Download Targeting Cancer Stem Cells and Stemness

NATIONAL INSIGHTS
Targeting
Cancer Stem Cells
and Stemness
INTRODUCTION
Despite advances in therapy, cancer remains the second leading cause of death
in the United States.1 Disease recurrence after conventional therapy,2 metastasisrelated deaths,3 and the inconsistent or poor correlation of tumor regression with
patient outcome are significant clinical hurdles.4-6 Yet, the mechanisms underlying
these limitations in disease management are unclear.
Evidence indicates the presence of a small, intratumoral, subpopulation of
tumor-initiating cancer cells with dysregulated stem-cell–like characteristics—or
“stemness”—that enable them to be resistant to conventional therapies. These
tumorigenic cancer cells, called cancer stem cells (CSCs), may be the linchpins of
disease recurrence and may significantly contribute to metastasis.7,8 Specifically, CSCs
exhibit a functional stemness signature comprising dysregulated self-renewal and
differentiation, tumorigenicity, resistance to conventional therapy, metastatic potential,
and aberrant stemness signaling pathways.9,10 Targeting cancer stemness may provide
a new treatment paradigm to limit disease relapse and metastasis and may help
explain why bulk tumor reduction following surgery, chemotherapy, radiation therapy,
and conventional pharmacologic therapy can fail to improve patient outcomes.7,11-13
With the hope of developing more effective approaches to cancer management,
researchers are seeking greater clarity of CSC biology. They are developing strategies
that inhibit the stem-cell–like properties of CSCs and related signaling pathways or that
destroy them directly. National Insights has brought together clinicians and researchers
to discuss the role of cancer stemness in cancer development and progression and
potential investigational treatment approaches to interfere in these roles.
Supported by
EXPERT PANEL
John E. Dick, PhD
Senior Scientist, Princess
Margaret Cancer Centre;
Professor, Department
of Molecular Genetics
University of Toronto
Toronto, Canada
Stanton L. Gerson, MD
Director, National Center for
Regenerative Medicine and Director,
Case Comprehensive Cancer Center
at Case Western Reserve University;
Director, Seidman Cancer Center
at University Hospitals Case
Medical Center
Cleveland, Ohio
Carla F. Kim, PhD
Associate Professor, Genetics and
Associate Professor, Pediatrics
at Harvard Medical School;
Principal Faculty, Stem Cell
Program, Boston
Children’s Hospital
Boston, Massachusetts
Robert Weinberg, PhD
Founding Member, Whitehead
Institute for Biomedical Research;
Professor, Biology
at Massachusetts Institute
of Technology
Cambridge, Massachusetts
©2016 Boston Biomedical, Cambridge, MA 02139. All rights reserved. Printed in USA/December 2016. EDU-NPS-0131
Max S. Wicha, MD
Madeline and Sidney Forbes
Professor, Oncology and
Founding Director Emeritus,
University of Michigan
Comprehensive Cancer Center
Ann Arbor, Michigan
NATIONAL INSIGHTS
SECTION 1.
Cancer Stemness:
Key Stemness Properties
Cancer Stemness:
A Puzzle Piece of Cancer
and display dysregulated stemness signaling.9,10
These traits, in addition to aberrant self-renewal
and differentiation, collectively define the functional
characteristics of cancer stemness (Figure 1).
Over 160 years ago, microscope examinations of
cancerous tissue displaying features similar to that
of embryonic tissue first suggested that cancer
may derive from embryo-like cells. Refinement in
understanding tumor and stem cell biology has
culminated in the CSC hypothesis: tumors are
initiated and maintained by a population of cancer
cells that share similar biologic properties to normal
adult stem cells.14 Unsurprisingly, an important
implication of the CSC hypothesis is that normal
adult stem cells or their progenitors transform into
the cancer cells of origin.15 Central to this aspect
of the CSC hypothesis is the observation that
cancer arises from CSCs, a small subpopulation
of malignant, tumor-initiating cells with the ability
to aberrantly self-renew and differentiate into
heterogeneous tumors, similar to how normal stem
cells self-renew and differentiate to orchestrate
tissue development and homeostasis.12,14,15 Thus,
dysfunctional self-renewal and differentiation
define the quintessential “stemness” characteristics
of CSCs.9,16
FIGURE 1. Functional characteristics of cancer stemness.
Cancer Stem Cell Identification
and Characterization
Several molecular and phenotypic markers have been
developed to identify and study cellular stemness
among tumors. A growing list of cell surface and
intracellular protein markers (Table 1) are used to
isolate and enrich for cell stemness in vitro from
cancer cell lines or clinical samples.16-19
The use of molecular markers to isolate and enrich
for CSCs, however, has limitations: (1) molecular
stemness markers may be shared among different
types of tumors or among normal stem cells from
corresponding organs18; (2) no molecular stemness
marker set is exclusive to CSCs and not all CSCs
may express them9; and (3) expression of molecular
stemness markers may change over time or may
vary among CSCs of the same tumor type between
patients.21,22 Thus, molecular stemness markers alone
Dysfunctional self-renewal and
differentiation define the quintessential
“stemness” characteristics of CSCs.
Normal stem cells are the fundamental units of
organogenesis and homeostasis and are, therefore,
capable of migration, apoptosis resistance,
chemo- and radiotherapy resistance, and stemness
signaling.9,15 Consistent with evidence indicating that
cancer stemness may arise from the transformation
of normal stem cells or their progenitors,15 CSCs
have been shown to initiate tumor formation, resist
conventional therapy, contribute to metastasis,
2
Targeting Cancer Stem Cells and Stemness
may not be sufficient to unambiguously isolate and
enrich for cancer stemness.9
More sensitive in vitro techniques have been
developed to phenotypically verify stemness
potential among cancer cells. For example, the
tumorsphere-forming assay evaluates the number
of multicellular spheroid colonies grown under
serum-free, nonadherent culture conditions.23
Subsequent disassociation of aggregates and serial
reculturing of single cells into tumorspheres assess
the cellular capacity for prolonged proliferation
and self-renewal. Adding serum to culture media
and monitoring for lineage commitment or loss of
CSC marker expression assesses the capacity to
differentiate.23-25 The gold standard for identifying
functional cancer stemness is, however, the serial
transplantation assay, which assesses the capacity
of cancer cells to self-renew and initiate and
develop heterogeneous tumors via in vivo serial
passaging in immunocompromised mice.23 Such
techniques were used in a landmark in vivo study
in immunocompromised mice. In that study, a
subpopulation of CD34+, CD38- human leukemic
cells, comprising less than 0.01% of cancer cells in a
clinical sample, were shown to initiate and develop
leukemia bearing the same heterogeneity as the
original sample. The study also showed that the
rare population of CD34+, CD38- human leukemic
cells could expand their numbers by 30- to 100-fold
in primary recipient mice. Collectively, these data
TABLE 1.
Molecular Markers of Cancer Stemness16,19,20
Tumor Type
Phenotype of Cancer Stemness
Markers
Breast
ESA+, CD44+, CD24-/low, Lineage–,
ALDH1high
Brain
CD133+, BCRP1+, A2B5+, SSEA1+
Colon
CD133+, CD44+, CD166+, EpCAM+,
CD24+, CXCR4+, CK20+, CEA+, LGR5+,
ALDH1high
Gastric
CD133+, CD44+
Head and neck
CD44+, ALDH+, YAP1+, BMI1+
Leukemia
CD34+, CD38–, HLA-DR–, CD71–,
CD90–, CD117–, CD123+
Liver
CD133+, CD49f+, CD90+
Lung
CD133+, ABCG2high
Multiple myeloma CD138–
Pancreatic
CD133+, CD44+, EpCAM+, CD24+,
ABCG2high
Prostate
CD44+, α2β1high, CD133+
demonstrated the proliferative, differentiation,
and enormous self-renewal capacity of leukemic
stem cells.15,26 Since then, several studies have
confirmed the presence of cancer stemness within
a subpopulation of cells in many types of cancer,
including melanoma, lung, pancreatic, breast,
gastric, head and neck, liver, brain, colon, prostate,
and multiple myeloma (Table 1).9,27
CONSULTANT COMMENTARY
Dr Wicha: Cancer stem cells share a number of
properties with normal tissue stem cells. Both
are defined by their capacity for self-renewal and
differentiation. However, in normal stem cells
these processes are tightly regulated, whereas the
mutations in cancer stem cells lead to aberrant selfrenewal and blocks in cell differentiation.
3
NATIONAL INSIGHTS
SECTION 2.
Cancer Stemness:
A Radical Departure From How We
Thought Cancer Grows and Progresses
Genesis of Heterogeneous Tumors
increase phenotypic heterogeneity.28-30 The CE
model characterizes all cells within a tumor with
equal potential to recapitulate tumors with the same
heterogeneity as the parent tumor (Figure 2A).
Importantly, the CE model implies that, although any
tumor cell may be able to initiate tumor formation,
no specific type of cell is inherently tumorigenic.
Therefore, tumor-initiating activity cannot be isolated
or enriched using intrinsic characteristics of any
cancer cell population.30
The CE model stands in seemingly stark contrast
to the CSC, or hierarchical, model of initiation and
development of heterogeneous tumors predicted
by the CSC hypothesis. According to the CSC
model, CSCs arise from dysregulation of stemness
signaling pathways in normal stem or progenitor
cells and go on to initiate tumor formation.15,28
Evidence indicating that the capacity for initiation
and development of heterogeneous tumors is
almost exclusive to a rare population of cells in many
types of cancer challenges the conventional clonal
evolution (CE), or stochastic, model of heterogeneous
tumor formation.28 The CE model posits that
accumulation of oncogenic mutations within
normal somatic cells can initiate tumor formation.10
Intrinsic factors, such as genetic and epigenetic
programming, and extrinsic factors, such as tumor
microenvironmental interactions and immune
responses, result in stochastic and unpredictable
cellular phenotypes. Intrinsic and extrinsic factors
may eventually select for clonal subpopulations of
tumor cells with characteristics such as invasiveness,
treatment resistance, or tumorigenicity, which
FIGURE 2. Models of tumorigenesis and heterogeneity.
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Targeting Cancer Stem Cells and Stemness
Tumor heterogeneity would arise through the
differentiation of the founder CSC population into the
nontumorigenic tumor cells that comprise the bulk of
the tumor.10,15
tumor to increase heterogeneity.21,28 Observations
of stemness plasticity among nontumorigenic
cancer cells has added another layer of complexity
to the models of tumorigenesis and heterogeneity.
Similar to the drivers of CE in CSCs, epigenetic and
tumor microenvironmental factors likely facilitate
reacquisition of tumor-initiating phenotypes or
stemness molecular markers among nontumorigenic
differentiated cancer cells.34 Thus, a hybrid version
of the CE and CSC models, called the plastic
clonal CSC model, acknowledges the potential for
stemness plasticity and CSC clonal diversity in the
development of heterogeneous tumors (Figure 2C).
As the understanding of CSC biology improves, such
models of tumorigenicity and heterogeneity will
continue to be refined to help account for intra- and
intertumor variation in the frequency, genotype, and
phenotype of cancer stemness.9,35,36
According to the CSC model, CSCs arise
from dysregulation of stemness signaling
pathways in normal stem or progenitor cells
and go on to initiate tumor formation.
The CSC model organizes heterogeneous tumor
development into a rigid hierarchy that places cancer
cells with stemness traits at the apex—the exclusive
source—of tumor initiation and heterogeneity.30
An important implication of the CSC model is that,
by virtue of their capacity for self-renewal and
differentiation, CSCs are the only cells within a tumor
with inherent tumorigenicity (Figure 2B).29 The CSC
model, therefore, predicts that surrogate markers of
tumor-initiating activity, namely stemness molecular
markers, may be developed to help isolate, enrich,
and identify tumorigenic cancer cells from the
otherwise nontumorigenic bulk of the tumor.30
Although failure of conventional therapies based
on the CE model suggest that the CSC model is
the primary method of tumor growth,12 evidence of
clonal evolution among CSCs has suggested that the
2 models of tumorigenesis and heterogeneity are
reconcilable (Figure 2C)31:
•Initial populations of CSCs may be responsible
for cancer initiation and give rise to early tumor
cell diversity28,31-33
•Subsequent mutation of CSCs exposed to various
extrinsic factors may result in clonal expansion of
CSC subpopulations that propagate later stages
of heterogeneous tumor development28,31-33
•Dormant CSCs may be activated in later
stages of tumor development to contribute
to tumor heterogeneity21
It should be noted that different sets of CSCs,
each hierarchically developing into its own group
of differentiated, nontumorigenic progeny, may
simultaneously exist at any given time within a
The CE-CSC hybrid model, called the
plastic clonal CSC model, acknowledges
the potential for stemness plasticity and
CSC clonal diversity in the development
of heterogeneous tumors.
Epithelial-Mesenchymal and
Mesenchymal-Epithelial Transitions
Many types of cancer metastasize through a
reversible process known as epithelial-mesenchymal
transition (EMT), in which anchored epithelial cancer
cells acquire invasive, mesenchymal phenotypes to
detach and migrate from primary tumors, invade
local tissue, and disseminate through blood or
lymphatic systems to take residence at distal sites.37-39
The cancer cells subsequently reverse EMT through
a mesenchymal-epithelial transition (MET) that
reasserts an epithelial-like phenotype and facilitates
colonization and metastatic growth.38,39
EMT in cancer cells correlates with several
stemness-related phenotypes, including self-renewal,
differentiation, and tumorigenicity.39 Accordingly,
CSCs at the tumor periphery can undergo EMT
to become migratory and have been shown to
be enriched among circulating tumor cells.39-41
5
NATIONAL INSIGHTS
CSCs remain quiescent and
nonproliferative during EMT.
At distal sites, the cells undergo
MET to resume self-renewal and
differentiation, which enables
colonization and development
of metastatic heterogeneous
tumors (Figure 3).41,42 Although
the specific mechanism of such
EMT-MET plasticity among
CSCs remains unclear, growing
evidence indicates strongly
that CSCs directly or indirectly
contribute to metastasis of
several types of cancers,
including pancreas, colon, and
breast.8,43 Moreover, a small
subset of highly metastatic
CSCs with long-term self-renewal, FIGURE 3. CSCs as mediators of metastasis.
increased chemoresistance, and
altered paracrine signaling may be the exclusive
dependencies of metastasis and cancer stemness is
source of cellular metastasis in several types of solid
important to help identify mechanisms that may be
8,43,44
tumors.
As most cancer-related deaths are
therapeutically targeted to limit cancer spread and
due to metastasis, defining the mutual molecular
tumor recurrence.45
CONSULTANT COMMENTARY
Dr Gerson: Our research into cancer stem cells
is teaching us a great deal about the role of
stemness signaling pathways and cancer stem cellmediated resistance to conventional therapy and
subsequent tumor recurrence.
biological state, which renders them intrinsically
more resistant to elimination by certain types
of therapy. It’s this nongenetic paradigm that
underlies the concept of cancer stem cells,
including those from the hematopoietic system
and from solid tumors.
Dr Weinberg: The prevailing paradigm has
been that cancer cells have certain mutations
that render them resistant to therapy. In truth,
much of resistance can also be explained by
nongenetic mechanisms. That is to say that if cells
enter into a cancer stem cell state, they may not
change their genomes, they may not change their
DNA sequences, but they will move into a cell
Dr Dick: I would add that tumors, be they
blood or solid cancers, are caricatures of normal
development. Many tissues in the body are
sustained in tissue hierarchies. In a sense, tumors
are perversions or perturbations of that normal
developmental hierarchy.
6
Targeting Cancer Stem Cells and Stemness
SECTION 3.
Cancer Stemness: Insights Into
Treatment Failure
Cancer Stemness and Therapy Resistance
TABLE 2.
Mechanisms of Innate Resistance in CSCs
Despite initial responses to therapy, many cancers
relapse.2,46 Indeed, early tumor shrinkage has been
shown to weakly correlate with progression-free or
overall survival in several types of cancer.4-6 Recent
studies have confirmed the presence of CSCs in
many chemo- and radiotherapy-resistant cancers,
including brain, lung, breast, liver, gastric, pancreas,
ovarian, colon, and prostate.47-55 As CSCs are
inherently resistant to conventional therapy, cancer
stemness may underlie the poor correlation between
tumor shrinkage and patient outcomes.30,56
Quiescence maintenance
Asynchronous DNA replication
Activation of DNA damage repair
High levels of anti-oxidant proteins
Upregulated anti-apoptotic proteins
Overexpression of drug efflux proteins
Conventional therapies increase the
proportion of treatment-resistant CSCs
in tumors.
Tumor microenvironment interactions
Aberrant stemness signaling pathways
are, therefore, enriched among residual post-therapy
tumor cells to mediate tumor recurrence.30,57,58
Subsequent use of conventional therapies further
increases the proportion of treatment-resistant CSCs in
recurrent tumors (Figure 4).57 Moreover, conventional
therapy has been shown to
actually enhance stemness in
non-stem cancer cells to drive
acquired treatment resistance.27,59
Thus, cancer stemness may be
a fundamental phenotype of
resistance selection and may
explain why tumor regression
from conventional therapy does
not strongly correlate with
patient survival.15,60
CSCs use a diverse set of
mechanisms to innately resist
conventional therapy (Table 2):
•Quiescence maintenance
to limit toxicity from cellcycle–dependent chemoand radiotherapy15,61
FIGURE 4. Treatment-resistant CSCs as drivers of tumor recurrence.
A new model of post-therapy tumor growth
proposes that CSCs drive tumor recurrence.
Conventional therapies kill non-stem bulk tumor cells,
which results in tumor shrinkage.57,58 CSCs, however,
are innately resistant to conventional therapies and
7
NATIONAL INSIGHTS
•Asynchronous DNA replication and activation of
DNA damage repair systems to maintain genomic
integrity and protect against DNA-targeting
therapies15,61
•High expression and activity of anti-oxidant proteins
to resist radiotherapy-induced oxidative damage61
•Upregulation of anti-apoptotic proteins, such as
Bcl-2, an inhibitor of apoptosis family proteins, to
resist cytotoxic therapy15,61
•Overexpression of drug efflux proteins to resist
chemotherapies by reducing their intracellular
concentrations61
•Interactions with the microenvironment through
treatment-responsive paracrine signaling and
stemness-promoting niches to protect against
chemotherapy61
•Aberrant stemness signaling to confer chemo- and
radiotherapy resistance61
The heterogeneous mechanisms of treatmentresistant CSCs may help explain why cancers recur
even after the use of multimodality therapies.61
Understanding the regulation of therapeutic
resistance among CSCs may help to develop novel
treatment modalities to limit tumor relapse.61
CONSULTANT COMMENTARY
Dr Gerson: One goal is to find the predictors of
whether a patient is going to respond to therapy
or not.
Dr Kim: A very important realization in cancer
is that most patients are dying because of
metastatic disease. We are interested in studying
the relationship between a cancer stem cell and
the cell that can give rise to these metastases. If
we can identify the molecules controlling them,
we might have a way to detect and block that
metastatic process.
Dr Weinberg: A major area requiring some
resolution is: cancer stem cells are widely
appreciated to be more resistant to various kinds
of therapy than are the non-stem cells, which
leads to minimal residual disease. Mechanistically,
why are cancer stem cells more resistant to various
kinds of therapies?
8
Targeting Cancer Stem Cells and Stemness
SECTION 4.
Signaling Pathways as a
Cornerstone of Stemness
Cancer Stemness Signaling
EMT transcription factors and mediated metastasis
among colon and pancreatic CSCs.72 Hedgehog
signaling was shown to be essential for long-term
serial tumorigenicity and tumor maintenance
among colon CSCs.74 Pancreatic CSCs were also
found to overexpress hedgehog pathway proteins
to resist chemotherapy via upregulation of drug
efflux proteins.75
•
Wnt/b-catenin Pathway—regulates developmental
processes and maintains adult tissue homeostasis
via cell differentiation, migration, and stem cell
maintenance.76 The Wnt/b-catenin signaling
pathway has been found to mediate self-renewal
in stem-cell–like tumor cells of several cancers,
including colon, gastric, and prostate.77-79
Studies have also indicated that the pathway is
important for CSC-mediated tumorigenesis that
yields heterogeneous tumors with differentiated
progeny cells.78,79 β-catenin depletion studies have
shown that hepatic CSCs rely on the pathway
for chemotherapy resistance. Similar studies of
the pathway also indicate that β-catenin may
modulate drug efflux protein expression to confer
chemotherapy resistance among ovarian CSCs.80
Metastatic potential analysis of stem-cell–like
breast cancer cells indicated dependency on the
pathway to mediate cellular migration.81
•
Notch Pathway—regulates cellular proliferation
and differentiation among embryonic and adult
stem cells to orchestrate development and adult
tissue homeostasis.82,83 CSCs within several types
of cancer, including liver, breast, and glioblastoma,
have been shown to require Notch
signaling to maintain self-renewal.84,85
JAK/STAT
Tumorigenesis assays have indicated that
Metastasis*
Hedgehog
lung CSCs require Notch signaling to
Self-renewal/
Innate resistance
Wnt/β-catenin
initiate and form heterogeneous tumors
differentiation
Notch
Tumorigenesis
with differentiated cells.82 Activation
Nanog
of Notch signaling has been shown to
*Some pathways may mediate metastasis-related phenotypes (eg, migration and EMT).
correlate with chemoresistance among
colon CSCs and inhibition of the pathway
FIGURE 5. Key cancer stemness signaling pathways.
resensitized the cells to chemotherapy.80
Stringent regulation of stemness pathways in normal
stem cells controls normal development and limits
their expansion in healthy tissue.62 CSCs, however,
have escaped such constraints and rely on key
dysfunctional stemness pathways to mediate cancer
stemness functions (Figure 5).9,62,63 The following
are examples of preclinical evidence supporting
the various roles (see underlined text) of stemness
signaling pathways in CSCs:
•
Janus kinase/signal transducers and activators of
transcription (JAK/STAT) Pathway—regulates
stemness genes required for modulating
normal stem cell self-renewal and maintaining
the stem cell niche.64,65 CSCs within glioma,
glioblastoma, and breast cancer were shown
to require JAK/STAT signaling to maintain selfrenewal.65,66 Blockade of the STAT3 signaling
pathway has been shown to inhibit the tumorinitiating potential of CSCs in prostate and colon
cancers.67,68 Knockdown or inhibition of STAT
in treatment-resistant leukemic or breast CSCs
was demonstrated to resensitize the cells to
therapy.69,70 A novel STAT inhibitor was shown to
significantly reduce CSC-mediated tumor relapse
and metastasis in pancreatic and colon cancer.7,71
•
Hedgehog Pathway—regulates cell fate,
differentiation, and migration during embryonic
organogenesis.72,73 High pathway activation has
been shown to promote self-renewal among
glioma, multiple myeloma, and breast CSCs. High
pathway activity also correlated with expression of
9
NATIONAL INSIGHTS
Similar Notch-dependent chemoresistance among
ovarian CSCs was found to be mediated by drug
efflux proteins.80 Inhibition of Notch has been
shown to decrease the proportion of breast CSCs
and reduce incidence of brain metastases.9
•
Nanog Pathway—maintains embryonic pluripotency
and regulates cell fate determination.86 CSC selfrenewal has been shown to depend on Nanog in
liver and brain cancers.25,87,88 Tumor-initiation tests of
liver cancer CSCs revealed that Nanog is required
for the genesis of heterogeneous tumors with
differentiated cells.25 Metastatic potential analysis
of the cells indicated dependency on Nanog to
mediate cellular migration, invasion, and expression
of EMT-related marker proteins, such as vimentin
and fibronectin.25 Chemoresistance studies indicated
that liver CSCs with high Nanog expression
correlated with increased therapy resistance and
elevated levels of drug efflux proteins.25
Mounting evidence indicates that dysfunction of
normal stem cell signaling pathways underlies cancer
stemness traits.9,62,63 In addition to the pathways
presented above, other mediators of cancer
stemness will likely be identified with continued
research of CSC biology. For example, the
phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian
target of rapamycin (mTOR) and the nuclear factor
kappa-B (NF-κB) signaling pathways have recently
been shown to modulate stemness in various types
of cancer.80,83,89,90 Additionally, ongoing research
indicates that the tumor microenvironment interacts
with CSCs through stemness signaling pathways
to modulate cancer stemness traits.83 The growing
number of molecular and cellular regulators of
CSC functions present opportunities to identify key
cancer stemness pathway determinants that may be
developed as novel cancer treatment options.
Mounting evidence indicates that dysfunction
of normal stem cell signaling pathways
underlies cancer stemness traits9,62,63
CONSULTANT COMMENTARY
Dr Weinberg: We should be clear about what
signaling pathways are. We’re talking about signals
that are transferred from the tumor stroma to the
tumor cells themselves. We’re also talking about
intracellular signaling cascades. We’re talking about
nuclear regulators of gene expression that are
specific, for example, to the cancer stem cell or to
the more mesenchymal state.
References
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Dr Wicha: The pathways used by cancer stem cells
and normal stem cells to regulate self-renewal and
differentiation are remarkably similar. The main
difference is that in normal stem cells signals from
the microenvironment or “stem cell niche” regulate
cell fate decisions. In cancer, mutations in the
cancer stem cell, as well as changes in the tumor
microenvironment, result in abnormal self-renewal
and differentiation of these cells.
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Targeting Cancer Stem Cells and Stemness
SECTION 5.
Cancer Stemness:
A Therapeutic Target
Multiple Potential Targets
for Investigation
Cancer stemness presents a new paradigm of
tumor biology that places CSCs at the core of
cancer pathophysiology and identifies dysfunctional
stemness as the causal agent of conventional
therapy failure and poor patient survival. Several
therapeutic approaches to target cancer stemness
are under development. Given the significant
reliance of CSC function on cancer stemness
pathways, signaling pathway inhibition is an area
of intense investigation (see Cancer Stemness
Signaling section).9,62,63 Other therapeutic
approaches targeting cancer stemness under
investigation include cell surface marker–specific
monoclonal antibodies or drug-conjugated therapy
delivery systems to directly target CSCs, drug
efflux inhibitors to limit therapy resistance, CSC
differentiation agonists to decrease self-renewal and
CSC frequency, and immunomodulatory agents to
induce anti-CSC immunogenic responses.91,92 Thus, a
multifaceted therapeutic approach that incorporates
CSC-directed therapies into conventional debulking
treatment regimens may optimally reduce the
likelihood of treatment resistance and regrowth to
improve patient outcomes.
CONSULTANT COMMENTARY
Dr Wicha: The promise of molecularly targeted
therapies and personalized medicine has been that if
we understood the genetic mutations in a particular
patient’s tumor, we could target the mutated genes
and this could lead to significant clinical benefit.
While we’ve certainly seen clinical benefit from some
of targeted therapies, in general, the responses have
been relatively short-lived.
Dr Dick: As a broad strategy, if one is going to
target the stemness components, we should look
also at various aspects of epigenetic regulation.
17.Tang DG. Understanding cancer stem
cell heterogeneity and plasticity. Cell Res.
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18.Boman BM, Wicha MS. Cancer stem cells:
a step toward the cure. J Clin Oncol.
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