Download Cancer Stem Cells: Current Perspectives, Future Directions

Supported by Boston Biomedical and Distributed as a Special
Edition with the November 10, 2015 Issue of Oncology Times
Cancer Stem Cells: Current Perspectives, Future Directions
C
ancer stem cells (CSCs) are becoming an increasingly greater focus of cancer research, as evidence
suggests that they may be integral to tumor formation. Understanding the properties and characteristics of CSCs may lead to improvements in cancer diagnosis, therapy, and outcomes. This Special
Edition, Cancer Stem Cells: Current Perspectives, Future Directions, distributed by Oncology Times, offers
insight into the role of CSCs in tumor initiation, progression, and metastasis, as well as the signaling
pathways implicated in cancer, with a focus on gastric and gastroesophageal cancers. The potential for
inhibition of these signaling pathways is also reviewed.
INSIDE
Do Cancer Stem Cells Hold the Key to Controlling Cancer Growth and Spread?
Interview with Max S. Wicha, MD
Dr Wicha notes that greater understanding of CSCs may hold a key to controlling cancer and potentially achieving
durable clinical responses to treatment............................................................................................................................ 2
Cancer Stem Cells: Lessons From Gastroesophageal Cancer Biology
Interview with Jaffer A. Ajani, MD
Dr Ajani discusses the role of CSCs in tumor development, relapse, and metastasis, as well as the challenges to clinical
practice posed by advanced gastric cancer........................................................................................................................ 8
Cancer Stem Cells: Where We Are and Where We’re Going
Dr Ajani and Dr Wicha answer questions about the current and
future state of CSC research. ..................................................... 14
Supported by:
Do Cancer Stem Cells Hold the Key to Controlling Cancer Growth
and Spread?
Interview with Max S. Wicha, MD
Max S. Wicha, MD
Distinguished Professor of Medical Oncology and Director Emeritus
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan
D
espite advances in chemotherapy, targeted
agents, and radiation therapy, the prognosis for
patients with advanced cancer has remained poor.1
Drug resistance, metastasis, and recurrence—even
after extended periods of remission—pose persistent
challenges to cancer management.2 A growing body
of evidence indicates, however, that a subset of cancer
cells, called cancer stem cells (CSCs), may hold a key
to controlling cancer and potentially achieving durable clinical responses.1 “Ultimately, patient survival
depends on getting rid of these cancer stem cells—the
seeds we see in the cancerous tumor after treatment,”
said Max S. Wicha, MD, Distinguished Professor of
Medical Oncology and Director Emeritus at the University of Michigan Comprehensive Cancer Center in
Ann Arbor.
CSCs Drive Tumorigenesis
Normal stem cells are undifferentiated cells in the body
that can self-renew, propagate differentiated cells, and
proliferate extensively.3 Laboratory studies have shown
that entire organs can be generated from a single stem
cell.3 These discoveries have fueled interest in stem cell
therapy for a wide variety of diseases, including neurological, inflammatory, and endocrine disorders.3
CSCs are malignant cancer cells that share the capacity of normal stem cells for self-renewal and proliferation
and can differentiate into the heterogeneous population
of cancer cells that comprise a malignant tumor,4 Dr
Wicha explained. A common misconception is that all
CSCs arise from mutated normal stem cells, but some
CSCs may arise from progenitor cells when a mutation
endows these cells with the capacity for self-renewal, normally reserved to stem cells (Figure 1).5,6 The CSC model
of cancer formation is hierarchical, in contrast with the
traditional stochastic model (see Models of Carcinogenesis
on page 3).5,7 A growing body of evidence suggests that
CSCs are the drivers not only of tumor initiation and
heterogeneity, but of treatment resistance, cancer recurrence, and metastasis.8,9
While the idea that cancers can arise from stem cells
goes back about 150 years,5 it was not supported by
experimental evidence until the late 1990s. Bonnet and
Dick showed that a small subset of acute myelogenous
leukemia (AML) cells were capable of transferring AML
into immunosuppressed mice. The proteins expressed
on these cells were similar to those expressed on normal
hematopoietic stem cells.10 A few years later, the role of
CSCs in tumorigenesis in solid tumors was supported
Models of Carcinogenesis
The classical model of cancer formation,
termed the stochastic model, defines
tumor cells as biologically equivalent.
Intrinsic factors, such as signaling
pathways and levels of transcription
factors, and extrinsic factors, such as the
microenvironment, host-specific factors,
and immune response, result in varied
and unpredictable behavior of the tumor
cells. Therefore, tumor-initiating activity
cannot be attributed to any specific
type of cells. Conversely, the hierarchy
model proposes that tumors are made
up of biologically distinct types of cells
with varying functions and behaviors.
Tumor growth can only be initiated by
a subset of cells known as cancer stem
cells (CSCs), which can self-renew and
differentiate to nontumorigenic progeny
that comprise the tumor mass (Figure).1
According to Max S. Wicha, MD,
research suggests that both models are
correct.2,3 “What we know now is that
the CSCs themselves can mutate. As
cancers develop, the CSC that started
the tumor can then mutate and produce
a new clone, and at the top of the clone
is a CSC. There can be more than one
CSC in an individual cancer. Therefore,
in a way, the stochastic model and the
CSC model are both correct: stem cells
mutate and get selected out and each
stem cell then generates a clone. Thus,
within the tumor are multiple stem cells
and multiple clones that come from
these tumors.”
3
The stochastic and hierarchy models of tumor heterogeneity.
The stochastic model holds that cancer arises through random mutation
and clonal selection. Other clones can be selected out with treatment,
but the cancers continually mutate. In this model, any cell can become
cancerous.4 The CSC model, termed the hierarchy model, is at the other
end of the spectrum. It holds that cancers originate only in cells that can
self-renew and then produce the differentiated cells that make up the bulk
of the tumor.4
1.Dick JE. Stem cell concepts renew cancer research. Blood. 2008;112:4793-4807.
2.
Chen K, Huang YH, Chen JL. Understanding and targeting cancer stem cells: therapeutic
implications and challenges. Acta Pharmacol Sin. 2013;34:732-740.
3.Chen S, Huang EH. The colon cancer stem cell microenvironment holds keys to future cancer
therapy. J Gastrointest Surg. 2014;18:1040-1048.
4.Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea—a paradigm shift. Cancer Res.
2006;66:1883-1890.
by the finding that human breast cancers also could be
transferred to immunosuppressed mice by a small tumorigenic subset constituting only about 1% to 5% of the
cancer cells.11
Figure 1. Stem cell development: normal and cancer stem cells
(CSCs). Normal tissues develop from a central stem cell that grows
and then differentiates to create progenitor and mature cell populations. Normal stem cells have the capacity to self-renew (shown
by a curved green arrow), develop into mature tissue (shown by
a variety of different color cells), and proliferate. CSCs develop
via mutation of normal stem cells or progenitor cells. They go on
to grow and differentiate to create primary tumors (the dashed line
shows that it is unknown which specific types of progenitors are involved in the generation of CSCs). CSCs can self-renew, generate
heterogeneous populations of daughter cells, and proliferate, just
like normal stem cells.6
“We need different clinical endpoints in
assessing clinical trials that are designed to
target CSCs.” – Dr Wicha
The finding that most cells in cancer tumors are nontumorigenic has important therapeutic implications,
Dr Wicha noted. Cancer treatments that target the nontumorigenic cells will cause tumor regression; however,
if they do not affect the CSCs or their signaling pathways,
these cells will persist and potentially regenerate the
tumor, resulting in relapse.11 One implication of this
finding is that “current evaluation of treatment may be
inadequate,” he pointed out.
Treatment efficacy is based on tumor shrinkage, which
is usually defined in the clinic as tumor shrinkage of at
least 50%.5 “The problem with that traditional endpoint
is that for the vast majority of cancers, tumor shrinkage
does not translate to patients living longer,” Dr Wicha
said. An explanation for this may be that tumor regression is a mark of the effect of a treatment on the bulk
tumor cell population, rather than the CSCs.12
CSCs tend to be resistant to conventional cancer
therapies, similar to the resistance to apoptotic therapies observed in normal stem cells.5 “An issue critical
Oncology Times • November 10, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions
Oncology Times • November 10, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions
2
to understanding why CSCs are treatment resistant
is whether CSCs are discrete populations of cells in
cancer or whether non-CSCs can revert to stem cells,”
Dr Wicha said. Recently, breast cancer stem cells were
shown to exist in two states: the epithelial-mesenchymal
transition (EMT) state and the mesenchymal-epithelial
transition state (MET). In the EMT state, the cells are
relatively quiescent but localized at the invasive tumor
front, from where they can disseminate via the bloodstream to distant sites and seed micrometastases. In the
MET state, the cells are capable of extensive proliferation, growing new tumors.13 Both cell states are needed
to form metastases, and evidence suggests that plasticity
of breast CSCs allows them to transition from one state
to the other.13
Stem Cell Divisions Predict Cancer Risk
The incidence of cancer across different tissues varies
widely, but the reason for these differences is unclear.14
For example, the lifetime risk for cancers in the alimentary tract varies by a factor of 24 (0.20% in the
small intestine but 4.82% in the large intestine). Such
differences cannot be explained fully by environmental
or genetic factors, which account for only one-third
of the risk variation.14 Recent evidence points to stem
cells as the key to the differences seen among the incidences of cancer in different organs. Most cells in tissues are differentiated and short-lived; however, stem
cells, with their capacity for self-renewal, are essentially “immortal.” Tomasetti and Vogelstein analyzed
stem cells in different organs and the number of times
these stem cells divide, because mutations can happen
any time a cell divides; they found a close linear relationship between the number of stem cell divisions in,
and the incidence of, cancer in that organ.14
“The findings of Tomasetti and Vogelstein have been
misunderstood as attributing cancer to ‘bad luck,’”
Dr Wicha said, “undercutting the role of stem cells in
tumorigenesis.” However, the data are highly supportive
of the origin of most cancers in stem cells. What the
investigators state is that the majority of the differences
in cancer risk can be attributed to “‘bad luck,’ that is,
random mutations arising during DNA replication in
normal, noncancerous stem cells.”14 In other words,
mutations occur at a constant rate based on how often
the cell divides. Based on the linear correlation of
0.804, 65% of the differences in cancer risk among
different tissues can be explained by the total number
of stem cell divisions in the tissues.14 However, mutations can be caused by other factors as well. “The best
example of this is carcinogenic tobacco smoke,” he
said. “In this case, the lung cancer incidence would be
higher than expected from just the number of stem cell
divisions in lung tissue because of the influence of the
environmental carcinogen.”
Target Selection May Be the Key to
Effective Therapy
During the self-renewal process, normal stem cells
interact with their microenvironment (termed the stem
cell niche) via tightly regulated signaling pathways. In
the early stage of cancer formation, after the stem cell or
progenitor cell receives its first mutation, these pathways
become dysregulated, allowing the CSCs to expand in an
abnormal fashion.5 “We are finding that CSCs are driven
by a limited number of key pathways,” Dr Wicha said
(Figure 2).8 CSCs also interact with other components of
the cellular microenvironment, such as cytokines, growth
factors, and stromal cells (Figure 3).1
“We are finding that CSCs are driven
by a limited number of key pathways.”
– Dr Wicha
An expanded understanding of the key signaling pathways of CSCs and of the interactions of these cells with
the tumor microenvironment is providing new insights
into the mechanisms responsible for the resistance of
CSCs to conventional cancer therapies and potential targets for new treatment approaches.8 Evidence has shown
that not only are CSCs resistant to chemotherapy and
radiation therapy, but that their number can actually be
increased by these treatments.15
Figure 2. Key signaling pathways in cancer stem cells (CSC)
development. Dysregulation of signaling pathways plays a
crucial role in the ability of CSCs to self-renew and differentiate.
Depending on the signaling pathway involved, CSCs gain the
ability to initiate cancer formation or cause tumor recurrence.8
As Dr Wicha explained, evidence shows that cells
being killed by chemotherapy secrete inflammatory
mediators such as cytokines; some of these are interleukin (IL)-6 and IL-8, which then act to stimulate
CSCs. Damage to normal tissue induces a similar
response. Injured cells release the same cytokines,
signaling the normal stem cells in the tissue to reproduce.16 “This is healthy when it occurs during normal
tissue regeneration, but during treatment of cancer
with chemotherapy CSC stimulation leads to their
increase,” he added.
Dr Wicha noted that new approaches to cancer
treatment include targeting CSCs and their signaling
pathways, such as Notch, Wnt, Hedgehog, and JAK/
STAT, which regulate the CSC internal circuitry. Cancer
treatments may also target inflammatory cytokines, such
as IL-6 and IL-8, which mediate the interaction between
CSCs and the tumor microenvironment, he added.
The blockade of IL-8 receptors as a potential treatment
approach has been studied in breast cancer by Dr Wicha’s
group and others.17 “Targeting some of the pathways
involved in CSC self-renewal may not only stop CSCs
from reproducing, but also lead to their differentiation
into non–stem cells, thereby making them chemotherapy-sensitive,” Dr Wicha said. Evidence suggests that
when IL-8 receptor blockers are used in combination
with chemotherapy, the CSC population decreases to a
greater degree than with chemotherapy alone, perhaps
Figure 3. The interaction of CSCs with their microenviron-
ment. CSCs exist within a microenvironment of stromal cells,
immune cells, neighboring vasculature, and secreted factors
that are produced by these cells. These elements create a niche
where CSCs survive and propagate into the cells that define the
tumor mass.1,5
because the CSCs are being prompted to differentiate
and become sensitive to chemotherapy.17
Regarding the development of new cancer treatment strategies for cancer, it is important to remember
that CSCs represent only a small fraction of the tumor
cell population, Dr Wicha noted. If these cells are not
killed, the tumor will regenerate. Even if the CSCs are
destroyed, the non-CSCs that form the bulk of the
tumor can, however, still undergo several rounds of cell
division leading to spreading of the cancer. Therefore, for
the treatment of advanced cancers, the optimal approach
is thought to be a combination of a stem-cell targeting
agent with a debulking agent that can destroy the large
mass of the tumor cells. That debulking agent can be
chemotherapy, for instance, because chemotherapy is
effective at targeting the bulk cells, while CSCs are resistant to chemotherapy and radiation therapy.16 According
to Dr Wicha, “When treating micrometastatic disease in
the adjuvant setting, CSC-targeted therapy alone may be
potentially curative. If we knock out the micrometastases,
the cancer may not grow back.” For this reason, treatment strategies that target CSCs and the mechanisms
responsible for the interaction between CSCs and their
microenvironment may represent an important approach
to improving patient outcomes.16
CSC Immunotherapy May
Improve Outcomes
New insights into the biology of CSCs and nontumorigenic cancer cells are providing the rationale for
immunologic approaches to targeting CSCs. The gene
expression profiles and expressed antigens displayed by
CSCs and non-stem cancer cells differ. Immunotherapies that target the differentiated cancer cells that form
the tumor bulk may not effectively target the antigens
expressed by CSCs. In addition, CSCs themselves exhibit
heterogeneity.1 Thus, molecular profiling of CSCs and
cancer tumors and targeting of immunotherapy at heterogeneous CSC populations “represent one of the most
exciting areas in cancer research. Specifically, targeted
immunotherapy offers the potential for durable responses
in patients with cancers who previously had few therapeutic options,” noted Dr Wicha.
CSCs can evade the immune system even more efficiently than the differentiated cells forming the tumor
bulk. For example, CSCs express high amounts of
programmed death (PD)–ligand 1 (PD-L1). The PD1/
PD-L1 pathway (an immune checkpoint) is one of
two recognized immunoinhibitory pathways that contribute to an immunosuppressive microenvironment
that protects cancer cells from immune destruction.1
Thus, a current approach to the treatment of a variety
5
Oncology Times • November 10, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions
Oncology Times • November 10, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions
4
of cancers focuses on combinations of such immune
checkpoint blocking therapies, other immunotherapies
(such as IL-6 or IL-8 inhibitors), and vaccines that
target CSCs.1
“The vision for the future of cancer therapy is to base treatment selection on a complete molecular diagnosis of the
tumor, including an evaluation of the stem-cell profile of
that particular tumor,” noted Dr Wicha. From an analysis
of the immune infiltrates of the tumor, it also will be possible to know whether the patient is mounting an immune
response against the tumor. Dr Wicha believes that cancer
treatment will move toward a combination approach–
targeting the tumor bulk, CSC populations, and immune
components. This will lead to “substantial, rather than
merely incremental, gains in treating cancer. Most importantly, this future approach may offer a more durable
patient response as opposed to an increase in survival of
only 1 or 2 months.”
New Therapies, New Challenges
With new treatments come new challenges. As Dr Wicha
explained, “The first challenge is to determine whether
an agent that targets CSC pathways will be cytotoxic to
normal stem cells, because they use the same pathways.
Early trials must test low doses of these agents and escalate them carefully,” he said. “Several phase 1 trials have
already shown that most agents targeting CSC pathways
can be given effectively with relatively low toxicities
and that, based on biopsies performed before and after
treatment, the targets are being hit.” Going forward,
researchers will analyze whether combining these agents
with chemotherapy or immunologic agents will have the
potential for increased side effects, such as inducing autoimmunity against the normal stem cells. “These investigations must proceed carefully,” he cautioned.
“The second challenge is the need to rethink the use
of traditional endpoints of tumor regression in clinical
trials,” Dr Wicha noted. Because CSC-targeting agents
do not cause tumor regression, he explained, investigators must work with the United States Food and Drug
Administration to determine how to demonstrate conclusively that these agents provide a benefit. “What are
the acceptable endpoints?” he asked. “What should we
be measuring?” Obviously, phase 1 trials are designed to
study potential agents that target CSC signaling alone,
with careful monitoring of potential toxicity risks.
Phase 2 studies will then assess chemotherapy alone
compared with chemotherapy plus an agent targeting a
CSC pathway. Potential endpoints in these studies will
likely be time to develop new metastases, time to tumor
progression, and progression-free or overall survival,
rather than tumor regression.
A neoadjuvant trial design that assesses the level of
complete pathological response has great appeal for
CSC research in a number of tumor types, Dr Wicha
said. Complete pathologic response with neoadjuvant
therapies is associated with a favorable outcome and has
already led to the approval of a new agent to be used as
dual anti-HER2 therapy in patients with HER2-positive
breast cancer.18 Another possible endpoint in the neoadjuvant setting is the measurement of residual CSCs after
treatment, as the presence of these cells after neoadjuvant
therapy has been associated with a poor prognosis.15
The other technology receiving increased attention
is the isolation of circulating tumor cells. As Dr Wicha
explained, circulating tumor cells are highly enriched in
stem cell markers in patients with breast cancer. Whereas
1% to 5% of cells are CSCs in primary cancers, studies
have shown that closer to 30% to 50% of circulating
tumor cells express stem cell markers.11,19,20 Circulating
tumor cells may prove useful as biomarkers for patients
in clinical trials; isolating and measuring circulating
tumor cells may be a way to monitor patients and determine the efficacy of potential treatments.20 “The utility
of these assays as predictive of outcomes must be proven
in rigorous clinical trials,” Dr Wicha noted, “but this is
the kind of research now being explored, as agents that
target CSC pathways are increasingly used in the clinical
research setting.”
Conclusion
CSCs as potential therapeutic targets may be instrumental
in developing therapies that control cancer and allow for
the achievement of durable clinical responses in patients.
Expanded understanding of the biology of CSCs, their key
signaling pathways, molecular diagnosis of tumors, and
appropriate clinical trial endpoints will help in the development of agents targeting key signaling pathways.
References
1.Pan Q, Li Q, Liu S, et al. Concise review: targeting cancer stem
cells using immunologic approaches. Stem Cells. 2015;33:20852092.
2.Touil Y, Igoudjil W, Corvaisier M, et al. Colon cancer cells escape
5FU chemotherapy-induced cell death by entering stemness and
quiescence associated with the c-Yes/YAP axis. Clin Cancer Res.
2014;20:837-846.
3.Liu Y, Yang R, He Z, Gao W-Q. Generation of functional organs
from stem cells. Cell Regen (Lond). 2013;2:1.
4.Clarke MF, Dick JE, Dirks PB, et al: Cancer stem cells—perspectives on current status and future directions: AACR Workshop on
cancer stem cells. Cancer Res. 2006;66:9339-9344.
5.Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea—a
paradigm shift. Cancer Res. 2006;66:1883-1890.
6.Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J
Med. 2006;355:1253-1261.
7.Dick JE. Stem cell concepts renew cancer research. Blood.
2008;112:4793-4807.
8.Chen K, Huang Y-H, Chen J-L. Understanding and targeting
cancer stem cells: therapeutic implications and challenges. Acta
Pharmacol Sin. 2013;34:732-740.
9.Tang DG. Understanding cancer stem cell heterogeneity and plasticity.
Cell Res. 2012;22:457-472.
10.Bonnet D, Dick JE. Human acute myeloid leukemia is organized
as a hierarchy that originates from a primitive hematopoietic cell.
Nat Med. 1997;3:730-737.
11.Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke
MF. Prospective identification of tumorigenic breast cancer cells.
Proc Natl Acad Sci USA. 2003;100:3983-3988.
7
12.Korkaya H, Liu S, Wicha MS. Regulation of cancer stem cells by
cytokine networks: attacking cancer’s inflammatory roots. Clin
Cancer Res. 2011;17:6125-6129.
13.Liu S, Cong Y, Wang D, et al. Breast cancer stem cells transition
between epithelial and mesenchymal states reflective of their normal
counterparts. Stem Cell Reports. 2014;2:78-91.
14.Tomasetti C, Vogelstein B. Cancer etiology. Variation in cancer
risk among tissues can be explained by the number of stem cell
divisions. Science. 2015;347:78-81.
15.Lee HE, Kim JH, Kim YJ, et al. An increase in cancer stem cell
population after primary systemic therapy is a poor prognostic factor
in breast cancer. Br J Cancer. 2011;104:1730-1738.
16.Korkaya H, Liu S, Wicha MS. Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J Clin Invest.
2011;121:3804-3809.
17.Ginestier C, Liu S, Diebel M, et al: CXCR1 blockade selectively
targets human breast cancer stem cells in vitro and in xenografts.
J Clin Invest. 2010;120:485-497.
18.Gianni L, Pienkowski T, Im Y-H, et al: Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced,
inflammatory, or early HER2-positive breast cancer (NeoSphere):
a randomised multicentre, open-label, phase 2 trial. Lancet Oncol.
2012;13:25-32.
19.Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R, Kasimir-Bauer
S. Stem cell and epithelial-mesenchymal transition markers are
frequently overexpressed in circulating tumor cells of metastatic
breast cancer patients. Breast Cancer Res. 2009;11:R46.
20.Lianidou ES, Markou A. Circulating tumor cells in breast cancer:
detection systems, molecular characterization, and future challenges. Clin Chem. 2011;57:1242-1255.
Oncology Times • November 10, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions
Oncology Times • November 10, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions
6
Cancer Stem Cells: Lessons From Gastroesophageal Cancer Biology
Interview with Jaffer A. Ajani, MD
Jaffer A. Ajani, MD
Professor
Department of Gastrointestinal Medical Oncology
University of Texas MD Anderson Cancer Center
Houston, Texas
Percent of Cases by Stage
Unknown
n
Localized
Loca
(Unstaged)
d)
(Con
(Confined
to
primary site)
prim
26%
10%
29%
35%
CSCs and the Role of the
Microenvironment
As defined by the American Association for Cancer
Research Workshop on Cancer Stem Cells, a CSC is a cell
within a tumor that possesses the capacity to selfrenew and to give rise to the heterogeneous lineages of
cancer cells that comprise the tumor. Because they have
an intrinsic ability to propagate tumor cells, CSCs are also
referred to as “tumor-initiating cells” or “tumorigenic cells”
(Table 1).4,5 The ability of stem cells to self-renew and give
rise to multiple cell lineages is termed “stemness.”6
The microenvironment plays an important role in the
support and development of CSCs. Essentially, CSCs
exist within a microenvironment consisting of stromal
cells, immune cells, neighboring vasculature, and secreted
factors that are produced by these cells. These elements
create a niche where CSCs can survive and subsequently
propagate into the cells that comprise the tumor mass.
As such, the niche may be considered to be a regulatory
microenvironment where the stem cell–like characteristics
of CSCs are nurtured to maintain their self-renewal and
differentiation activities. Studies have shown that pathological alterations in normal microenvironments may produce tumor microenvironments that serve as CSC niches.4
Distant
ant
Regional
Region
(Cancer has
metastasized)
zed)
(Spread to regional
lymph nodes)
n
5-Year Relative Survival
100
Tumor Progression and Metastasis
As noted, gastric cancer is usually diagnosed at later
stages. This may be because patients often do not exhibit
symptoms until their disease has progressed, or their
symptoms have been vague and attributed initially to
causes other than cancer. “Patients with gastric cancer
often have nonspecific symptoms for a long time. It
is not unusual for them to see multiple doctors, until
finally, when the diagnosis is made, the tumor is well
established,” Dr Ajani said.
“One of our biggest problems is that most
patients have very advanced tumors when
finally seen at our clinic. To me, that signals
an older tumor, with many generations of
evolved cancer cells and a great deal of
resistance to therapy.” – Dr Ajani
Research is pointing to the migration of CSCs from
the primary tumor site as an underlying mechanism of
tumor progression and metastasis. The clinical pattern of
patients with metastatic disease bears this out, Dr Ajani
said. “Often, we can’t find the metastatic tumors in patients
who are treated initially with a curative intent,” he noted.
“When the primary tumor is treated, whether with preoperative chemotherapy and/or chemoradiation followed by
surgery, we observe several phenomena. The primary tumor
is often resistant to therapy. We know from our experience,
that the more resistant the primary tumor, the more metastatic potential it has. In other words, this aggressive biology, which is probably related to the number of CSCs (and
evolved species of CSCs) present in the primary tumor
or volume of the tumor, dictates metastatic potential,” he
explained. In addition, although it may appear that local
treatment has been successful, highly resistant metastatic
disease often becomes apparent very quickly.
80
Percent
G
astric and esophageal cancers are, respectively, the
third and sixth most common causes of cancerrelated deaths worldwide.1 During the past several
decades, the incidence of these cancers has decreased.
In the United States, the incidence has shifted rapidly
from esophageal squamous cell carcinoma and distal
gastric carcinoma to adenocarcinoma of the esophagus
and proximal stomach.2 In essence, gastric and esophageal cancers are now being seen more commonly at the
gastroesophageal junction.2
In the United States, gastric cancer is mostly diagnosed
in later stages, when survival is at its poorest.3 Indeed,
localized gastric cancer represents only about one quarter
of all gastric cancer diagnosed in the United States (Figure
1).3 “The survival advantage provided by current therapies
for patients with regional and metastatic disease is pitifully
marginal,” Jaffer A. Ajani, MD, commented. Dr Ajani is
Professor in the Department of Gastrointestinal Medical
Oncology at the University of Texas MD Anderson Cancer
Center in Houston. “Our research is now showing that
cancer stem cells (CSCs) are central to the lack of success
when we treat patients with gastric or esophageal cancer.”
65.4
60
40
29.9
20
0
21.3
4.5
LLocalized
li d R
Regional
i
l Distant
Di t t
Stage
Unstaged
U t
d
Figure 1. Percentage of cases and 5-year relative survival
by stage at diagnosis: stomach cancer. Cancer stage at
diagnosis determines treatment options and has a strong
influence on the length of survival. The earlier stomach
cancer is diagnosed, the better chance a person has of
surviving 5 years after diagnosis. For stomach cancer, 26.0%
and 29.0% of cases are diagnosed at the local and distant
stage, respectively. Of note, the stage of disease is unknown
at diagnosis in more than one-third of cases. The 5-year
survival for localized stomach cancer is 65.4%, compared
with 4.5% for distant stomach cancer.3
Table 1. Key Characteristics of Cancer Stem
Cells (CSCs)4,5
Self-renewal
CSCs serially transplant through
multiple generations
Differentiation
CSCs generate symmetrical and
asymmetrical cells
Tumorigenicity
CSCs can propagate tumor cells
Specific surface
markers
Allow for separation of CSCs from
non–stem cells
Treatment Patterns
Unfortunately, current treatments for gastric cancers provide only a marginal overall survival benefit, as Dr Ajani
noted. The 5-year relative survival of all patients with
gastric cancer is less than 30%.7 A recent study followed
more than 600 patients with localized esophageal or
gastroesophageal cancer after treatment with chemoradiation and/or surgery. Regardless of treatment, more than
one-third of the patients developed distant metastasis less
than 2 years after treatment.8 In a review of second-line
therapy in advanced gastric cancer, the overall survival
was only about 5 months in most patients.9 While antiHER2–targeted therapy is showing efficacy, Dr Ajani
pointed out that only about 20% of gastric cancers and
30% of gastroesophageal cancers overexpress HER2.9 In
a review of first-line therapy in patients with metastatic
disease, the inclusion of an anti-HER2–targeted agent
provided a modest increase in survival to slightly more
than 1 year.9 Patients receiving anti-HER2 therapy eventually develop resistance as well, he added.
Treatment resistance is usually due to crossactivation of the HER2 signaling pathway by other
pathways, including insulin-like growth factor,
c-MET, growth differentiation factor 15, and other
members of the ERBB family. Moreover, hyperactivation of downstream HER2 pathway components, such
as MAPK and PI3K/AKT, may further contribute to
anti-HER2 therapy resistance.10 “There is a need for
better targeted therapies,” Dr Ajani said.
The molecular events involved in tumorigenesis have
been explored to a great extent in many types of cancer,
Dr Ajani said, but those involved in gastric and gastroesophageal cancers are not well understood10 (see The
Molecular Side of Gastric Cancer on page 10).
“The CSC phenomenon is seen repeatedly in the
clinic,” Dr Ajani said, “but we’re not yet able to do anything about it.” He described three patterns of response
and resistance observed in patients with advanced and
metastatic tumors following first-line therapy.
“In patients with gastroesophageal cancer, there is
almost a 50% chance they will experience some reduction in tumor volume and improvement in their symptoms for a short time,” he said, “but after a few months,
the cancer starts to grow.” Second-line therapy produces
less reduction in tumor volume and for a shorter duration response. This supports some of the preclinical
research demonstrating that the CSC population is
enriched by cancer treatments, making the tumor more
resistant, he added.
A second pattern involves patients whose tumors
exhibit primary resistance, according to Dr Ajani. These
patients never experience tumor shrinkage even with
9
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8
“We have conducted a fair amount of
research on tumors at the juncture of the
esophagus and stomach. Our preclinical
findings show that CSCs are central to lack
of treatment success of these tumors.”
– Dr Ajani
Gastric and Gastroesophageal Biology
and CSCs
CSCs provide a rational explanation for the presence of
tumor heterogeneity and the development and progression of cancer, Dr Ajani believes. As he explained,
normal stem cells are the source of the propagation of the
entire tissue in organs. They are capable of self-renewal,
as well as multi-lineage differentiation. They can create
an exact copy of themselves or produce progenies with
limited renewal and differentiation potential. While normal stem cells possess long life spans, their differentiated
progenies can possess limited life spans.11 As examples of
these characteristics, Dr Ajani said that investigators have
shown that a single breast stem cell can be used to create
all the different types of cells that compose a functional
breast tissue.12 Using mouse models, a similar phenomenon has been observed in gastric tissue. In addition, the
stem cells that propagate the tissue in the inner lining of
the stomach have been shown to survive for the majority
of the life span of a mouse, that is, 48 weeks, while also
producing mature stomach lining cells, mucous cells,
that live for only a few days.13 The majority of human
gastric cancers originate from the stomach mucosa.7
The Molecular Side of Gastric Cancer
Gastric cancer is a heterogeneous disease with diverse
molecular characteristics. Multiple experimental and
clinical investigations have implicated a wide range
of germline and somatic alterations that drive tumor
progression.1 Recently, the Cancer Genome Atlas Research Network analyzed nearly 300 samples of previously untreated gastric and gastroesophageal cancer
and grouped them into four major molecular subtypes.2
• T he Epstein-Barr Virus (EBV)–positive group,
which made up 9% of gastric cancers. This group
displays high prevalence of DNA hypermethylation, including promoter methylation of the tumor
suppressor CDKN2A (p16INK4A). There is a high
incidence of PIK3CA mutations, amplifications of
several oncogenes, including ERBB2, and recurrent amplifications of chromosome p9 (leading to
overexpression of PD L1/2 and JAK2).2
• T he microsatellite instability (MSI) group, which
made up 22% of gastric cancers. This group is
characterized by enrichment for microsatellite
instability (MSI), including hypermethylation at the
MLH1 promoter. The MSI subgroup exhibits mutations in many cancer “hotspots,” such as PIK3CA,
ERBB3, ERBB2, EGFR, and overexpresses mitotic
pathway components.2
The inner lining of the stomach is organized into a cryptlike structure, containing normal stem cells at the bottom,
which is similar to that seen in the inner intestinal lining,
but not as deep, Dr Ajani explained (Figure 2).14-17 Like
other stem cells, gastric stem cells self-renew and produce
the remaining components of the mucosa. Studies have
shown that these stem cells depend on the Wnt/β-catenin
pathway to maintain the number of stem and non-stem
mucosa cells. Dr Ajani noted that the Wnt/β-catenin pathway is important for the embryonic development of stomach stem mucosa cells as well. These mucosa cells begin to
form precancerous mucosa cells when the inhibiting component of the Wnt/β-catenin pathway, called adenomatous
polyposis coli (APC), is removed from the stem cells.14 This
suggests that CSCs may be involved in the initiation and
progression of gastric cancer, he said.
Other stemness signaling pathways have been implicated
in esophageal cancer progression, as well. The Hedgehog
(Hh) pathway, for example, is transiently upregulated in
progenitor cells to induce proliferation after tissue injury.
These stem cell progenitors are usually quiescent and return
to this state after tissue regeneration via tight regulation of
the Hh signaling pathway. Chemoradiation-resistant esophageal cancer has been shown to induce the Hh stemness
signal pathway after treatment. Blockade of the Hh pathway
components results in reversal of therapy resistance. This
suggests that these tumors may be activating this regenerative signaling pathway to support tumor regrowth after
injury or chemoradiation.18 A similar phenomenon was
• T he genomically stable subgroup, which made up
20% of gastric cancers. This group exhibited mutations in CDH1 and in RHOA, a protein important
in cell motility and the STAT3 signaling pathway.2
•
The high chromosomal instability (CIN) group,
which made up about 50% of gastric cancers.
This subgroup is concentrated at the gastroesophageal junction.2 The CIN group exhibited hyperactivation of EGFR and other RAS-driven receptor
tyrosine kinases, mutation of the tumor suppressor
TP53, and high levels of aneuploidy.2 Chromosomal instability has been shown to be prevalent
in several solid tumors, including those of the
head and neck, testes, lung, and liver, as well as
in gastric and gastroesophageal cancers. Fewer
CINs are seen in melanoma, and even fewer in
Wilms’ tumors.3
1. Wadhwa R, Song S, Lee JS, Yao Y, Wei Q, Ajani JA. Gastric cancer: molecular and clinical dimensions. Nat Rev Clin Oncol. 2013;10:643-655.
2. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202-209.
3.Rooney PH, Murray GI, Stevenson DAJ, Haites NE, Cassidy J, McLeod HL. Comparative genomic hybridization and chromosomal instability in solid tumours.
Br J Cancer. 1999;80:862-873.
Normal Crypt
observed in gastric cancer in which chemotherapy-resistant
cells exhibited increased CSC properties, along with an
increase in the CSC marker BMI1. Depletion of BMI1
resulted in therapy sensitization.19
Chemotherapy resistance is also associated with increased
levels of the CSC marker ALDH1. In research conducted
by Dr Ajani’s group, expression of ALDH1 after chemoradiation therapy correlated directly with worse clinical
response.20 Dr Ajani added that this suggests that CSCs may
play an important role in chemoradiation therapy resistance.
“Chromosomal instability-related cancers
are more common in organs, such as the
lungs, stomach, esophagus, head and neck,
and skin, which are exposed to external
factors. When they become cancerous, it’s
because these malignancies are all carcinogendriven and they have a large number of
DNA alterations. On the other hand,
pediatric cancers and leukemia are more
genetically driven and have very few
alterations.” – Dr Ajani
CSCs have been shown to play a role in gastric and
gastroesophageal cancer metastasis, too. Helicobacter pylori
infection has been shown to increase expression of epithelial-mesenchymal transition (EMT) markers during the
progression from normal tissue to dysplasia to gastric cancer.
An increase in CSC potential (marked by an increase in the
Cancerous Crypt
Normal gastric epithelium cells
Myofibroblast cells
Normal stem cells
Cancer stem cells
Tumor cell
Inflammatory
microenvironment cells
Wnt
the initial treatment option, nor do they fare any better
with a second-line therapy. “We have lost many patients
like that.”
A third resistance pattern is one in which the
patient has a mixed treatment response. Metastatic
lesions in the liver, for example, will become smaller,
Dr Ajani said, while those in abdominal lymph nodes
will increase in size. “This is a curious phenomenon,”
he said, “but we observe it frequently and it reflects
intra-patient tumor heterogeneity.” Not only can
tumors in different organs exhibit different molecular
characteristics, but multiple metastases in the same
organ can have different somatic profiles. “These are
real problems in the clinic that we cannot control,” he
added. “We need to know about the underpinnings of
these phenomena.”
Signaling/phenotypic
gradient
Figure 2. Gastric stem cells and tumor formation. Multipotent stem cells positioned at the base of the pyloric antrum gastric crypt support
long-term renewal of gastric mucosa, and give rise to all cell lineages of the crypt.15,16 These normal stem cells express the leucine-rich
repeat-containing G-protein coupled receptor 5 (Lgr5) stem cell marker,15 and are dependent on Wnt signaling to maintain their stem cell
functions at the base of the gastric crypt.14 Loss of adenomatous polyposis coli in Lgr5 positive cells may be a driver of tumor formation.14
Inflammatory microenvironment components, such as fibroblasts, lymphocytes, mast cells, and macrophages, may support transformation of
gastric stem cells to cancer stem cells.17
11
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Oncology Times • November 10, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions
10
stem cell and CSC marker CD44) has been observed, as
well. The expression of these markers decreased a year after
eradication of infection—a trend that persisted several years
after eradication of the H. pylori. Together, this suggests
that H. pylori infection promotes EMT in gastric cancer via
CSC-mediated tumorigenesis.21
As discussed earlier, anti-HER2–targeted therapy has
been shown to be effective in some patients with gastric
cancer. Recently, the mechanism of acquired resistance to
the anti-HER2–targeted agent trastuzumab in gastric cancer has been explored. Treatment of gastric cancer cells for
20 weeks with trastuzumab resulted in EMT induction in
drug-resistant cells. This EMT induction was characterized
by loss of E-cadherin (the hallmark of EMT) and ZO1, as
well as overexpression of claudin-1, vimentin, β-catenin,
ZEB1, Slug, and Snail.22 These drug-resistant cells also
exhibited an aggressive tumor phenotype, including higher
motility, invasion potential, tumor formation potential,
and metastatic capacity.22 Furthermore, the drug-resistant
cells exhibited other CSC properties, including higher
sphere-forming capacity and expression of the CSC
markers Oct4, CD133, and CD44.22 The increase in CSC
potential was accompanied by down-regulation of the
AKT signaling pathway and upregulation of the STAT3
pathway. The STAT3 pathway was activated by Notch-dependent autocrine secretion of interleukin 6.22
Conclusion
Advanced gastric or gastroesophageal cancer remains one of
the most difficult challenges in clinical practice. Research
has shown that CSCs can initiate tumor development
and play a significant role in tumor relapse and metastasis.
Indeed, evidence is accumulating that treatments, such as
chemotherapy and radiation, can increase the proliferation
of CSCs. Investigations are underway into the molecular
signaling pathways involved in tumor cell repopulation. The
small subpopulation of CSCs in gastroesophageal and other
solid tumors may be a rational treatment target.
References
1.Centers for Disease Control and Prevention. Global cancer statistics. http://www.cdc.gov/cancer/international/statistics.htm. 2012.
Accessed July 6, 2015.
2.Crew KD, Neugut AI. Epidemiology of upper gastrointestinal
malignancies. Semin Oncol. 2004;31:450-464.
3.National Cancer Institute. Surveillance, Epidemiology, and End
Results Program (SEER). SEER Stat Fact Sheets: Stomach Cancer.
http://seer.cancer.gov/statfacts/html/stomach.html. Accessed
August 3, 2015.
4.Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones
DL, et al. Cancer stem cells−perspectives on current status and
future directions: AACR Workshop on cancer stem cells. Cancer
Res. 2006;66:9339-9344.
5.Han L, Shi S, Gong T, Zhang Z, Sun X. Cancer stem cells: therapeutic implications and perspectives in cancer therapy. Acta Pharm
Sin B. 2013;3:65-75.
6.Wong DJ, Segal E, Chang HY. Stemness, cancer and cancer stem
cells. Cell Cycle. 2008;7:3622-3624.
7.American Cancer Society. Stomach cancer: survival rates for stomach cancer, by stage. http://www.cancer.org/cancer/stomachcancer/detailedguide/stomach-cancer-survival-rates. 2015. Accessed
August 11, 2015.
8.Shiozaki H, Sudo K, Xiao L, et al. Distribution and timing of
distant metastasis after local therapy in a large cohort of patients
with esophageal and esophagogastric junction cancer. Oncology.
2014;86:336-339.
9.Elimova E, Shiozaki H, Wadhwa R, et al. Medical management of gastric cancer: a 2014 update. World J Gastroenterol.
2014;20:13637-13647.
10.Wadhwa R, Song S, Lee JS, Yao Y, Wei Q, Ajani JA. Gastric
cancer-molecular and clinical dimensions. Nat Rev Clin Oncol.
2013;10:643-655.
11. Passegué E, Jamieson CHM, Ailles LE, Weissman IL. Normal and
leukemic hematopoiesis: are leukemias a stem cell disorder or a
reacquisition of stem cell characteristics? Proc Natl Acad Sci USA.
2003;100(suppl 1):11842-11849.
12.Liu Y, Yang R, He Z, Gao WQ. Generation of functional organs
from stem cells. Cell Regen (Lond). 2013;2:1.
13.Bjerknes M, Cheng H. Multipotential stem cells in adult mouse
gastric epithelium. Am J Physiol Gastrointest Liver Physiol.
2002;283:G767-G777.
14.Barker N, Huch M, Kujala P, et al. Lgr5(+ve) stem cells drive
self-renewal in the stomach and build long-lived gastric units in
vitro. Cell Stem Cell. 2010;6:25-36.
15.Singh SR. Gastric cancer stem cells: A novel therapeutic target.
Cancer Lett. 2013;338:110-119.
16.Schepers A, Clevers H. Wnt signaling, stem cells, and cancer
of the gastrointestinal tract. Cold Spring Harb Perspect Biol.
2012;4:a007989.
17.Quante M, Wang TC. Inflammation and stem cells in gastrointestinal carcinogenesis. Physiology (Bethesda). 2008;23:350-359.
18.Sims-Mourtada J, Izzo JG, Apisarnthanarax S, et al. Hedgehog: an attribute to tumor regrowth after chemoradiotherapy
and a target to improve radiation response. Clin Cancer Res.
2006;12:6565-6572.
19.Xu ZY, Tang JN, Xie HX, et al. 5-Fluorouracil chemotherapy of
gastric cancer generates residual cells with properties of cancer
stem cells. Int J Biol Sci. 2015;11:284-294.
20.Ajani JA, Wang X, Song S, et al. ALDH-1 expression levels
predict response or resistance to preoperative chemoradiation in
resectable esophageal cancer patients. Mol Oncol. 2014;8:142-149.
21.Choi YJ, Kim N, Chang H, et al. Helicobacter pylori-induced
epithelial-mesenchymal transition, a potential role of gastric
cancer initiation and an emergence of stem cells. Carcinogenesis.
2015;36:553-563.
22.Yang Z, Guo L, Liu D, et al. Acquisition of resistance to trastuzumab in gastric cancer cells is associated with activation of
IL-6/STAT3/Jagged-1/Notch positive feedback loop. Oncotarget.
2015;6:5072-5087.
Cancer Stem Cells: Where We Are and Where We’re Going
13
Max S. Wicha, MD, and Jaffer A. Ajani, MD
Q
A
Why is cancer stem cell (CSC) research so
important?
Dr Wicha: Many of our current treatments don’t
target CSCs effectively. If these cells are essentially
the cells that cause regrowth of tumors after treatment
and are the seeds that carry cancer metastasis, it will be
necessary to get rid of these cells to really improve the
outcome of cancer patients.
Dr Ajani: We need to understand some of the properties of CSCs to learn how they can be overcome. In
addition to being treatment-resistant, CSCs prefer a
hypoxic environment. They don’t need much oxygen to
survive and can remain dormant for quite some time.
Research that improves our understanding of these
characteristics may ultimately lead to depletion of CSCs
in the tumor.
Q
A
Why is the concept of targeting CSCs so
attractive?
Dr Wicha: A mutation that is driving a cancer
sometimes is also driving the CSC. A good
example is human epidermal growth factor receptor
2 (HER2) in human breast cancer. HER2 is a very
potent driver of breast CSCs, and we think that’s why
HER2-targeted therapies have been so successful. However, in some cancers where the epidermal growth factor
receptor (EGFR) appears to be important, the benefit
of EGFR inhibitor therapies appears to be short-lived.
This may be because we’re selecting clones that are resistant to those therapies, but also because the stem cells
in those tumors don’t depend on HER2 signaling but
rather different pathways.
Dr Ajani: Another aspect to consider is that if we
can target CSCs effectively, we may reduce the tumor
burden in patients. We may not be able to eradicate the
tumor, but we can certainly reduce the tumor bulk. A
tumor with fewer stem cells could become indolent.
That’s what we hope we can do.
Q
A
Do you think that all cancers will be shown to
have CSCs as the key player?
Dr Wicha: I think they do play a role in all types
of cancers; however, the frequency of cells
that are stem-like varies tremendously between different
cancers. At one end of the spectrum are hematologic
malignancies, where it looks like maybe 1 of 1,000 or 1
of 10,000 cells may be a CSC. The tumors that probably
have the highest percentage of CSCs are melanoma.
All tumors probably have CSCs within, but to
understand these cells we must understand not only
the biology of the cell but how it relates to the microenvironment, including the immune system, in our
patients.
Dr Ajani: The short answer to that question is yes;
many researchers believe cancer originates in the stem
cells and there is a nice explanation for that. In a cell
with stem cell properties, damaging the deoxyribonucleic acid (DNA) could cause the cell to become malignant. However, if the DNA is damaged in a cell with no
stem cell properties, the cell dies because it has a limited
number of life cycles. If, for example, DNA damage
occurs in 100 cells but only 1 of them is a stem cell,
that cell will survive with the DNA damage and eventually accumulate more damage and become cancerous.
Q
A
What should practicing oncologists know
today about CSCs?
Dr Wicha: Practicing oncologists will start seeing
more clinical trials of CSCs and immunotherapies.
The key is to follow very closely the results of these
clinical trials because oncology is moving at a quicker
pace than we’ve ever seen before. I think we’re going
to see advances in the CSC area, with the potential for
achieving much more durable responses. I would also
encourage practicing oncologists to participate in these
trials as members of cooperative groups.
Understanding CSCs may help us to develop new
approaches to cancer prevention. Some interventions, like weight reduction, diet, and exercise, may
affect stem cells through inflammatory mediators, like
interleukin (IL)-6 and IL-8. We know that IL-6 is an
important driver of breast CSCs. Women with breast
cancer who either lose weight or undergo an active exercise intervention program lower their levels of inflammatory cytokines, such as IL-6, by 50%.
Dormancy of cancers is also an issue. In diseases like
estrogen receptor–positive breast cancer, cancers can
recur after 15 or even 20 years, and molecular analyses
are able to show that the recurrent cancers share almost
all the same mutations as the original cancers—that
they’re actually the same cancer. How did this happen?
We think that these are dormant CSCs. Normal stem
cells can sit for long periods and become active only
Oncology Times • November 10, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions
Oncology Times • November 10, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions
12
after damage is sustained; CSCs may act the same way.
This may be why a cancer recurs 1 or 2 years after a
woman has a great trauma, like losing a spouse or being
involved in an accident. This might not be a coincidence
and may be related to dormant CSCs, which can be
found on biopsies in the bone marrow and may present
during times of extreme stress and inflammation. If that’s
the case, it tells us that stress reduction and exercise are
important, and that potentially there may be new ways
in the future of administering a therapy and eradicating
these dormant CSCs. This is just speculation at this
stage, but it’s exciting to think about the possibilities.
In addition, many of the practicing oncologists are
members of cooperative groups. They will start seeing
many more cancer stem cell trials be added, along with
immunotherapy trials, giving them many more options
for their patients who may be appropriate candidates. I
would highly encourage practicing oncologists to participate in these trials.
Dr Ajani: Oncologists in the community need to be
aware of the ramifications of treating stem cells and
non–stem cells. Certain cancers behave like an organ.
For example, when skin is injured, normal adult stem
cells are animated and cause the skin to heal. They
repopulate and maintain the skin. The same phenomenon occurs with cancer. When CSCs are injured by
chemotherapy, they will also automatically repopulate.
Further, in patients with colon cancer, it has been
shown that if all the CSCs are killed, some of the non–
stem bulk tumor cells will reformulate and transform
into CSCs.
Most clinicians tend to focus on the non–stem cells
when treating cancer. We use cytotoxic drugs against
this proliferative group of cells and sometimes we have
success, but most of the time they produce only a transient effect. Treatment success will occur when CSCs
and non–stem bulk tumor cells are treated in unison.
That is where we need to go.
To learn more about cancer stem cells, visit:
www.bostonbiomedical.com or scan
EDU-NPS-0051 ©2015 Boston Biomedical, Cambridge, MA 02139. All rights reserved. Printed in USA/November 2015
NOTES:
15
Oncology Times • November 10, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions
Oncology Times • November 10, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions
14
Now Available
Cancer Stem Cells: The Promise and The Potential
A Seminars in Oncology Supplement
Despite advancements in
treatment modalities, many
patients with cancer experience tumor recurrence and
metastasis at regional or
distant sites. Evolving understanding of tumor biology
has led to the hypothesis that
tumors possess a stem cell–
like subpopulation known
as cancer stem cells (CSCs),
which may be involved in
driving pathogenesis and
tumor propagation.
This supplement updates
clinicians on the accumulated
evidence characterizing
the role of CSCs in tumor
initiation, heterogeneity,
therapy resistance, recurrence and metastasis, and
the potential for
effectively treating patients
by targeting these cells.
Jaffer A. Ajani, MD
Howard S. Hochster, MD
Shumei Song, MD, PhD
Ira B. Steinberg, MD
The University of Texas
MD Anderson Cancer Center
Houston, Texas
The University of Texas
MD Anderson Cancer Center
Houston, Texas
Yale School of Medicine
New Haven, Connecticut
Boston Biomedical
Cambridge, Massachusetts
Published April 2015
Cancer Stem Cells: The Promise and The Potential
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