1 The Challenge
Definitions are important. In mathematics and law, the definition will determine the outcome. In engineering we define certain parameters and we design accordingly. If there is a concern, we spend a great deal of time on the definition. In cancer studies the term "cancer stem cell" has been introduced.
Definitions should be clear and they should be actionable.
Namely the definition should present a way to ascertain through objective
measures readily understood by someone trained in the science or art to
determine if what is presented satisfies the definition. Namely we should with
a good definition know if what we have is a cancer stem cell.
The results below are a sample of what seems to be
definitions from the literature. Reading these one can readily see what the
complexity is in understanding this topic.The descriptions are each from the source noted.
2 Definitions
Ailles, and Weissman: Cancer stem cells (CSCs) are cells that drive tumorigenesis, as well as giving rise to a large population of differentiated progeny that make up the bulk of the tumor, but that lack tumorigenic potential. CSCs have been identified in a variety of human tumors, as assayed by their ability to initiate tumor growth in immuno-compromised mice… In addition, specific signaling pathways play a functional role in CSC self-renewal and/or differentiation, and early studies indicate that CSCs are associated with a micro environmental niche… several important biological properties of CSCs: first, what is the cell of origin for a given tumor? Second, what are the signaling pathways that drive self-renewal and/or differentiation of CSCs? Third, are there molecules uniquely expressed on CSCs, regardless of whether they are functional, that will allow targeted therapies to be developed? Fourth, what are the mechanisms by which CSCs escape conventional therapies and can we defeat these mechanisms?
2 Definitions
Ailles, and Weissman: Cancer stem cells (CSCs) are cells that drive tumorigenesis, as well as giving rise to a large population of differentiated progeny that make up the bulk of the tumor, but that lack tumorigenic potential. CSCs have been identified in a variety of human tumors, as assayed by their ability to initiate tumor growth in immuno-compromised mice… In addition, specific signaling pathways play a functional role in CSC self-renewal and/or differentiation, and early studies indicate that CSCs are associated with a micro environmental niche… several important biological properties of CSCs: first, what is the cell of origin for a given tumor? Second, what are the signaling pathways that drive self-renewal and/or differentiation of CSCs? Third, are there molecules uniquely expressed on CSCs, regardless of whether they are functional, that will allow targeted therapies to be developed? Fourth, what are the mechanisms by which CSCs escape conventional therapies and can we defeat these mechanisms?
Burgess: Should stem mitotic activity become
unregulated or uncontrolled, a tumorigenic and perhaps malignant phenotype may
result hence the term cancer stem cell…tumor initiating sells that have
malignant properties have been referred to as CSCs…
Dalerba et al: Stem cells are defined by three
main properties:
1. differentiation—the ability to give rise to a
heterogeneous progeny of cells, which progressively diversify and specialize
according to a hierarchical process, constantly replenishing the tissue of
short-lived, mature elements;
2. self-renewal—the ability to form new stem cells with
identical, intact potential for proliferation, expansion, and differentiation,
thus maintaining the stem cell pool;
3. homeostatic control—the ability to modulate and balance
differentiation and self-renewal according to environmental stimuli and genetic
constraints
Like their normal tissue counterparts, tumors are composed
of heterogeneous populations of cells that differ in their apparent state of
differentiation. Indeed, the differentiation features of a tumor, morphological
and architectural, are the key parameter used in routine clinical practice by
surgical pathologists to define a tumor’s primary anatomical origin.
This simple observation suggests that tumors are not mere
monoclonal expansions of cells but might actually be akin to “abnormal organs,”
sustained by a diseased “cancer stem cell” (CSC) population, which is endowed
with the ability to self-renew and undergo aberrant differentiation. This
hypothesis is further reinforced by the fact that cancer is known to result
from the accumulation of multiple genetic mutations in a single target cell,
sometimes over a period of many years (3). Because stem cells are the only
long-lived cells in many tissues, they are the natural candidates in which
early transforming mutations may accumulate.
Dubrovska, A., et al: One possible explanation
for the initial positive response to therapy followed by androgen-refractory
disease is that although current therapies eliminate the bulk of the tumor,
they fail to eliminate cancer stem cells (CSCs) or tumor-initiating cells (TICs).
In fact, it has been argued that many cancers are maintained in a hierarchical
organization of rare CSCs, rapidly dividing cells, and differentiated tumor
cells; the CSCs are not only a renewable source of tumor cells but are also a
source of tumor resistance leading to tumor recurrence, metastasis, and tumor
progression. Support for this hypothesis came with the identification of TICs
in leukemia in 1994 and, subsequently, in a variety of cancers, including solid
tumors. In addition, cancer cell lines have been shown to harbor cancer
stem-like cells and are a promising model for CSC research because these progenitors
can be readily expanded under anchorage independent (sphere formation)
serum-free conditions
Fang et al: Recent studies suggest that cancer
can arise from a cancer stem cell (CSC), a tumor-initiating cell that has
properties similar to those of stem cells. CSCs have been identified in several
malignancies, including those of blood, brain, and breast.
Hurt et al: The cancer stem cell hypothesis
suggests the existence of a small subpopulation of cells within the tumour that
give rise to differentiated tumour cells. It is thought that the cancer stem
cells survive conventional treatment to later re-emerge more resistant to therapy.
To date, putative cancer stem cells have been identified in blood, brain,
breast, lung, skin, pancreas, colon, and prostate….
Jordan et al: Stem cells have three
distinctive properties: self renewal (i.e., at cell division, one or both
daughter cells retain the same biologic properties as the parent cell), the
capability to develop into multiple lineages, and the potential to proliferate
extensively. The combination of these three properties makes stem cells unique.
The attribute of self-renewal is especially notable, because its subversion is
highly relevant to oncogenesis and malignancy. Aberrantly increased
self-renewal, in combination with the intrinsic growth potential of stem cells,
may account for much of what is considered a malignant phenotype. Biologically distinct and relatively rare
populations of “tumor-initiating” cells have been identified in cancers of the
hematopoietic system, brain, and breast. Cells of this type have the capacity
for self-renewal, the potential to develop into any cell in the overall tumor
population, and the proliferative ability to drive continued expansion of the
population of malignant cells. Accordingly, the properties of tumor-initiating
cells closely parallel the three features that define normal stem cells.
Malignant cells with these functional properties have been termed “cancer stem
cells”
Lawson and Witte: Two theories were proposed
to explain this paradox. The stochastic theory suggested that all cancer cells
are equally malignant but only clones that randomly possess favorable
biological properties will grow upon transplantation. An alternative theory
predicted that tumors are hierarchical like normal tissues and only the rare
subpopulation of cells at the pinnacle of that hierarchy have the unique
biological properties necessary for tumor initiation. Studies by John Dick and
colleagues provided evidence for the hierarchy model. This group demonstrated that
only the small subpopulation (0.1%–1.0%) of Lin–CD34+CD38– cells within human
acute myelogenous leukemia samples were capable of initiating disease when
transplanted into immune-deficient mice (10). These cells possessed the same
antigenic profile as normal human HSCs, which are at the pinnacle of the normal
hematopoietic hierarchy. This population also had the unique capacity to
selfrenew to propagate the disease as well as differentiate to produce the many
leukemic cell types represented in the original leukemia. Since these cancer
cells possess properties unique to normal tissue stem cells, they have been
termed “cancer stem cells” (CSCs).
Lobo et al: Stem cell: a primitive cell
defined by its capacity to self-renew and differentiate into at least one
mature cell type Cancer stem cell: a self-renewing cell within a tumor that has
the capacity to regenerate the phenotypic diversity of the original tumor
NCI: 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.
Pavlovic and Balint: As the stem cells that
created the tumor to begin with are so few in number, scans following treatment
usually fail to identify populations of CSCs in this limited population….[1]
Perego et al: Although there is no definitive
consensus on the phenotype and frequency of CSCs in the majority of human
tumors, much experimental evidence supports the contentions that many tumors of
both epithelial and nonepithelial origin have operationally defined CSCs (cells
able to propagate tumors in immunodeficient mice) and that the presence of
these CSCs affects tumor biology.
Rajasekhar: The "cancer stem cell
model" CSC …envisions tumors as "pathological organs" sustained
in their aberrant growth by a mutated population of stem cells, in which normal
homeostatic controls on tissue expansion have been lost.
Roesch et al: The CSC concept postulates a
unidirectional hierarchy of tumor cells…According to the traditional CSC
concept, tumor initiation is regarded as an exclusive characteristic of CSCs
Rosen and Jordan: Thus, the CSC paradigm
refers to the ability of a subpopulation of cancer cells to initiate
tumorigenesis by undergoing self-renewal and -differentiation, like normal stem
cells, whereas the remaining majority of the cells are more “differentiated”
and lack these properties.
Soltysova, et al: Normal stem cells in the
adult organism are responsible for tissue renewal and repair of aged or damaged
tissue. A substantial characteristic of stem cells is their ability for
self-renewal without loss of proliferation capacity with each cell division.
The stem cells are immortal, and rather resistant to action of drugs. They are
able to differentiate and form specific types of tissue due to the influence of
microenvironmental and some other factors. Stem cells divide asymmetrically
producing two daughter cells – one is a new stem cell and the second is
progenitor cell, which has the ability for differentiation and proliferation,
but not the capability for self-renewal. Cancer stem cells are in many aspects
similar to the stem cells. It has been proven that tumor cells are
heterogeneous comprising rare tumor initiating cells and abundant non-tumor
initiating cells. Tumor initiating cells – cancer stem cells have the ability
of self-renewal and proliferation, are resistant to drugs, and express typical
markers of stem cells. It is not clear whether cancer stem cells originate from
normal stem cells in consequence of genetic and epigenetic changes and/or by
redifferentiation from somatic tumor cells to the stem-like cells. Probably
both mechanisms are involved in the origin of cancer stem cells. Dysregulation
of stem cell self-renewal is a likely requirement for the development of
cancer. Isolation and identification of cancer stem cells in human tumors and
in tumor cell lines has been successful.
Visvader: It is important to note that the
cell of origin, the normal cell that acquires the first cancer-promoting
mutation(s), is not necessarily related to the cancer stem cell (CSC), the
cellular subset within the tumour that uniquely sustains malignant growth. That
is, the cell-of-origin and CSC concepts refer to cancer-initiating cells and cancer-propagating
cells, respectively. Although the tumourinitiating cell and the CSC have been
used interchangeably, the tumour-initiating cell more aptly denotes the cell of
origin. There is considerable evidence that several diverse cancers, both
leukaemias and solid tumours, are hierarchically organized and sustained by a
subpopulation of self-renewing cells that can generate the full repertoire of
tumour cells (both tumorigenic and non-tumorigenic cells). The cell of origin,
the nature of the mutations acquired, and/ or the differentiation potential of
the cancer cells are likely to determine whether a cancer follows a CSC model.
In most instances, the phenotype of the cell of origin may differ substantially
from that of the CSC. Normal cellular hierarchy comprising stem cells that
progressively generate common and more restricted progenitor cells, yielding
all the mature cell types that constitute a particular tissue. Although the
cell of origin for a particular tumour could be an early precursor cell such as
a common progenitor, the accumulation of further epigenetic mutations by a cell
within the aberrant population (in this case expanded) during neoplastic
progression may result in the emergence of a CSC. In this model, only the CSCs
(and not other tumour cells) are capable of sustaining tumorigenesis. Thus, the
cell of origin, in which tumorigenesis is initiated, may be distinct from the
CSC, which propagates the tumour.
3 References
3 References
1. Ailles, L and I. Weissman, Cancer stem cells in solid tumors, Current
Opinion in Biotechnology 2007, 18:460–466
2. Burgess, R., Stem Cells, Wiley (New York) 2016.
3. Dalerba et al, Cancer Stem Cells: Models and Concepts, Annu.
Rev. Med. 2007. 58:267–84
4. Dubrovska, A et al, The role of PTEN/Akt/PI3K signaling in the maintenance
and viability of prostate cancer stem-like cell populations, PNAS, Jan 2009 V
106 N 1
5. Fang et al, A Tumorigenic Subpopulation with Stem Cell
Properties in Melanomas, Cancer Res 2005; 65: (20). October 15, 2005
6. Hurt et al, CD44þCD24prostate cells are early cancer
progenitor/stem cells that provide a model for patients with poor prognosis, British
Journal of Cancer (2008) 98(4), 756 – 765
7. Jordan et al, Cancer Stem Cells, NEJM, 355;12 September 21, 2006
8. Lawson, Witte, Stem cells in prostate cancer initiation and
progression, The Journal of Clinical Investigation http://www.jci.org Volume
117 Number 8 August 2007
9. Lobo et al, The Biology of Cancer Stem Cells, Annu. Rev. Cell
Dev. Biol. 2007. 23:675–99
10. Pavlovic, M., B. Balint, Bioengineering and Cancer Stem Cell
Concept, Springer (New York) 2015
11.
Perego et al, Heterogeneous
Phenotype of Human Melanoma Cells with In Vitro and In Vivo Features of
Tumor-Initiating Cells, Journal of Investigative Dermatology (2010), Volume 130
12.
Rajasekhar, V., Cancer Stem
Cells, Wiley (New York) 2014.
13. Roesch et al, A Temporarily Distinct Subpopulation of
Slow-Cycling Melanoma Cells Is Required for Continuous Tumor Growth, Cell 141,
583–594, May 14, 2010
14. Rosen, J., C. Jordan, The Increasing Complexity of the Cancer
Stem Cell Paradigm, Science, 26 JUNE 2009 VOL 324.
15. Soltysova, A., et al, Cancer stem cells, NEOPLASMA, 52, 6, 2005
16. Visvader, J., Cells of Origen in Cancer, Nature, V 469 20 Jan
2011.
[1]
This book is near incomprehensible in my opinion. It appears impossible to find a definition, only
secondary referral characteristics at best!
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