiate into all different lineages of
progeny and even to reconstitute an organ, as exemplified by a single
hematopoietic SC (HSC) to reconstitute the whole blood and rescue an irradiated
mouse. SC development is a continuous and dynamic process, in which cells with
distinct self-renewal, proliferative, and differentiation abilities may
co-exist.
For example, mouse HSC are heterogeneous populations of
cells containing long-term HSC (LT-HSC), which can sustain life-long
self-renewal and reconstitution, and short-term HSC (ST-HSC), which can sustain
self-renewal and reconstitution for only 8 wk. The ST-HSC generate multi-potent
progenitor (MPP) cells exhibiting only limited self-renewal capacity, which
then further develop into lineage-restricted progenitor (or precursor) cells
that have lost self-renewal ability.
Although this paradigm of LT-HSCST-HSC early progenitors
(MPP) late progenitors differentiated cells in mouse bone marrow can, in
principle, be applied to other SC developmental processes, in reality, little
is known about most tissue SC lineages and we often name the subsets of cells
in a specific tissue/organ with certain self-renewal and differentiation
abilities simply stem/progenitor cells. Such is the case with the putative
prostate epithelial stem and progenitor cells.
Consequently, throughout this review, we shall frequently
use the term ‘(prostate) stem/ progenitor cells.’
The above feature of maturing into various lineages is clearly
seen in blood cells but one may question just where it functions say in
prostate cells. Is there a single stem cell which generates either a basal or
luminal cell or if so where does it reside, and how does this differentiation occur?
This is the point made by Tang et al towards the end of the above quote.
Cancer stem cells are a variant of the benign stem cell.
Namely a cancer stem cell is a cell which behaves like a stem cell in terms of
cell proliferation but now has genetic changes which reflect malignant
behavior. In an NIH report the authors define cancer stem cells as follows:
A consensus panel
convened by the American Association of Cancer Research has defined a CSC as
"a cell within a tumor that possesses the capacity to self-renew and to
cause the heterogeneous lineages of cancer cells that comprise the tumor." It
should be noted that this definition does not indicate the source of these
cells—these tumor-forming cells could hypothetically originate from stem, progenitor,
or differentiated cells.
As such, the terms
"tumor-initiating cell" or "cancer-initiating cell" are
sometimes used instead of "cancer stem cell" to avoid confusion.
Tumors originate from the transformation of normal cells through the accumulation
of genetic modifications, but it has not been established unequivocally that
stem cells are the origin of all CSCs.
The CSC hypothesis
therefore does not imply that cancer is always caused by stem cells or that the
potential application of stem cells to treat conditions such as heart disease
or diabetes, as discussed in other chapters of this report, will result in
tumor formation. Rather, tumor-initiating cells possess stem-like
characteristics to a degree sufficient to warrant the comparison with stem
cells; the observed experimental and clinical behaviors of metastatic cancer
cells are highly reminiscent of the classical properties of stem cells.
The stem cell theory, and there seems now to be significant
evidence of its validity in prostate cancer, is principally that the clonal
theory has merit to a point but that the development is more complex and the
cancer stem cell plays a critical role in fostering growth of the cancer cells,
most of which has less aggressive a growth characteristic if any at all.
Lawson and Witte present a recent overview of this concept
as applied to the prostate and PCa. Recent studies apparently indicate that the
cancer stem cells, CSC, are necessary to sustain later stages of the
development of the malignancy. Only a small subpopulation of the cancer cells,
the CSC population, has a demonstrated ability to maintain the malignancy as
well. Lawson and Witte present two theories of this CSC process. One is called
the stochastic theory which is that all cells are equally malignant. The other
theory, the one for CSC, called the hierarchical theory is that only the CSC
has the ability to multiply.
The CSC or in this case the PSC, prostate stem cell, yields
a TAC, or transition amplifying cells, then yield progenitor cells, LP or BP,
and then finally a luminal or basal cell. This is slight contrast to the
Goldstein model. This model applies for both benign as well as cancer cells, at
least as viewed by Lawson and Witte.
Now if one looks at the CSC theory, then we see a CSC has
progeny, and yet those progeny may not have the ability to multiply. Thus the
explosive exponential growth of cancer is not as clear in a CSC model, because
almost all of the progeny of the CSC are no reproducing progeny. Thus the
growth models for a CSC based malignancy are more complex and are dependent on
limited CSC reproduction and non-CSC reproduction. However the CSC model also
argues for there being some CSC support for the progeny which are not CSC. The
dynamics of cell growth then becomes quite complex here, for the stem cells
replicate themselves at a slow rate but are replicating other cells at a higher
rate. However the other cells do not replicate themselves they just go through
a standard cell process. If the cells are benign then they go through apoptosis
as seen in red blood cells and the skin keratinocytes.
We quote Lawson and Witte as follows:
Models of prostate
epithelial differentiation. The traditional model for prostate epithelial
differentiation proposes that PSCs residing in the basal cell layer give rise
to intermediate, transit-amplifying cells that produce large numbers of
terminally differentiated secretory luminal cells …. This model implies a
linear differentiation scheme in which basal and luminal cells comprise one
lineage and basal cells are essentially luminal cell progenitors …
This hypothesis is
supported by the existence of cells of intermediate phenotype that express both
basal- and luminal cell–specific cytokeratins in both fetal and adult stages of
prostate development … Intermediate cells can also be identified in in vitro
cultures of primary prostate epithelium … Several studies have also suggested
basal cells can differentiate into luminal cells in vitro … Alternative
theories for prostate epithelial differentiation propose basal and luminal
cells may represent separate epithelial lineages … This is similar to
prevailing models for epithelial differentiation in the mammary gland, a tissue
that is anatomically and functionally analogous to the prostate …
Now there have been several others who have examined the
stem cell model for PCa. Another of recent merit is that of Hurt et al. They
summarize their work as follows:
Recent evidence
supports the hypothesis that cancer stem cells are responsible for tumor initiation
and formation. Using flow cytometry, we isolated a population of CD44+CD24- prostate cells that display
stem cell characteristics as well as gene expression patterns that predict
overall survival in prostate cancer patients. CD44+CD24- cells form colonies in soft
agar and form tumours in NOD/SCID mice when as few as 100 cells are injected.
Furthermore,
CD44+CD24- cells
express genes known to be important in stem cell maintenance, such as BMI-1 and
Oct-3/4. Moreover, we can maintain CD44+CD24- prostate stem-like cells as non-adherent spheres in
serum-replacement media without substantially shifting gene expression.
Addition of serum results in adherence to plastic and shifts gene expression
patterns to resemble the differentiated parental cells.
Thus, we propose that
CD44+CD24- prostate
cells are stem-like cells responsible for tumor initiation and we provide a
genomic definition of these cells and the differentiated cells they give rise
to. Furthermore, gene expression patterns of CD44+CD24- cells have a genomic signature that is predictive of poor
patient prognosis. Therefore, CD44+CD24-
LNCaP prostate cells offer an attractive model system to both explore
the biology important to the maintenance and differentiation of prostate cancer
stem cells as well as to develop the therapeutics, as the gene expression
pattern in these cells is consistent with poor survival in prostate cancer
patients.
Jordan et al characterize cancer stem cells as having three
characteristics:
1. Self-Renewal: at the end of mitosis of the stem cell,
either one or both retain all the characteristics of the parent. The stem cell
goes through a mitotic doubling and when it does it always retains one or two
stem cell daughters.
2. Capability to generate multiple lineages. This means that
a stem cell can generate offspring which can become anyone of many cell types.
3. Potential to proliferate extensively. The cell can keep
replicating, it has no limitation within reason and thus contains the elements
ultimately for metastasis.
A normal stem cell may mutate to a cancer stem cell or a
normal progenitor cell may morph back to a cancer stem cell.
As Delarbra et al state:
Although monoclonal in origin, most tumors appear to contain a
heterogeneous population of cancer cells. This observation is traditionally explained by postulating variations
in tumor microenvironment and coexistence of multiple genetic subclones,
created by progressive and divergent accumulation of independent somatic
mutations.
An additional explanation, however, envisages human tumors not as mere
monoclonal expansions of transformed cells, but rather as complex
tridimensional tissues where cancer cells become functionally heterogeneous as
a result of differentiation.
According to this
second scenario, tumors act as caricatures of their corresponding normal
tissues and are sustained in their growth by a pathological counterpart of
normal adult stem cells, cancer stem cells.
The statement starts with the accepted monoclonal hypothesis
and then departs to a polyclonal alternative view. It retains the CSC, cancer
stem cell, paradigm for solid tumors as well. In the context of HGPIN we see a
change in the cells and we have heard the argument that they have made one or
several of the unchangeable steps towards PCa. Thus using the CSC theory one
would expect that it would be from one or several of these cells that PCa would
arise. In addition, we could assume that there is no unique pathway mutations
or changes which result in PCa but a plethora of them. Simply stated, cancer is
complex, it finds ways to migrate forward no matter what the path.
The statement starts with the accepted monoclonal hypothesis
and then departs to a polyclonal alternative view. It retains the CSC, cancer
stem cell, paradigm for solid tumors as well. In the context of HGPIN we see a
change in the cells and we have heard the argument that they have made one or
several of the unchangeable steps towards PCa.
Thus using the CSC theory one would expect that it would be
from one or several of these cells that PCa would arise. In addition, we could
assume that there is no unique pathway mutations or changes which result in PCa
but a plethora of them. Simply stated, cancer is complex, it finds ways to
migrate forward no matter what the path.
A recent study by Deleyrolle et al has
focused on the stem cell and its dynamics[3]. The reviewers state:
The method, published in the online journal PLoS ONE in
January, may rev up efforts to develop stem cell therapies for Alzheimer's,
Parkinson's and other diseases. It may also help get to the root of the
cancer-stem cell theory, which puts forth the idea that a tiny percentage of
loner cancer cells gives rise to tumors.
"Math is going to be the new microscope of the 21st
century because it is going to allow us to see things in biology that we cannot
see any other way," said Brent Reynolds, Ph.D., an associate professor of
neurosurgery at UF's McKnight Brain Institute and a member of the UF Shands
Cancer Center. "Stem cells and the cells that drive cancer may be as
infrequent as one in 10,000 or one in 100,000 cells. The problem is how do you
understand the biology of something whose frequency is so low?"
Inspired by a 2004 essay by Joel E. Cohen, Ph.D., of The
Rockefeller University and Columbia University that described the explosive
synergy between mathematics and biology, Reynolds and postdoctoral associate
Loic P. Deleyrolle set out to build an algorithm that could determine the rate
stem cells and cancer stem cells divide.
High hopes to treat or prevent diseases have been pinned
on these indistinguishable cells, which are often adrift in populations of
millions of other cells. Scientists know stem cells exist mainly because their
handiwork is everywhere — tissues heal and regenerate because of stem cells,
and somehow cancer may reappear years after it was thought to be completely
eliminated.
The concept of the cancer stem cell (CSC) has taken off
rapidly over the past 10 years. CSCs are cells with properties that are similar
to those described for tissue stem cells: self-renewal and asymmetric division
resulting in the generation of daughter cells destined to differentiate,
enabling the regeneration of a tissue. Initial research into the properties of
CSCs was based on identifying and verifying markers of this subset of cancer
cells.
However, most studies have now moved on to understanding
the biology of CSCs and the cancers in which they maintain tumour growth, as
well as how and why they are able to serially generate a tumour. It is thought
that a key element regulating the biology of stem cells is their niche — cells
and extracellular matrix that support self-renewal and survival. As we begin to
understand the pathways that are crucial for the properties of CSCs, including
signals provided by the niche, we will hopefully be able to effectively target
this cell population.
Linked to the identification of CSCs is the cell of
origin. These are cells that when mutated are able to give rise to a tumour. Although
these cells may share properties with CSCs, in most cases it is not yet clear
whether these cells are one and the same. This poster highlights some of the
recent findings regarding the biology of CSCs and the identification of cell
types from which cancers can arise.
As regards to prostate cancer they state:
In the normal prostate, epithelial cells with
tissue-regenerating capacity that are Sca1+, CD49fhi, TROP2hi, CD44+, CD133+
and CD117+ (mouse) or CD133+, CD44+, CD49fhi and TROP2+ (human) seem to reside
in the basal layer of the prostate. However, studies in mice indicate the
existence of luminal cells with progenitor characteristics that can regenerate
the prostate after androgen withdrawal. As castration resistance is also a
property of basal stem cells in the prostate, it suggests a complex cellular
hierarchy.
Studies in mice indicate that prostate tumours can arise
after transformation of basal stem cells and luminal progenitor cells. A subset
of cells that are CD133+, a2b1 + and CD44+ and have basal cell characteristics
have been shown to be tumorigenic, but whether these cells can serially
propagate tumours in mice has yet to be verified.
Again and interesting experiment can be performed:
1. Take biopsies from N men with HGPIN diagnosed on initial
biopsies. Perform sampling from say 20 cores.
2. Wait 9 months, and rebiopsy, again with near saturation
cores, 20+ .. There are three possible outcomes:
a. HGPIN remains
b. PCa has been determined
c. HGPIN regresses and only benign cells are left
3. The question is why did (c) above happen? What percent of
the HGPIN have regressed? If the percent of HGPIN that have regressed equals
the probability of having actually excised the cancer stem cell or cells, we
can calculate this, then by chance we have removed the CSC from the HGPIN and
this would affirm its existence by inference.
Now a similar article appears in Science which speaks to colon cancer and
the cancer stem cell theory[5]:
In normal colon tissue, intestinal stem cells (ISCs) that
reside at the base of mucosal wells, named crypts, expand through mitosis and
move upward toward the crypt tip. The cells then undergo cell cycle arrest and
terminal differentiation, finally becoming the mucosal epithelium of the colon.
In the recent study, the investigators identified in mouse ISCs a gene signature
that was specifically marked by high expression of the ephrin type-B receptor 2
gene(Ephb2),
which encodes a receptor tyrosine kinase, the leucine-rich repeat–containing G
protein–coupled receptor 5 gene (Lgr5), which encodes a
G-coupled protein receptor of unknown function, and ~50 other genes.
This gene signature also defined a specific population of
stem-like cells at the base of colorectal tumor structures in mice that were
morphologically similar to normal mouse intestinal crypts. The authors then
similarly inspected tumor samples from 340 colorectal patients and discovered a
10-fold increase in the relative risk of recurrence in patients whose tumors
displayed high expression of the human counterparts of the mouse ISC genes,
relative to patients whose tumors showed low expression of these genes.
To test whether the mouse colorectal tumor cells with
the ISC gene signature were cancer stem cells; the investigators isolated the
cells and introduced them into an immunodeficient mouse model. The stem-like
cancer cells demonstrated both a tumor-initiating capacity and self-renewal
capability in vivo.
These findings pinpoint potential markers that may allow
a clinician to predict a patient’s future with respect to recurrence. These
differentially expressed genes also may give rise to therapeutic targets that
quell cancer stem cells.
What is clear is that the CSC is becoming a viable model for
understanding cancer at another level.
We first relook at the progression and regression dynamics.
The key driver for the analysis herein has been the regression often seen in
HGPIN. Knowing that most likely the methylation of GSTP1 has given rise to
development of PIN we then ask what gives rise to its regression and why have
the HGPIN cells themselves not only stopped growing but have disappeared. Again
we have seen this in melanomas, and this is also the Rosenberg effect in certain
sporadic cancer regressions.
To look more closely we first return to the stem cell model
for cancer which we developed earlier. The stem cell theory states that there
are a certain number of cancer stem cells which in turn may replicate
themselves but also create what are termed post mitotic differentiated cells.
Not really stem cells but cells which exhibit the phenotypic characteristics of
a cancer cell. One of the questions one may pose is do these PMDC exhibit a
different genotypic character as well or are they controlled by some epigenetic
factors.
Now we can also see as Weinberg has noted (Weinberg p 419)
that a progression may occur in a somewhat more complex mechanism as we depict
below. Now from the stem cell arises Transit Amplifying Cells and then the
PMDC.
Now in reality there may be multiple genetic hits which give
rise to the stem cell, the pluripotent self-replicating core of a cancer. The
Figure below provides a generic profile, namely we may see many genetic
changes, some leading to cancer as in mutation 3 below and others just
wandering off into self-replicating cells but not with a malignant tendency.
Finally when we return to the HGPIN model we see the benign
cell migrating to a dysplasia, say HGPIN, and then to a malignant cell, but
then there is the regression back to a benign cell. The question is then; what
pathway elements takes us one way and what elements take us back. And what
happened to the dysplastic cells? Did they just die, apoptosis, or were they
scavenged?
Wang and Shen have
written a quite useful review of the cancer stem cell thesis for prostate
cancer. There is no definitive conclusion but the review covers a wide path
through what has been accomplished to date.
Recall as we have
written before the cancer stem cell (CSC) model, and it is a model,
hypothesizes that there are certain core cells which control the malignant
growth of other cells and that the other cancerous type cells do not in and of
themselves have the ability to continue to grow. In fact it could be concluded,
although not part of the current theory, that removal of a CSC from a tumor,
say the only CSC, would result in the apoptosis of the remaining cells. Namely,
a remission.
In contrast to the CSC
model we have the clonal model which says that the cells have progressed
through a set of pathway modifications that have resulted in a single cell
which takes off and multiples and that the progeny have identical genetic
makeup or further genetically modified makeup but all and equally malignant.
These are two
fundamentally different views of cancer. One could also state that recent work
with melanoma as we have discussed also posit that the CSC “communicates” to
progeny to have them multiply and that arguably the loss of the CSC
There is a great deal
of difficulty in identifying the CSC, usually attempting to do so via surface
markers such as CD44 and the like.
Wang and Shen then
discuss the controversy regarding the CSC concept. They state:
Much of the confusion
in the literature arises through inconsistencies in nomenclature within the
field. In particular, due to the wide use of xenotransplantation as a
functional assay for CSCs, transformed cells that can initiate tumor formation
in this assay are often referred to as CSCs in the literature. However, a tumor
initiating cell
(TIC) represents a
different concept from that of a CSC, as TICs unquestionably exist within
tumors and their identification does not by itself imply a hierarchical
organization of a tumor.
Indeed, the majority
of cells within a tumor could potentially possess TIC properties and
nonetheless follow a clonal evolution model. Consequently, it is important to
distinguish CSCs that have been strictly defined by their position and function
within a lineage hierarchy in vivo from
CSCs that have been identified as rare TICs in transplantation studies.
A similar confusion
arises with respect to the cell of origin for
cancer, which corresponds to a normal tissue cell that is the target for the
initiating events of tumorigenesis. In principle, a normal adult stem cell
could be a logical cell of origin for cancer, as it would retain the ability to
self-renew and generate a hierarchy of differentiated lineages within a tumor.
However, it is also possible that a cell of origin could correspond to a
downstream progenitor cell or conceivably even a terminally differentiated cell
that acquires stem cell properties during oncogenic transformation.
Our argument has been
that the CSC may most likely exist and that it has undergone certain pathway
changes and that as a result it may influence the growth of not identically
genetically changed cells to multiply but not in and of themselves have the
potential to multiply.
Wang and Shen
continue:
The identification of
normal cells that can serve as a cell of origin for prostate cancer is highly
relevant for understanding the applicability of a CSC model, and is currently
under intense investigation. The cell of origin may also have clinical significance,
as in the case of breast cancer, distinct tumor subtypes have been proposed to
originate through transformation of different progenitors within the mammary
epithelial lineage. Thus, it is conceivable that there may be distinct cells of
origin for other epithelial cancers, and different cells of origin may give
rise to clinically relevant subtypes that differ in their prognosis and
treatment outcome.
Thus there are either
basal cells or luminal cells as the cell of origin. Goldstein et al in Witte’s
lab had developed a murine model demonstrating the basal cell as the cell of
origin. However there may be strong issue regarding this model as applied to
human prostate cancer. It represents a viable pathway but not necessarily the
only. The issue is one of pathways as well as one of intercellular
communications with debilitated pathways.
Now to follow the
Wang and Shen model we have the following. Fist we show a normal prostate gland
with basal and luminal cells.
Then we show their
view of a Tumor Initiating Cell in either the basal or luminal layer. The
Goldstein et al murine model argue for the basal layer and there are others
arguing for the luminal.
The Wang and Shen
model is as follows.
1. A normal prostate
cell has both luminal and basal cells.
2. TICs may be formed
in either basal or luminal cells.
3. Neoplasia starts
with intro acinar proliferation.
4. Carcinoma
starts when it expands beyond the gland and starts up its own quasi-glandular
structures.
Now what causes
this? Genetic changes result in pathway changes. We show two pathways below. We
lose PTEN and we may activate myc and other parts of the pathway control
mechanism.
We now make a
different argument. If there exists a true PCa CSC then perhaps one may
putatively validate it as follows. The logic then is:
1. Assume a PCa CSC
exists.
2. Assume that the
PCa CSC replicates its CSC self at a low rate and is initially confined to the
prostate gland.
3. Assume that the
PCa CSC can influence the growth of TIC which themselves cannot sustain a
malignancy. Specifically we assume that the TICs require the CSC for continued
growth and further the CSC does so via cell growth as well as intercellular
communications.
4. Now let us assume
we have performed an 18 core biopsy on a 60 cc prostate gland and find
histologically extensive high grade focal prostatic intraepithelial neoplasia.
According to Wang and Shen they are most likely TICs and furthermore there may
be a CSC somewhere so that eventually we see a PCa. There may be one or a few
CSC in one or all of the glands yet we have no definitive marker to indicate as
such.
5. Now assume we
perform a second multi core biopsy on the gland and say do 22 cores in a 60 cc
gland. This is the same gland but say 9 months later. We would arguably expect
one of two possible outcomes. First that the HGPIN remains in place and
possibly has expanded. Second that there was a CSC and the HGPIN had become
classic PCa with say Gleason 2 or 3 at a minimum about the HGPIN
clusters.
6. If however,
we examine the cores and find no evidence of any neoplasia or PCa, namely the
gland has totally reverted to benign histology, we may have a reasonable
argument that perhaps the CSC was present initially, and it was somehow removed
along with the HGPIN in the initial biopsy leaving the TIC alone behind. Thus
the TICs requiring a CSC to survive go into an apoptotic state and are removed
from the prostate. Perhaps.
We have seen that
specific situation occur and one could then argue that the Wang and Shen model
for CSCs may be a viable model and further if such can be shown more
extensively than we may have a basis for PCa progression.
There is an interesting article by Clevers in Nature Medicine which is an up to date
review of the cancer stem cell issue. In light of the flurry of reports stating
the wonders of having identified genes which appear in many tumors, prostate
being the case, and my previous remarks that perhaps is the CSC is in fact
existent, that then one should be identifying it and its genetic makeup as well
as the dynamics of its pathways.
Now Clevers suggests a four step process, albeit with
limited experimental evidence, but a superb start. It is as follows:
The above are the first two steps. Perhaps a dysplasia or
neoplasia but with the kernel of a stem cell. This is the first "hit"
theory. The epithelium starts to grow in a strange manner. Say a polyp in the
colon or HGPIN in the prostate. Then we see a second hit and the formation of
extraepithelial growth.
Then the third hit for the author and we see transmission
via the blood stream. Then the fourth hit and the explosion from a few to
almost all cancer stem cells.
Whether this is a good or bad model is yet to be seen. As
Clevers states:
Central to the cancer stem cell (CSC) concept is the
observation that not all cells in tumors are equal. The CSC concept postulates
that, similar to the growth of normal proliferative tissues such as bone
marrow, skin or intestinal epithelium, the growth of tumors is fueled by
limited numbers of dedicated stem cells that are capable of self-renewal. The
bulk of a tumor consists of rapidly proliferating cells as well as postmitotic,
differentiated cells. As neither of these latter two classes of cells has the
capacity to self-renew, the contribution of these non-CSC tumor cells to the
long-term sustenance of the tumor is negligible.
The increased focus on the CSC is truly needed because if it
is indeed a key paradigm in cancer then it and not large tumor masses should be
examined. Clevers concludes with:
Epilogue: are CSCs and clonal evolution mutually
exclusive?
To date, the CSC field has treated tumors as genetically
homogeneous entities, by and large ignoring the fact that the observed tumor
heterogeneity may result from underlying genetic differences. However, it is
well known that most solid tumors show extensive genomic instability. Moreover,
genetic defects in a large variety of molecules that are involved in the
maintenance of the integrity of the genome are well-known drivers of
oncogenesis. Even in a disease like CML, so clearly driven by stem cells,
clonal evolution can be seen at work when imatinib is administered: the
malignancy becomes tumor-resistant through the emergence of clones that carry
mutations in the target of imatinib, the BCR-ABL1 fusion gene75. And the
progression of CML into ALL blast crisis is caused by the emergence of
subclones that harbor inactivating lesions in the cyclin-dependent kinase
inhibitor 2A (CDKN2A, also known as ARF) gene in addition to the BCR-ABL1
translocation76. The evidence for clonal evolution in the pathogenesis of
cancer is so overwhelming that it appears inescapable that all models should be
integrated with it.
The recent rapid advances in DNA sequencing are now
allowing the global analysis of genomic changes of cancer cells. These analyses
have confirmed many previously known common genetic alterations in cancer, and
they have also revealed some new common mutations as well as unexpectedly large
numbers of rare mutations. As a next step, this technology can be applied to
chart genetic heterogeneity within individual tumors as well as between primary
tumors and their local recurrences and metastases.
It should
thus be possible to map, in both space and time, the genetic evolution of a
tumor.
The last sentence is the most compelling. Cancer may be more
than just a cellular disease; it may require the spatial domain as well. This
is an exceptionally good review and should be a focus for future research.
Recent work by Qin et al. examine the more detailed nature
of the prostate cancer stem cell (PCa CSC). We here look at that as a starting
point and then examine some of the surrounding literature to see if the results
from that work can be extensible. The cancer stem cell model is one which akin
to the stem cell model above states that there are a class of stem like cells
which have been mutated and the development of cancer results from the turning
on of these cells.
Before proceeding let us review a few issues. It should be
noted that we are simplifying the analysis to intensify several points and let
the reader focus on the literature to assist in resolving some of the lost
complexities. Now:
1. Stem cells have certain characteristic and the only one
we focus on here is that for the most part they are the only cells of a class
which have the ability to reproduce. In a stable environment, the stem cells
reproduce at a rate equal to the loss of mature functional cells. Thus in the
skin, the basal stem cells reproduce at a rate equivalent to the death and loss
of the keratinocytes, no more or less. Let there be an injury then they produce
more by being activated by some ligand on some receptor on the stem cell. Cells
reproduce until equilibrium is reached.
2. Mature cells, derivative from stem cells, do not
reproduce. They just do what they were intended to do, no more or less.
As Wang and Shen state in a recent article (2011):
The cancer stem cell (CSC) model proposes that cells
within a tumor are organized in a hierarchical lineage relationship and display
different tumorigenic potential, suggesting that effective therapeutics should
target rare CSCs that sustain tumor malignancy…CSCs are instead
defined in practical terms through the use of several functional assays.
The most frequently used methodology involves xenotransplantation of flow sorted
populations of primary cancer cells into immunodeficient mice. In this assay, CSCs
are defined as a subpopulation of cells within a primary tumor that can
initiate tumor formation in mice following transplantation, unlike the
remaining tumor cells
This is a definition limited to the assay produced. It is
not a broad based definition.
Wang and Shen then discuss the types of prostate cells:
In human and mouse, the normal prostate gland epithelium
contains three primary differentiated cell types.
1.
Luminal cells are
columnar epithelial cells that express secretory proteins as well as markers
such as cytokeratin 8 (CK8), CK18, Nkx3.1, prostate-specific antigen and high
levels of androgen receptor (AR).
2.
Basal cells are
localized beneath the luminal layer and express markers including CK5, CK14 and
p63, but express low levels of AR.
3.
A rare third type of
cells termed neuroendocrine cells express endocrine markers such as
synaptophysin and chromogranin A, but do not express AR.
Then they allege:
Prostatic intraepithelial neoplasia (PIN) is often
considered a precursor of prostate cancer, and is characterized histologically
by luminal epithelial hyperplasia and a progressive loss of basal cells …
Here we have previously expressed concern regarding
counter-examples. Namely it is known that there are patients where a diffuse
HGPIN may be present upon a high density sampling and then after a second high
grade sampling the HGPIN is totally gone. The question is why? If as many agree
HGPIN is the precursor of PCa and if moreover HGPIN is already a representation
of a CSC mutation, then what has reversed the mutation. Perhaps it was the
fortuitous removal on the CSC in the initial sampling? We have argued that such
may be inductively deduced from examining the number of times this occurred
related to the statistical chance of such happening.
In a recent paper, Qin et al state[6]:
Prostate cancer (PCa) is heterogeneous and contains both
differentiated and undifferentiated tumor cells, but the relative functional
contribution of these two cell populations remains unclear. Here we report
distinct molecular, cellular, and tumor-propagating properties of PCa cells
that express high (PSA+) and low (PSA−/lo) levels of the
differentiation marker PSA. PSA−/lo PCa cells are quiescent and
refractory to stresses including androgen deprivation, exhibit high clonogenic
potential, and possess long-term tumor-propagating capacity.
They preferentially express stem cell genes and can
undergo asymmetric cell division to generate PSA+ cells.
Importantly, PSA−/lo PCa cells can initiate
robust tumor development and resist androgen ablation in castrated hosts, and
they harbor highly tumorigenic castration-resistant PCa cells that can be
prospectively enriched using ALDH+CD44+α2β1+
phenotype.
In contrast, PSA+ PCa cells possess more
limited tumor-propagating capacity, undergo symmetric division, and are
sensitive to castration. Altogether, our study suggests that PSA−/lo
cells may represent a critical source of castration-resistant PCa cells.
Specifically:
1. PSA−/lo
PCa cells are quiescent and refractory to anti-androgen and chemotherapy
2. These cells express
stem cell genes and can undergo asymmetric cell division
3. They also possess
long-term tumor-propagating capacity in intact male mice
4. PSA−/lo
PCa cells are highly tumorigenic and resist androgen ablation in vivo
We depict the details
from the paper and show it below:
As Merville states in commenting on the work of Qin et al[7]:
In cell lines and mouse model experiments, the low-PSA
cells resisted chemotherapy and thrived under hormone deprivation, the two main
prostate cancer drug treatments, the researchers found.
Low-PSA cells were found to be both self-renewing and
capable of differentiating into other prostate cancer cell types upon division,
a hallmark of stem cells called asymmetric cell division. "Asymmetric cell
division is the gold standard feature of normal stem cells," Tang said.
"Using time-lapse fluorescent microscopy, we were able to show asymmetric
cell division by filming a low-PSA cell dividing into one high-PSA cell and one
low-PSA cell."
When the team implanted the two
cell types in hormonally intact male mice, the rapidly
reproducing PSA-positive cells
caused faster growth and larger
tumors in the first
generation. However, after that the low-PSA cells generated larger, faster-growing tumors and tumor incidence in the
high-PSA cells dropped.
In fact, the
low-PSA prostate cancer cells
possess indefinite tumor-propagating capacity. In contrast, when implanted
in the castrated mice, the low-PSA prostate cancer cells
developed much larger tumors than the
corresponding high-PSA cells.
In another experiment, mice with tumors generated by either cell
type were then castrated and treated with hormonal therapy.
Low-PSA tumors
grew better in these
doubly androgen-deprived
mice
than the high-PSA tumors. "These
findings closely resemble progression
observed in patients after androgen-deprivation treatment and reflect reduced PSA-producing
cells in patient tumors after
androgen depletion," Tang said.
As Jeet et al state regarding their view of the prostate
related stem cell:
Stem cells are unspecialized cells that can self-renew
and differentiate to yield a diverse range of specialized cell types of a
tissue or organ. The mouse prostate comprises dorsal, lateral, ventral, and
anterior lobes, each containing three regions of proliferating cells—distal,
intermediate, and proximal. It has been suggested that the prostatic stem cells
reside in the proximal region of the mouse prostate.
These findings, together with tissue recombination
approaches (that allow the study of mesenchymal-epithelial interactions in
developing tissues), led to the elegant work that developed a new prostate
regeneration system by combining CD117 (a prostate stem cell marker
predominantly expressed in the proximal region) positive fractions from C57BL/6
mouse donors with rat embryonic urogenital sinus mesenchymal stromal cells.
These cells were then placed under the renal capsule of athymic nu/nu mouse
hosts to generate functional, secretion-producing prostates. This is the first
model to demonstrate the ability of mesenchyme to trigger prostate genesis thus
opening up possibilities for developing insights into the earliest changes that
evolve into cancer.
Jeet et al argue that their worked demonstrates the ability
of these identified stem cells to have a form of prostate related pluripotency.
They like many others have been using cell markers as a means of tracking the
stem cell. One may then ask what is the cell receptors and activating ligands
which result in the stem cell ability to perform its regenerative functions.
As Zhang stated:
Importantly, Staege and Max also noted that tumor stem
cells in EFT have been identified. These tumor stem cells expressed some
markers of embryonic stem cells. There are cell populations with the phenotype
of embryonic stem cells in the adult body.
It remains unclear as to whether such cell populations are permissive
for EWSR1-FLI1 induced transformation and whether EFT is derived from these
cell populations.
Zhang has extended this identification somewhat but the
issue of good markers remains.
Yet as Gupta et al state:
Some of the controversy surrounding the CSC model seems
to arise from confusion regarding the definition of CSCs, leading to two key
objections against the use of this term.
The first
objection derives from the fact that, unlike the case for normal stem cells,
which are usually oligo or multipotent, it is currently unclear whether CSCs
can give rise to multiple differentiated cell types….
A second key objection to the CSC model is that it is
currently unclear whether the normal cellular precursors of CSCs are, in fact, bona
fide stem cells. It is clear, however, that the traits used to define
CSCs do not rely on knowledge of their cellular origins within normal tissues.
Accordingly, the CSC model must stand or fall on the basis of experimental
characterizations of cancer cell populations
The Gupta et al observations are quite important. Namely, is
a stem cell born or made. Namely is there an unbroken lineage from stem cell to
stem cell? Also his first observation is the pluripotency issue, namely, are
stem cells able to generate a broad number of cells or are stem cells
cell-specific? The current nature of the Gupta et al observations do raise
issues as to how well we understand the stem cell model.
As Tang et al conclude:
The hypothetical model of hierarchical organization of
PCa cells has several important implications. Above all, it can help explain
how the tremendous heterogeneity associated with the PCa can be generated. The
rare PCa SC that persist in a tumor will continue to generate a repertoire of
progenitor cells that in turn will develop into a spectrum of cells at
different stages of differentiation , thus engendering the heterogeneous
phenotype of the tumor. The model posits that the tumorigenic stem/progenitor
cells are mostly undifferentiated cells as supported by the observations that
most CD44 and CD133 cells are AR. The model also implies that most
differentiated, luminal-like cells, which constitute the bulk of the tumor,
might be much less or even non-tumorigenic (Figure 6A). In support,
prospectively purified CD57 cells are non-clonogenic
and non-invasive [44] and prospectively purified PSAþ
cells are less tumorigenic than the isogenic PSA_
cells.
They also note the positive and negative PSA in the prior
paper by Tang.
There is a great deal of concern as regards to where the
stem cells come from. Namely the issue of the cells of origin. Previously we
had reviewed the Goldstein model, where they had indicate a basal stem source
as compared to a luminal cell source.
Wang and Shen state:
The identification of normal cells that can serve as a
cell of origin for prostate cancer is highly relevant for understanding the
applicability of a CSC model, and is currently under intense investigation. The
cell of origin may also have clinical significance, as in the case of breast
cancer, distinct tumor subtypes have been proposed to originate through
transformation of different progenitors within the mammary epithelial lineage hierarchy.
Thus, it is conceivable that there may be distinct cells of origin for other
epithelial cancers, and different cells of origin may give rise to clinically
relevant subtypes that differ in their prognosis and treatment outcome.
They consider several sources. For basal cells they state:
Although prostate tumors display a strongly luminal
phenotype, this does not exclude the possibility that basal cells could be a
cell of origin for prostate cancer. In particular, it is possible that
transformed basal cells could differentiate to generate large numbers of
luminal cancer cells. For example, prostate-specific conditional deletion of
Pten
by a probasin-Cre driver allele has been shown to result in a basal cell
expansion accompanied by increased number of intermediate cells, suggesting a
basal cell of origin … An important recent study from the Witte laboratory has
used similar approaches with primary human prostate tissues to show that basal
cells are a cell of origin for human prostate cancer
The Witte lab results are those of Goldstein et al which we
have discussed at length (See Appendix A).
In contrast we have luminal cell origin as stated as
follows:
Other studies have provided evidence that luminal cells
can serve as cells of origin for prostate cancer. For example, pathological
analysis of high-grade PIN samples, which still retain basal cells, suggest
that molecular events associated with human prostate cancer initiation such as
upregulation of c-MYC and shortening of telomere length occur exclusively in
luminal cells but not their basal neighbors …
In Moscatelli and Wilson, the authors state:
There is nothing inherently contradictory in the results
described by Wang et al. and Goldstein et
al., because it is possible that both basal and luminal stem/progenitor
cells may independently serve as cells of origin for prostate cancer.
Indeed, it is also possible that oncogenic stimuli may
differ in their effectiveness in transforming distinct cell populations. The
tumors that arise from different target cells may also vary in their biological
behavior and genetic profiles.
There are also indications that normal prostate stem
cells may reside in both the basal and the luminal compartments. Thus, if stem
cells are preferentially targeted during malignant transformation, both
compartments may contain cells of origin for prostate cancer.
Most of the scientific evidence indicates that prostate
stem cells reside in the basal layer and give rise to the secretory luminal
cells via transit-amplifying cells, which are intermediate in phenotype between
stem cells and terminally differentiated cells.
There is definitive evidence that
(i) secretory cells of the adult murine prostate derive
from cells that express p63, a transcription factor that is expressed by all
basal cells in the prostate , and
(ii) p63- expressing basal cells are required for
prostate development. In addition, prostate basal cells (human and murine) have
greater proliferative activity in vitro and in vivo than luminal cells.
The molecular signature of prostate stem cells also
identifies a basal-like phenotype, as they express cytokeratins 5/14, p63, and
integrin á6
(11). There is also evidence, however, that the luminal
compartment may contain stem/progenitor cells and that these give rise to basal
cells.
Experiments involving labeling cells with the synthetic
nucleoside bromo-deoxy-uridine to detect those that are proliferating indicate
that slow-cycling stem cells are concentrated in the proximal region of
prostatic ducts adjacent to the urethra and that both basal and luminal
compartments contain slow-cycling cells. Cells from this region have
substantial growth potential in vivo and in vitro and can be serially passaged
in vivo at least four times. It is not known whether CARNs are concentrated in
the proximal region, but if so, CARNs may comprise some of the slow-cycling
proximal luminal cell population.
These results provide a possible means to address the CSC
signature issue. However, it is not clear that the result is definitive nor of
immediate clinical use.
Stem cells are known in hematopoietic cell generation. They
are isolated, separate and their ability to develop the full plethora of blood
cells is well known. The stem cell concept applied to say prostate cells or
skin cells is of more recent structure and is in many ways still open for debate.
Taking that construct one step further and considering a cancer stem cell is
possible even more of a conjecture. We can accept the concept of a cancer stem
cell in the many blood cancers. We know that CML may very well have a
translocation, as is found in other leukemias. Yet the establishment of the
same for say prostate and melanoma malignancies is I believe still a work in
progress.
For example as Jeet et al state:
Different stages of prostate cancer progression: (a)
prostatic intraepithelial neoplasia, a premalignant lesion considered to be a
precursor to invasive carcinoma; (b) primary localized
adenocarcinoma, dependent on androgen stimulus and can be treated by androgen
ablation; (c) androgen-independent
prostate cancer, tumor then becomes androgen independent and metastasizes to
other organs (e.g., lung, bone, and lymph node)
The linear progression we have disputed in prior writings
based upon clinical observations. The reason is that we have observed the
remission of diffuse HGPIN in patients at first biopsy and then the absence in
subsequent. Not just reduction of HGPIN, but total elimination. Our hypothesis is
that there has been the presence of a stem cell and its removal during the
first extensive core biopsy, usually 16 or more cores, not classic sextant
biopsy.
Stem cells are a powerful paradigm which may very well align
with the clonal model. For if it is the stem cell which has suffered the
genetic change then if this cell has the controlling powers attributed to it,
then the stem cell model will also tell us a great deal regarding treatment,
and our inability to do so.
For example, a stem cell will itself generate other stem
cells as well as non-stem cells.
There are many questions still posed regarding the cancer
stem cell:
1. What are the pathway dynamics and are they the same in
the non-stem like cells?
2. What is the driver for the kinetics of a CSC? Namely do
we have a dramatically different set of kinetics?
3. What is the mechanism for the progression of subsequent
mutations in a CSC?
4. How do we identify the CSC in a sample biopsy? Are there
specific cell markers and are they consistent or do they change?
5. What are the driving ligands which activate a CSC?
6. Do stem cells have true pluripotency or are they cell
specific?
7. What are the stem cell surface ligands and receptors
which promote mitosis and how are they transmitted across a group of cells?
8. What causes a stem cell, specifically a CSC, to evolve
and how does that occur?
We can continue with a great number of these types of
questions. However if one hopes to be able to model cancer pathway dynamics one
must first address the issue of the CSC, for if the CSC has the definitive
characteristics that we have discussed then it and it alone is what should be
focused upon. Furthermore the examination of cells for pathway markers may very
well have to be done only on the CSC, which then argues that we need
sophisticated techniques to identify them and extract them as well.
1.
Alberts et al, Molecular
Biology of the Cell, Garland (New York) 2010.
2.
Clevers, The Cancer Stem
Cell: Premises, Promises, and Challenges, Nature Med V 17 March 2011, p 313.
3.
Dalerba, P., Robert W. Cho,
and Michael F. Clarke, Cancer Stem Cells: Models and Concepts, Annu. Rev. Med.
2007. 58:267–84.
4.
Deleyrolle, et al, Determination of Somatic and Cancer
Stem Cell Self-Renewing Symmetric Division Rate Using Sphere Assays, PLOS
January 2011, http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0015844
5.
Dreesen, O., A., Brivanlou,
Signalling Pathways in Cancer and Embryonic Stem Cells, Stem Cell Rev, 2007.
6.
Floor, S., Cancer Cells in Epithelial
to Mesenchymal Transition and Tumor Propagating Cancer Stem Cells: Distinct,
Overlapping or Same Populations, Oncogene V 30, pp 4609-4621, 2011.
7.
Goldstein, A. et al,
Identification of a Cell of Origin for Human Prostate Cancer, Science, 2010 V 329,
pp 568-571.
8.
Gupta, P, et al, Cancer
Stem Cells, Mirage or Reality, Nature Medicine, 2009, p. 1010.
9.
Gupta, P., et al,
Identification of Selective Inhibitors of Cancer Stem Cells by High Throughput
Screening, Cell, V 138, pp 645-659, Aug 2009.
10. Hong, D., A Fountain of Cancer, Sci Transl Med 4 May 2011: Vol. 3, Issue 81, p. 81
11. Hurt, E., et al, CD44+CD44- Prostate Cells are Early Cancer
Progenitor Stem Cells that Provide a Model for Patients with Poor Prognosis,
Brit Jrl Can 2008 pp 756-765.
12. Jeet, et al, Modeling prostate cancer: a perspective on transgenic mouse models, Cancer
Metastasis Rev (2010) 29:123–142.
13. Jordan, C., et al, Cancer Stem Cells, NEJM 2006.
14. Lawson, D., O. Witte,
Stem Cells in Prostate Cancer Initiation and Progression, Jrl Clin Inv, 2007 pp
2044-2050.
15. Leder, K., etal, The Theraputic Implications of Plasticity of
the Cancer Stem Cell Type, PLOS One V 5 Dec 2010.
16. Lobo, N., Yohei Shimono, Dalong Qian, and Michael F. Clarke, The
Biology of Cancer Stem Cells, Annu. Rev. Cell Dev. Biol. 2007. 23:675–99.
17. Mendelsohn, M., Cell Cycle Kinetics and Mitotically Linked
Chemotherapy, Can Res V 29 pp 2390-2393, 1969.
18. Moscatelli, D., F. Wilson, PINing Down the Origin of Prostate
Cancer, Science Translational Medicine, 4 August 2010 Vol 2 Issue 43 pp 43-48.
19. Qin, J., et al, The PSA−/lo Prostate Cancer Cell
Population Harbors Self-Renewing Long-Term Tumor-Propagating Cells that Resist
Castration, Cell Stem Cell, Volume 10, Issue 5, 556-569, 4 May 2012.
20. Reya, T., et al, Stem Cells, Cancer and Cancer Stem Cells,
Nature, V 414 Nov 2001.
21. Reya, T., H. Clevers, Wnt Signalling in Stem Cells and Cancer,
Nature V 434 p 843, 2005.
22. Risbridger, G., R. Taylor, Regulation of Prostatic Stem Cells by
Stromal Niche in Health and Disease, Endocrinology 2008 149:4303-4306.
23. Sole, R., Cancer Stem Cells as the Engine of Tumor Progression,
Journal of Theoretical Biology 253 (2008) 629– 637.
24. Tang, d., Lubna Patrawala,1 Tammy Calhoun,1 Bobby Bhatia, Grace
Choy,1 Robin Schneider-Broussard,and Collene Jeter, Prostate
Cancer Stem/Progenitor Cells: Identification, Characterization, and
Implications, MOLECULAR CARCINOGENESIS 46:1–14 (2007).
25. Wang, Z., M. Shen, Revisiting the concept of cancer stem cells
in prostate cancer, Oncogene (2011) 30, 1261–1271.
26. Weinberg, R., Biology of Cancer, Garland (New York) 2008.
27. Werbowetski-Ogilvie, T., et al, Evidence for the Transition of
Neoplastic Properties From Transformed to Normal Human Stem Cells, Oncogene, V
30, pp 4632-4644, 2011.
28. Wolfram Kleeberger, G. Steven Bova, Matthew E. Nielsen, et al., Roles
for the Stem Cell–Associated Intermediate Filament Nestin in Prostate Cancer
Migration and Metastasis, Cancer Res 2007;67:9199-9206. Published online
October 1, 2007.
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