Cancer Stem Cells: Exploring the Roots of Cancer
Tumor Microenvironment/Niche
(Fibroblasts, Myofibroblasts,
Inflammatory Cells, Immune
Cells, Extracellular Matrix)
Heterogeneous
Tumor Cells
Cancer
Stem Cells
Experimental evidence suggests the entire population of tissues
making up organs can be propagated from a single stem cell.2
Stem cells (like those found in hematopoiesis) possess long life
spans, can self-renew, and differentiate into short-lived progenies
(red blood cells). Tumors, which have been shown to possess
characteristics of organ tissue, also have been shown to contain
stem-like cells. They also use the same signal pathways as stem
cells to propagate the tumor cells.3
Tumor Microenvironment
Cancer Stem Cells
Interacting With Tumor
Microenvironment
2
Like normal stem cells, cancer stem cells (CSCs) are slow-cycling,
can self-renew, and can differentiate to give rise to the heterogeneous tumor.4 CSCs are identified by markers, including CD133,
CD44, CXCR4, and ALDH. CSCs depend on stemness signals
secreted from cells in the tumor microenvironment to maintain selfrenewal, as well as differentiate into the rest of the heterogeneous
tumor cells.5
3
TUMOR DEVELOPMENT
Vasculature
Tumors are composed of a heterogeneous population of cancer
cells, characterized by sustained proliferative signaling, evasion
of growth suppressors, resistance to cell death signals, acquisition
of replicative immortality, induction of angiogenesis, activation of
invasion and metastasis, reprogramming of energy metabolism,
and evasion of immune destruction.1 The tumor is perceived as an
organ. Like other organs, tumors contain “individual specialized
cell types” (cancer cells and non-cancer cells), which cooperate to
promote tumorigenesis.1
Apoptosis of Proliferating
Tumor Cells
Chemotherapy of Tumor
Non-CSCs
CSCs
Radiotherapy of Tumor
Extensive advances have been made in our understanding of cancer
pathogenesis, the mechanisms of disease progression, and disease
management. Even with these advancements, metastasis and drug
resistance remain major limitations to improving clinical outcomes.6
Current therapeutic modalities, including chemotherapy and radiation
therapy, target mostly rapidly proliferating cells. In contrast, CSCs are
slow-cycling and drug-resistant. While effective in reducing tumor size
and slowing tumor growth, chemotherapy and radiation therapy also
affect the tumor microenvironment.7 For example, radiation has been
shown to induce recruitment of proinflammatory cells to the site of
treatment, as well as induce a hypoxic tumor microenvironment, both
of which support CSC stemness pathways and eventually tumor
progression.8
CSC-Containing Inflamed Scar
After Conventional Therapy
4
5
Pro-Stemness
Ligand Released
Into Tumor
Microenvironment
Tumor
Microenvironment (Niche)
Extracellular
Matrix
Stem cell stemness pathways are highly regulated. For example, the
intestinal crypt depends on stemness pathways (especially the Wnt/
β-catenin pathway) to maintain epithelial homeostasis. Deregulation
of Wnt/β-catenin signaling results in precancerous adenomas.10
Dysregulation and unrestricted crosstalk between multiple stemness
pathways result in CSC pathogenesis. This is the major difference
between normal stem cells and CSCs.11
Ligand Receptor
on CSC
Cell Membrane
6
7
STEMNESS PATHWAYS
Stem cells interact with their microenvironment (niche) to maintain their
stemness potential. The stem cell niche is comprised of a variety of cells,
including stromal cells, immune cells, and vascular endothelial cells. These
cells secrete factors to create a “fertile soil” for stem cells to self-renew
(maintain undifferentiated stem cells) and propagate mature differentiated
progenies.9 Depletion of the niche factors or detachment of stem cell from
the niche can lead to differentiation.5
Outside Cell
The same signal transduction pathways, including Wnt, Hedgehog, Notch, and
STAT, that govern normal stem cells are suggested to govern CSC pathogenesis.
Receptor
Ligand
In Wnt signaling, Wnt ligands, secreted from stromal cells, bind to Wnt receptors
on the cell membrane. This leads to the nuclear translocation of β-catenin. Nuclear
β-catenin activates the transcription of “stemness” factors, including the self-renewal
genes LRG5 and AXIN2,12 as well as the prosurvival signal survivin.13
Cell
Membrane
Ligand-Bound
Receptor
STAT3, in a complex with Nanog signaling, is required for the expression of genes
involved in the modulation of pluripotency.14 STAT3 hyperactivation has been shown
in CSCs compared with non-CSCs or the unfractionated tumor population.15
Activation of Hedgehog signaling leads to modulation of many genes involved in
cell proliferation, differentiation, invasion, and survival. Nanog is a direct target
of Hedgehog signaling.16
Activation of Notch results in the transcription of protumorigenic proteins, including
cyclin D.17 Notch activation has been implicated in epithelial-to-mesenchymaltransition (EMT) and therapy resistance.18 Notch also has been shown to crosscommunicate with other pro-oncogenic pathways, including Hedgehog, Wnt,
PDGF, TGF-β, PI-3K/AKT, mTOR, and NF-κB signaling.17
Inside Cell
Signal
Transduction
8
Nucleus
9
CSC-Mediated Tumor Relapse
at Primary Site (Recurrence)
CSCs encompass a small percentage of the tumor population. Via stemness
signaling, CSCs propagate the tumor population by asymmetric cell division to
produce a daughter CSC and a progenitor cell that is capable of expanding into
different types of tumor tissue cells.19
Experimental evidence from many research groups has suggested that, although
current therapeutic regimens affect a significant amount of the tumor cells, there is
an enrichment of highly tumorigenic and therapy-resistant CSCs, leading to tumor
relapse (recurrence).20,21
Furthermore, inflammatory cytokines released by inflammatory cells at primary
sites after therapy have been shown to further promote tumor relapse by inducing
mesenchymal stem cells to release proangiogenic factors.22 In head and neck
tumors, the majority of CSCs are located in close proximity to blood vessels and
depend on signals secreted from endothelial cells to promote CSC stemness
signaling (self-renewal and survival).23 This may promote tumor metastasis.
Angiogenesis of Recurrent Tumor
Relapse of Tumor at Primary
Site (Recurrence)
10
11
Blood or
Lymphatic
Vessels
Research in prostate cancer suggests that radiation therapy results in an adherent
senescent population, which resumes proliferation after termination of radiation
exposure, as well as a nonadherent population. The radio-resistant cells, compared
with the non-treated cell population, express pro-EMT characteristics, including
SNAIL, and CSC markers, including CD133, SOX2, OCT4, and Nanog. The
nonadherent therapy-resistant population express the highest levels of EMT and
CSC markers.24
A similar phenomenon has been observed in lung cancer after exposure to an
epidermal growth factor receptor (EGFR) inhibitor.25
CSC With EMT
Characteristics
Entering Vessel
12
Analysis of peritoneal washings from colorectal cancer patients after curative
surgery indicates that higher expression of CSC markers predicted lymph node
metastasis, greater tumor stage, and shorter overall survival and peritoneal
recurrence-free survival.26
13
DISSEMINATION AND METASTASIS
CSCs possess a higher propensity for metastasis and worse prognosis in several
cancers, including prostate, lung, and colorectal. EMT may be an important
component of these events.
Red Blood Cell
Distant Site
Circulatory
System
CSC in Circulatory
System
CSC
Induction of EMT and survival of circulating tumor cells (CTCs) is dependent on
extracellular signal-regulated kinase (ERK) signaling.24 CTCs, which can contain
CSCs, travel to distant sites through the circulatory and lymphatic systems. The
presence of CTCs correlate with worse clinical outcomes.27,28 A subpopulation of
these CTCs may be tumor-initiating CSCs that, upon exiting the circulatory system,
can interact with the microenvironment at distant sites to promote tumor metastasis.
Currently, methods of isolating circulating CSCs are under investigation. These CSCs
have been shown to possess tumor-initiating properties.27
CSCs Exiting From
Circulatory System
at Distant Site
Dissemination of CSCs Into
Blood or Lymphatic System
CSC
Some cancer patients with CSC-positive CTCs have a significantly higher risk of lymph
node metastasis, tumor recurrence, and distant metastasis compared with patients
with CSC-negative CTCs or patients with no CTCs.29 Just as CSCs are responsible for
the propagation of a tumor at a primary site, CSCs in CTCs may be responsible for
propagating tumors at distant sites.
CSC
Non-CSC
CSC-Mediated Propagation
of Tumor at Metastatic Site
CSCs at Metastatic Site
14
15
Combining anti-CSC therapy with conventional treatment modalities provides a
rational approach to targeting the underlying subpopulation that drives the growth
of the entire heterogeneous tumor. This combination would target highly proliferative tumor cells, which make up the bulk of the tumor, and the drug-resistant stemlike cell subpopulation responsible for propagating the entire tumor mass at both
the primary and distant sites. This may lead to a decrease in tumor recurrence and
metastasis and an improved patient prognosis.4,7
After Inhibition of
Stemness Pathways
Before Inhibition of
Stemness Pathways
Apoptosis of CSCs
16
17
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19
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