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 charac-
teristics 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
Supported by:
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
 2 Do Cancer Stem Cells Hold the Key to Controlling Cancer Growth Models of Carcinogenesis 3
and Spread? The classical model of cancer formation,
termed the stochastic model, defines
Oncology Times • November 10, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions

Oncology Times • November 10, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions
tumor cells as biologically equivalent.
Interview with Max S. Wicha, MD Intrinsic factors, such as signaling
Max S. Wicha, MD pathways and levels of transcription
Distinguished Professor of Medical Oncology and Director Emeritus factors, and extrinsic factors, such as the
microenvironment, host-specific factors,
University of Michigan Comprehensive Cancer Center
and immune response, result in varied
Ann Arbor, Michigan and unpredictable behavior of the tumor
cells. Therefore, tumor-initiating activity
cannot be attributed to any specific
type of cells. Conversely, the hierarchy

D espite advances in chemotherapy, targeted

agents, and radiation therapy, the prognosis for
patients with advanced cancer has remained poor.1
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
model proposes that tumors are made
up of biologically distinct types of cells
with varying functions and behaviors.
Drug resistance, metastasis, and recurrence—even Dick showed that a small subset of acute myelogenous Tumor growth can only be initiated by
a subset of cells known as cancer stem
after extended periods of remission—pose persistent leukemia (AML) cells were capable of transferring AML
cells (CSCs), which can self-renew and
challenges to cancer management.2 A growing body into immunosuppressed mice. The proteins expressed differentiate to nontumorigenic progeny
of evidence indicates, however, that a subset of cancer on these cells were similar to those expressed on normal that comprise the tumor mass (Figure).1
cells, called cancer stem cells (CSCs), may hold a key hematopoietic stem cells.10 A few years later, the role of
According to Max S. Wicha, MD,
to controlling cancer and potentially achieving dura- CSCs in tumorigenesis in solid tumors was supported research suggests that both models are
ble clinical responses.1 “Ultimately, patient survival correct.2,3 “What we know now is that
depends on getting rid of these cancer stem cells—the the CSCs themselves can mutate. As The stochastic and hierarchy models of tumor heterogeneity.
seeds we see in the cancerous tumor after treatment,” cancers develop, the CSC that started The stochastic model holds that cancer arises through random mutation
said Max S. Wicha, MD, Distinguished Professor of the tumor can then mutate and produce and clonal selection. Other clones can be selected out with treatment,
Medical Oncology and Director Emeritus at the Uni- a new clone, and at the top of the clone but the cancers continually mutate. In this model, any cell can become
versity of Michigan Comprehensive Cancer Center in is a CSC. There can be more than one cancerous.4 The CSC model, termed the hierarchy model, is at the other
CSC in an individual cancer. Therefore, end of the spectrum. It holds that cancers originate only in cells that can
Ann Arbor.
in a way, the stochastic model and the self-renew and then produce the differentiated cells that make up the bulk
CSC model are both correct: stem cells of the tumor.4
CSCs Drive Tumorigenesis
Normal stem cells are undifferentiated cells in the body mutate and get selected out and each
that can self-renew, propagate differentiated cells, and stem cell then generates a clone. Thus, 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
within the tumor are multiple stem cells
proliferate extensively.3 Laboratory studies have shown implications and challenges. Acta Pharmacol Sin. 2013;34:732-740.
and multiple clones that come from 3. Chen S, Huang EH. The colon cancer stem cell microenvironment holds keys to future cancer
that entire organs can be generated from a single stem these tumors.” therapy. J Gastrointest Surg. 2014;18:1040-1048.
cell.3 These discoveries have fueled interest in stem cell 4. Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea—a paradigm shift. Cancer Res.
2006;66:1883-1890.
therapy for a wide variety of diseases, including neuro-
logical, inflammatory, and endocrine disorders.3
CSCs are malignant cancer cells that share the capac-
ity of normal stem cells for self-renewal and proliferation by the finding that human breast cancers also could be tumor, resulting in relapse.11 One implication of this
and can differentiate into the heterogeneous population transferred to immunosuppressed mice by a small tum- finding is that “current evaluation of treatment may be
of cancer cells that comprise a malignant tumor,4 Dr origenic subset constituting only about 1% to 5% of the inadequate,” he pointed out.
Wicha explained. A common misconception is that all cancer cells.11 Treatment efficacy is based on tumor shrinkage, which
CSCs arise from mutated normal stem cells, but some Figure 1. Stem cell development: normal and cancer stem cells is usually defined in the clinic as tumor shrinkage of at
“We need different clinical endpoints in
CSCs may arise from progenitor cells when a mutation (CSCs). Normal tissues develop from a central stem cell that grows least 50%.5 “The problem with that traditional endpoint
and then differentiates to create progenitor and mature cell popu- assessing clinical trials that are designed to is that for the vast majority of cancers, tumor shrinkage
endows these cells with the capacity for self-renewal, nor-
mally reserved to stem cells (Figure 1).5,6 The CSC model
lations. Normal stem cells have the capacity to self-renew (shown target CSCs.” – Dr Wicha does not translate to patients living longer,” Dr Wicha
by a curved green arrow), develop into mature tissue (shown by
of cancer formation is hierarchical, in contrast with the a variety of different color cells), and proliferate. CSCs develop The finding that most cells in cancer tumors are non- said. An explanation for this may be that tumor regres-
traditional stochastic model (see Models of Carcinogenesis via mutation of normal stem cells or progenitor cells. They go on tumorigenic has important therapeutic implications, sion is a mark of the effect of a treatment on the bulk
on page 3).5,7 A growing body of evidence suggests that to grow and differentiate to create primary tumors (the dashed line tumor cell population, rather than the CSCs.12
Dr Wicha noted. Cancer treatments that target the non-
shows that it is unknown which specific types of progenitors are in- CSCs tend to be resistant to conventional cancer
CSCs are the drivers not only of tumor initiation and volved in the generation of CSCs). CSCs can self-renew, generate tumorigenic cells will cause tumor regression; however,
heterogeneity, but of treatment resistance, cancer recur- heterogeneous populations of daughter cells, and proliferate, just if they do not affect the CSCs or their signaling pathways, therapies, similar to the resistance to apoptotic thera-
rence, and metastasis.8,9 like normal stem cells.6 these cells will persist and potentially regenerate the pies observed in normal stem cells.5 “An issue critical
 4 to understanding why CSCs are treatment resistant higher than expected from just the number of stem cell As Dr Wicha explained, evidence shows that cells because the CSCs are being prompted to differentiate 5
is whether CSCs are discrete populations of cells in divisions in lung tissue because of the influence of the being killed by chemotherapy secrete inflammatory and become sensitive to chemotherapy.17
cancer or whether non-CSCs can revert to stem cells,” environmental carcinogen.” mediators such as cytokines; some of these are inter- Regarding the development of new cancer treat-
Oncology Times • November 10, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions

Oncology Times • November 10, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions
Dr Wicha said. Recently, breast cancer stem cells were leukin (IL)-6 and IL-8, which then act to stimulate ment strategies for cancer, it is important to remember
shown to exist in two states: the epithelial-mesenchymal Target Selection May Be the Key to CSCs. Damage to normal tissue induces a similar that CSCs represent only a small fraction of the tumor
transition (EMT) state and the mesenchymal-epithelial Effective Therapy response. Injured cells release the same cytokines, cell population, Dr Wicha noted. If these cells are not
transition state (MET). In the EMT state, the cells are During the self-renewal process, normal stem cells signaling the normal stem cells in the tissue to repro- killed, the tumor will regenerate. Even if the CSCs are
relatively quiescent but localized at the invasive tumor interact with their microenvironment (termed the stem duce.16 “This is healthy when it occurs during normal destroyed, the non-CSCs that form the bulk of the
front, from where they can disseminate via the blood- cell niche) via tightly regulated signaling pathways. In tissue regeneration, but during treatment of cancer tumor can, however, still undergo several rounds of cell
stream to distant sites and seed micrometastases. In the the early stage of cancer formation, after the stem cell or with chemotherapy CSC stimulation leads to their division leading to spreading of the cancer. Therefore, for
MET state, the cells are capable of extensive prolifera- progenitor cell receives its first mutation, these pathways increase,” he added. the treatment of advanced cancers, the optimal approach
tion, growing new tumors.13 Both cell states are needed become dysregulated, allowing the CSCs to expand in an Dr Wicha noted that new approaches to cancer is thought to be a combination of a stem-cell targeting
to form metastases, and evidence suggests that plasticity abnormal fashion.5 “We are finding that CSCs are driven treatment include targeting CSCs and their signaling agent with a debulking agent that can destroy the large
of breast CSCs allows them to transition from one state by a limited number of key pathways,” Dr Wicha said pathways, such as Notch, Wnt, Hedgehog, and JAK/ mass of the tumor cells. That debulking agent can be
to the other.13 (Figure 2).8 CSCs also interact with other components of STAT, which regulate the CSC internal circuitry. Cancer chemotherapy, for instance, because chemotherapy is
the cellular microenvironment, such as cytokines, growth treatments may also target inflammatory cytokines, such effective at targeting the bulk cells, while CSCs are resis-
Stem Cell Divisions Predict Cancer Risk factors, and stromal cells (Figure 3).1 as IL-6 and IL-8, which mediate the interaction between tant to chemotherapy and radiation therapy.16 According
The incidence of cancer across different tissues varies CSCs and the tumor microenvironment, he added. to Dr Wicha, “When treating micrometastatic disease in
widely, but the reason for these differences is unclear.14 “We are finding that CSCs are driven The blockade of IL-8 receptors as a potential treatment the adjuvant setting, CSC-targeted therapy alone may be
For example, the lifetime risk for cancers in the ali- by a limited number of key pathways.” approach has been studied in breast cancer by Dr Wicha’s potentially curative. If we knock out the micrometastases,
mentary tract varies by a factor of 24 (0.20% in the – Dr Wicha group and others.17 “Targeting some of the pathways the cancer may not grow back.” For this reason, treat-
small intestine but 4.82% in the large intestine). Such involved in CSC self-renewal may not only stop CSCs ment strategies that target CSCs and the mechanisms
An expanded understanding of the key signaling path-
differences cannot be explained fully by environmental from reproducing, but also lead to their differentiation responsible for the interaction between CSCs and their
ways of CSCs and of the interactions of these cells with
or genetic factors, which account for only one-third into non–stem cells, thereby making them chemother- microenvironment may represent an important approach
the tumor microenvironment is providing new insights
of the risk variation.14 Recent evidence points to stem apy-sensitive,” Dr Wicha said. Evidence suggests that to improving patient outcomes.16
into the mechanisms responsible for the resistance of
cells as the key to the differences seen among the inci- when IL-8 receptor blockers are used in combination
CSCs to conventional cancer therapies and potential tar-
dences of cancer in different organs. Most cells in tis-
gets for new treatment approaches.8 Evidence has shown with chemotherapy, the CSC population decreases to a CSC Immunotherapy May
sues are differentiated and short-lived; however, stem
that not only are CSCs resistant to chemotherapy and greater degree than with chemotherapy alone, perhaps Improve Outcomes
cells, with their capacity for self-renewal, are essen- New insights into the biology of CSCs and nontu-
radiation therapy, but that their number can actually be
tially “immortal.” Tomasetti and Vogelstein analyzed morigenic cancer cells are providing the rationale for
increased by these treatments.15
stem cells in different organs and the number of times immunologic approaches to targeting CSCs. The gene
these stem cells divide, because mutations can happen expression profiles and expressed antigens displayed by
any time a cell divides; they found a close linear rela- CSCs and non-stem cancer cells differ. Immunothera-
tionship between the number of stem cell divisions in, pies that target the differentiated cancer cells that form
and the incidence of, cancer in that organ.14 the tumor bulk may not effectively target the antigens
“The findings of Tomasetti and Vogelstein have been expressed by CSCs. In addition, CSCs themselves exhibit
misunderstood as attributing cancer to ‘bad luck,’” heterogeneity.1 Thus, molecular profiling of CSCs and
Dr Wicha said, “undercutting the role of stem cells in cancer tumors and targeting of immunotherapy at het-
tumorigenesis.” However, the data are highly supportive erogeneous CSC populations “represent one of the most
of the origin of most cancers in stem cells. What the exciting areas in cancer research. Specifically, targeted
investigators state is that the majority of the differences immunotherapy offers the potential for durable responses
in cancer risk can be attributed to “‘bad luck,’ that is, in patients with cancers who previously had few thera-
random mutations arising during DNA replication in peutic options,” noted Dr Wicha.
normal, noncancerous stem cells.”14 In other words, CSCs can evade the immune system even more effi-
mutations occur at a constant rate based on how often ciently than the differentiated cells forming the tumor
the cell divides. Based on the linear correlation of bulk. For example, CSCs express high amounts of
0.804, 65% of the differences in cancer risk among programmed death (PD)–ligand 1 (PD-L1). The PD1/
different tissues can be explained by the total number Figure 3. The interaction of CSCs with their microenviron- PD-L1 pathway (an immune checkpoint) is one of
of stem cell divisions in the tissues.14 However, muta- Figure 2. Key signaling pathways in cancer stem cells (CSC) ment. CSCs exist within a microenvironment of stromal cells,
two recognized immunoinhibitory pathways that con-
development. Dysregulation of signaling pathways plays a immune cells, neighboring vasculature, and secreted factors
tions can be caused by other factors as well. “The best tribute to an immunosuppressive microenvironment
crucial role in the ability of CSCs to self-renew and differentiate. that are produced by these cells. These elements create a niche
example of this is carcinogenic tobacco smoke,” he Depending on the signaling pathway involved, CSCs gain the where CSCs survive and propagate into the cells that define the that protects cancer cells from immune destruction.1
said. “In this case, the lung cancer incidence would be ability to initiate cancer formation or cause tumor recurrence.8 tumor mass.1,5 Thus, a current approach to the treatment of a variety
 6 of cancers focuses on combinations of such immune study potential agents that target CSC signaling alone, References 7
checkpoint blocking therapies, other immunotherapies with careful monitoring of potential toxicity risks. 1. Pan Q, Li Q, Liu S, et al. Concise review: targeting cancer stem 12. Korkaya H, Liu S, Wicha MS. Regulation of cancer stem cells by
(such as IL-6 or IL-8 inhibitors), and vaccines that Phase 2 studies will then assess chemotherapy alone cells using immunologic approaches. Stem Cells. 2015;33:2085- cytokine networks: attacking cancer’s inflammatory roots. Clin
Oncology Times • November 10, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions

Oncology Times • November 10, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions
target CSCs.1 compared with chemotherapy plus an agent targeting a 2092. Cancer Res. 2011;17:6125-6129.
“The vision for the future of cancer therapy is to base treat- CSC pathway. Potential endpoints in these studies will 2. Touil Y, Igoudjil W, Corvaisier M, et al. Colon cancer cells escape 13. Liu S, Cong Y, Wang D, et al. Breast cancer stem cells transition
ment selection on a complete molecular diagnosis of the likely be time to develop new metastases, time to tumor 5FU chemotherapy-induced cell death by entering stemness and between epithelial and mesenchymal states reflective of their normal
quiescence associated with the c-Yes/YAP axis. Clin Cancer Res. counterparts. Stem Cell Reports. 2014;2:78-91.
tumor, including an evaluation of the stem-cell profile of progression, and progression-free or overall survival, 2014;20:837-846. 14. Tomasetti C, Vogelstein B. Cancer etiology. Variation in cancer
that particular tumor,” noted Dr Wicha. From an analysis rather than tumor regression. 3. Liu Y, Yang R, He Z, Gao W-Q. Generation of functional organs risk among tissues can be explained by the number of stem cell
of the immune infiltrates of the tumor, it also will be pos- A neoadjuvant trial design that assesses the level of from stem cells. Cell Regen (Lond). 2013;2:1. divisions. Science. 2015;347:78-81.
sible to know whether the patient is mounting an immune complete pathological response has great appeal for 4. Clarke MF, Dick JE, Dirks PB, et al: Cancer stem cells—perspec- 15. Lee HE, Kim JH, Kim YJ, et al. An increase in cancer stem cell
response against the tumor. Dr Wicha believes that cancer CSC research in a number of tumor types, Dr Wicha tives on current status and future directions: AACR Workshop on population after primary systemic therapy is a poor prognostic factor
cancer stem cells. Cancer Res. 2006;66:9339-9344. in breast cancer. Br J Cancer. 2011;104:1730-1738.
treatment will move toward a combination approach– said. Complete pathologic response with neoadjuvant 5. Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea—a 16. Korkaya H, Liu S, Wicha MS. Breast cancer stem cells, cyto-
targeting the tumor bulk, CSC populations, and immune therapies is associated with a favorable outcome and has paradigm shift. Cancer Res. 2006;66:1883-1890. kine networks, and the tumor microenvironment. J Clin Invest.
components. This will lead to “substantial, rather than already led to the approval of a new agent to be used as 6. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J 2011;121:3804-3809.
merely incremental, gains in treating cancer. Most impor- dual anti-HER2 therapy in patients with HER2-positive Med. 2006;355:1253-1261. 17. Ginestier C, Liu S, Diebel M, et al: CXCR1 blockade selectively
tantly, this future approach may offer a more durable breast cancer.18 Another possible endpoint in the neoad- 7. Dick JE. Stem cell concepts renew cancer research. Blood. targets human breast cancer stem cells in vitro and in xenografts.
2008;112:4793-4807. J Clin Invest. 2010;120:485-497.
patient response as opposed to an increase in survival of juvant setting is the measurement of residual CSCs after 8. Chen K, Huang Y-H, Chen J-L. Understanding and targeting 18. Gianni L, Pienkowski T, Im Y-H, et al: Efficacy and safety of neoadju-
only 1 or 2 months.” treatment, as the presence of these cells after neoadjuvant cancer stem cells: therapeutic implications and challenges. Acta vant pertuzumab and trastuzumab in women with locally advanced,
therapy has been associated with a poor prognosis.15 Pharmacol Sin. 2013;34:732-740. inflammatory, or early HER2-positive breast cancer (NeoSphere):
New Therapies, New Challenges The other technology receiving increased attention 9. Tang DG. Understanding cancer stem cell heterogeneity and plasticity. a randomised multicentre, open-label, phase 2 trial. Lancet Oncol.
With new treatments come new challenges. As Dr Wicha is the isolation of circulating tumor cells. As Dr Wicha Cell Res. 2012;22:457-472. 2012;13:25-32.
10. Bonnet D, Dick JE. Human acute myeloid leukemia is organized 19. Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R, Kasimir-Bauer
explained, “The first challenge is to determine whether explained, circulating tumor cells are highly enriched in as a hierarchy that originates from a primitive hematopoietic cell. S. Stem cell and epithelial-mesenchymal transition markers are
an agent that targets CSC pathways will be cytotoxic to stem cell markers in patients with breast cancer. Whereas Nat Med. 1997;3:730-737. frequently overexpressed in circulating tumor cells of metastatic
normal stem cells, because they use the same pathways. 1% to 5% of cells are CSCs in primary cancers, studies 11. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke breast cancer patients. Breast Cancer Res. 2009;11:R46.
Early trials must test low doses of these agents and esca- have shown that closer to 30% to 50% of circulating MF. Prospective identification of tumorigenic breast cancer cells. 20. Lianidou ES, Markou A. Circulating tumor cells in breast cancer:
late them carefully,” he said. “Several phase 1 trials have tumor cells express stem cell markers.11,19,20 Circulating Proc Natl Acad Sci USA. 2003;100:3983-3988. detection systems, molecular characterization, and future chal-
lenges. Clin Chem. 2011;57:1242-1255.
already shown that most agents targeting CSC pathways tumor cells may prove useful as biomarkers for patients
can be given effectively with relatively low toxicities in clinical trials; isolating and measuring circulating
and that, based on biopsies performed before and after tumor cells may be a way to monitor patients and deter-
treatment, the targets are being hit.” Going forward, mine the efficacy of potential treatments.20 “The utility
researchers will analyze whether combining these agents of these assays as predictive of outcomes must be proven
with chemotherapy or immunologic agents will have the in rigorous clinical trials,” Dr Wicha noted, “but this is
potential for increased side effects, such as inducing auto- the kind of research now being explored, as agents that
immunity against the normal stem cells. “These investi- target CSC pathways are increasingly used in the clinical
gations must proceed carefully,” he cautioned. research setting.”
“The second challenge is the need to rethink the use
of traditional endpoints of tumor regression in clinical Conclusion
trials,” Dr Wicha noted. Because CSC-targeting agents CSCs as potential therapeutic targets may be instrumental
do not cause tumor regression, he explained, investiga- in developing therapies that control cancer and allow for
tors must work with the United States Food and Drug the achievement of durable clinical responses in patients.
Administration to determine how to demonstrate con- Expanded understanding of the biology of CSCs, their key
clusively that these agents provide a benefit. “What are signaling pathways, molecular diagnosis of tumors, and
the acceptable endpoints?” he asked. “What should we appropriate clinical trial endpoints will help in the devel-
be measuring?” Obviously, phase 1 trials are designed to opment of agents targeting key signaling pathways.
 8 Cancer Stem Cells: Lessons From Gastroesophageal Cancer Biology Treatment Patterns 9
Percent of Cases by Stage Unfortunately, current treatments for gastric cancers pro-
Interview with Jaffer A. Ajani, MD vide only a marginal overall survival benefit, as Dr Ajani
Oncology Times • November XX, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions

Oncology Times • November 10, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions
Unknown
n Localized
Loca
Jaffer A. Ajani, MD (Unstaged)
d) (Con
(Confined to noted. The 5-year relative survival of all patients with
26% primary site)
prim gastric cancer is less than 30%.7 A recent study followed
Professor
Department of Gastrointestinal Medical Oncology more than 600 patients with localized esophageal or
10% gastroesophageal cancer after treatment with chemoradi-
University of Texas MD Anderson Cancer Center
Houston, Texas 29% ation and/or surgery. Regardless of treatment, more than
one-third of the patients developed distant metastasis less
35% than 2 years after treatment.8 In a review of second-line
therapy in advanced gastric cancer, the overall survival
G astric and esophageal cancers are, respectively, the
third and sixth most common causes of cancer-
related deaths worldwide.1 During the past several
microenvironment where the stem cell–like characteristics
of CSCs are nurtured to maintain their self-renewal and
differentiation activities. Studies have shown that patho-
Distant
(Cancer has
ant

metastasized)
zed)
Regional
Region
(Spread to regional
lymph nodes)
n
was only about 5 months in most patients.9 While anti-
HER2–targeted therapy is showing efficacy, Dr Ajani
decades, the incidence of these cancers has decreased. logical alterations in normal microenvironments may pro- pointed out that only about 20% of gastric cancers and
In the United States, the incidence has shifted rapidly duce tumor microenvironments that serve as CSC niches.4 5-Year Relative Survival 30% of gastroesophageal cancers overexpress HER2.9 In
from esophageal squamous cell carcinoma and distal 100 a review of first-line therapy in patients with metastatic
gastric carcinoma to adenocarcinoma of the esophagus Tumor Progression and Metastasis disease, the inclusion of an anti-HER2–targeted agent
and proximal stomach.2 In essence, gastric and esopha- As noted, gastric cancer is usually diagnosed at later 80 provided a modest increase in survival to slightly more
65.4 than 1 year.9 Patients receiving anti-HER2 therapy even-
geal cancers are now being seen more commonly at the stages. This may be because patients often do not exhibit

Percent
60 tually develop resistance as well, he added.
gastroesophageal junction.2 symptoms until their disease has progressed, or their
In the United States, gastric cancer is mostly diagnosed symptoms have been vague and attributed initially to Treatment resistance is usually due to cross-
40
in later stages, when survival is at its poorest.3 Indeed, causes other than cancer. “Patients with gastric cancer 29.9 activation of the HER2 signaling pathway by other
21.3 pathways, including insulin-like growth factor,
localized gastric cancer represents only about one quarter often have nonspecific symptoms for a long time. It 20
of all gastric cancer diagnosed in the United States (Figure is not unusual for them to see multiple doctors, until 4.5 c-MET, growth differentiation factor 15, and other
1).3 “The survival advantage provided by current therapies finally, when the diagnosis is made, the tumor is well 0 members of the ERBB family. Moreover, hyperactiva-
LLocalized
li d RRegional
i l Distant
Di t t Unstaged
U t d tion of downstream HER2 pathway components, such
for patients with regional and metastatic disease is pitifully established,” Dr Ajani said.
Stage as MAPK and PI3K/AKT, may further contribute to
marginal,” Jaffer A. Ajani, MD, commented. Dr Ajani is
“One of our biggest problems is that most anti-HER2 therapy resistance.10 “There is a need for
Professor in the Department of Gastrointestinal Medical
Oncology at the University of Texas MD Anderson Cancer patients have very advanced tumors when Figure 1. Percentage of cases and 5-year relative survival better targeted therapies,” Dr Ajani said.
finally seen at our clinic. To me, that signals by stage at diagnosis: stomach cancer. Cancer stage at The molecular events involved in tumorigenesis have
Center in Houston. “Our research is now showing that diagnosis determines treatment options and has a strong
cancer stem cells (CSCs) are central to the lack of success an older tumor, with many generations of been explored to a great extent in many types of cancer,
influence on the length of survival. The earlier stomach
when we treat patients with gastric or esophageal cancer.” evolved cancer cells and a great deal of cancer is diagnosed, the better chance a person has of Dr Ajani said, but those involved in gastric and gastro-
resistance to therapy.” – Dr Ajani surviving 5 years after diagnosis. For stomach cancer, 26.0% esophageal cancers are not well understood10 (see The
CSCs and the Role of the and 29.0% of cases are diagnosed at the local and distant Molecular Side of Gastric Cancer on page 10).
Microenvironment Research is pointing to the migration of CSCs from stage, respectively. Of note, the stage of disease is unknown “The CSC phenomenon is seen repeatedly in the
at diagnosis in more than one-third of cases. The 5-year
As defined by the American Association for Cancer the primary tumor site as an underlying mechanism of clinic,” Dr Ajani said, “but we’re not yet able to do any-
survival for localized stomach cancer is 65.4%, compared
Research Workshop on Cancer Stem Cells, a CSC is a cell tumor progression and metastasis. The clinical pattern of with 4.5% for distant stomach cancer.3 thing about it.” He described three patterns of response
within a tumor that possesses the capacity to self- patients with metastatic disease bears this out, Dr Ajani and resistance observed in patients with advanced and
renew and to give rise to the heterogeneous lineages of said. “Often, we can’t find the metastatic tumors in patients metastatic tumors following first-line therapy.
cancer cells that comprise the tumor. Because they have who are treated initially with a curative intent,” he noted. “In patients with gastroesophageal cancer, there is
an intrinsic ability to propagate tumor cells, CSCs are also “When the primary tumor is treated, whether with preop- almost a 50% chance they will experience some reduc-
Table 1. Key Characteristics of Cancer Stem
referred to as “tumor-initiating cells” or “tumorigenic cells” erative chemotherapy and/or chemoradiation followed by tion in tumor volume and improvement in their symp-
(Table 1).4,5 The ability of stem cells to self-renew and give surgery, we observe several phenomena. The primary tumor Cells (CSCs)4,5
toms for a short time,” he said, “but after a few months,
rise to multiple cell lineages is termed “stemness.”6 is often resistant to therapy. We know from our experience, CSCs serially transplant through the cancer starts to grow.” Second-line therapy produces
Self-renewal
The microenvironment plays an important role in the that the more resistant the primary tumor, the more met- multiple generations less reduction in tumor volume and for a shorter dura-
support and development of CSCs. Essentially, CSCs astatic potential it has. In other words, this aggressive biol- tion response. This supports some of the preclinical
CSCs generate symmetrical and
exist within a microenvironment consisting of stromal ogy, which is probably related to the number of CSCs (and Differentiation research demonstrating that the CSC population is
asymmetrical cells
cells, immune cells, neighboring vasculature, and secreted evolved species of CSCs) present in the primary tumor enriched by cancer treatments, making the tumor more
factors that are produced by these cells. These elements or volume of the tumor, dictates metastatic potential,” he Tumorigenicity CSCs can propagate tumor cells resistant, he added.
create a niche where CSCs can survive and subsequently explained. In addition, although it may appear that local A second pattern involves patients whose tumors
propagate into the cells that comprise the tumor mass. treatment has been successful, highly resistant metastatic Specific surface Allow for separation of CSCs from exhibit primary resistance, according to Dr Ajani. These
As such, the niche may be considered to be a regulatory disease often becomes apparent very quickly. markers non–stem cells
patients never experience tumor shrinkage even with
10 the initial treatment option, nor do they fare any better Gastric and Gastroesophageal Biology The inner lining of the stomach is organized into a crypt- observed in gastric cancer in which chemotherapy-resistant 11
with a second-line therapy. “We have lost many patients and CSCs like structure, containing normal stem cells at the bottom, cells exhibited increased CSC properties, along with an
like that.” CSCs provide a rational explanation for the presence of which is similar to that seen in the inner intestinal lining, increase in the CSC marker BMI1. Depletion of BMI1
Oncology Times • November 10, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions

Oncology Times • November 10, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions
A third resistance pattern is one in which the tumor heterogeneity and the development and pro- but not as deep, Dr Ajani explained (Figure 2).14-17 Like resulted in therapy sensitization.19
patient has a mixed treatment response. Metastatic gression of cancer, Dr Ajani believes. As he explained, other stem cells, gastric stem cells self-renew and produce Chemotherapy resistance is also associated with increased
lesions in the liver, for example, will become smaller, normal stem cells are the source of the propagation of the the remaining components of the mucosa. Studies have levels of the CSC marker ALDH1. In research conducted
Dr Ajani said, while those in abdominal lymph nodes entire tissue in organs. They are capable of self-renewal, shown that these stem cells depend on the Wnt/β-catenin by Dr Ajani’s group, expression of ALDH1 after chemo-
will increase in size. “This is a curious phenomenon,” as well as multi-lineage differentiation. They can create pathway to maintain the number of stem and non-stem radiation therapy correlated directly with worse clinical
he said, “but we observe it frequently and it reflects an exact copy of themselves or produce progenies with mucosa cells. Dr Ajani noted that the Wnt/β-catenin path- response.20 Dr Ajani added that this suggests that CSCs may
intra-patient tumor heterogeneity.” Not only can limited renewal and differentiation potential. While nor- way is important for the embryonic development of stom- play an important role in chemoradiation therapy resistance.
tumors in different organs exhibit different molecular mal stem cells possess long life spans, their differentiated ach stem mucosa cells as well. These mucosa cells begin to
characteristics, but multiple metastases in the same
“Chromosomal instability-related cancers
progenies can possess limited life spans.11 As examples of form precancerous mucosa cells when the inhibiting com-
organ can have different somatic profiles. “These are these characteristics, Dr Ajani said that investigators have ponent of the Wnt/β-catenin pathway, called adenomatous are more common in organs, such as the
real problems in the clinic that we cannot control,” he shown that a single breast stem cell can be used to create polyposis coli (APC), is removed from the stem cells.14 This lungs, stomach, esophagus, head and neck,
added. “We need to know about the underpinnings of all the different types of cells that compose a functional suggests that CSCs may be involved in the initiation and and skin, which are exposed to external
these phenomena.” breast tissue.12 Using mouse models, a similar phenome- progression of gastric cancer, he said. factors. When they become cancerous, it’s
non has been observed in gastric tissue. In addition, the Other stemness signaling pathways have been implicated because these malignancies are all carcinogen-
“We have conducted a fair amount of in esophageal cancer progression, as well. The Hedgehog
stem cells that propagate the tissue in the inner lining of driven and they have a large number of
research on tumors at the juncture of the the stomach have been shown to survive for the majority (Hh) pathway, for example, is transiently upregulated in DNA alterations. On the other hand,
esophagus and stomach. Our preclinical of the life span of a mouse, that is, 48 weeks, while also progenitor cells to induce proliferation after tissue injury. pediatric cancers and leukemia are more
findings show that CSCs are central to lack producing mature stomach lining cells, mucous cells, These stem cell progenitors are usually quiescent and return genetically driven and have very few
of treatment success of these tumors.” that live for only a few days.13 The majority of human to this state after tissue regeneration via tight regulation of
alterations.” – Dr Ajani
– Dr Ajani gastric cancers originate from the stomach mucosa.7 the Hh signaling pathway. Chemoradiation-resistant esoph-
ageal cancer has been shown to induce the Hh stemness CSCs have been shown to play a role in gastric and
signal pathway after treatment. Blockade of the Hh pathway gastroesophageal cancer metastasis, too. Helicobacter pylori
The Molecular Side of Gastric Cancer components results in reversal of therapy resistance. This infection has been shown to increase expression of epithe-
Gastric cancer is a heterogeneous disease with diverse MLH1 promoter. The MSI subgroup exhibits muta- suggests that these tumors may be activating this regener- lial-mesenchymal transition (EMT) markers during the
molecular characteristics. Multiple experimental and tions in many cancer “hotspots,” such as PIK3CA, ative signaling pathway to support tumor regrowth after progression from normal tissue to dysplasia to gastric cancer.
clinical investigations have implicated a wide range ERBB3, ERBB2, EGFR, and overexpresses mitotic injury or chemoradiation.18 A similar phenomenon was An increase in CSC potential (marked by an increase in the
of germline and somatic alterations that drive tumor pathway components.2
progression.1 Recently, the Cancer Genome Atlas Re- • T he genomically stable subgroup, which made up
search Network analyzed nearly 300 samples of previ- Normal Crypt Cancerous Crypt
20% of gastric cancers. This group exhibited muta-
ously untreated gastric and gastroesophageal cancer tions in CDH1 and in RHOA, a protein important Normal gastric epithelium cells
and grouped them into four major molecular subtypes.2 in cell motility and the STAT3 signaling pathway.2 Myofibroblast cells
• T he Epstein-Barr Virus (EBV)–positive group, • 
The high chromosomal instability (CIN) group, Normal stem cells
which made up 9% of gastric cancers. This group which made up about 50% of gastric cancers.
displays high prevalence of DNA hypermethyla- Cancer stem cells
This subgroup is concentrated at the gastroesoph-
tion, including promoter methylation of the tumor ageal junction.2 The CIN group exhibited hyper- Tumor cell
suppressor CDKN2A (p16INK4A). There is a high activation of EGFR and other RAS-driven receptor
incidence of PIK3CA mutations, amplifications of tyrosine kinases, mutation of the tumor suppressor Inflammatory
several oncogenes, including ERBB2, and recur- TP53, and high levels of aneuploidy.2 Chromo- microenvironment cells
rent amplifications of chromosome p9 (leading to somal instability has been shown to be prevalent

Wnt
overexpression of PD L1/2 and JAK2).2 in several solid tumors, including those of the
• T he microsatellite instability (MSI) group, which head and neck, testes, lung, and liver, as well as
Signaling/phenotypic
made up 22% of gastric cancers. This group is in gastric and gastroesophageal cancers. Fewer
gradient
characterized by enrichment for microsatellite CINs are seen in melanoma, and even fewer in
instability (MSI), including hypermethylation at the Wilms’ tumors.3
Figure 2. Gastric stem cells and tumor formation. Multipotent stem cells positioned at the base of the pyloric antrum gastric crypt support
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. 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
2. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202-209. repeat-containing G-protein coupled receptor 5 (Lgr5) stem cell marker,15 and are dependent on Wnt signaling to maintain their stem cell
3. Rooney PH, Murray GI, Stevenson DAJ, Haites NE, Cassidy J, McLeod HL. Comparative genomic hybridization and chromosomal instability in solid tumours. 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
Br J Cancer. 1999;80:862-873. Inflammatory microenvironment components, such as fibroblasts, lymphocytes, mast cells, and macrophages, may support transformation of
gastric stem cells to cancer stem cells.17
12 stem cell and CSC marker CD44) has been observed, as cells exhibited other CSC properties, including higher Cancer Stem Cells: Where We Are and Where We’re Going 13
well. The expression of these markers decreased a year after sphere-forming capacity and expression of the CSC Max S. Wicha, MD, and Jaffer A. Ajani, MD
eradication of infection—a trend that persisted several years markers Oct4, CD133, and CD44.22 The increase in CSC
Oncology Times • November 10, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions

Oncology Times • November 10, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions
after eradication of the H. pylori. Together, this suggests potential was accompanied by down-regulation of the
that H. pylori infection promotes EMT in gastric cancer via
CSC-mediated tumorigenesis.21
AKT signaling pathway and upregulation of the STAT3
pathway. The STAT3 pathway was activated by Notch-de-
Q Why is cancer stem cell (CSC) research so
important?
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
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
pendent autocrine secretion of interleukin 6.22

Conclusion
A  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
understand these cells we must understand not only
the biology of the cell but how it relates to the micro-
environment, including the immune system, in our
the anti-HER2–targeted agent trastuzumab in gastric can- Advanced gastric or gastroesophageal cancer remains one of and are the seeds that carry cancer metastasis, it will be patients.
cer has been explored. Treatment of gastric cancer cells for the most difficult challenges in clinical practice. Research necessary to get rid of these cells to really improve the
20 weeks with trastuzumab resulted in EMT induction in has shown that CSCs can initiate tumor development outcome of cancer patients. Dr Ajani: The short answer to that question is yes;
drug-resistant cells. This EMT induction was characterized and play a significant role in tumor relapse and metastasis. many researchers believe cancer originates in the stem
Dr Ajani: We need to understand some of the prop- cells and there is a nice explanation for that. In a cell
by loss of E-cadherin (the hallmark of EMT) and ZO1, as Indeed, evidence is accumulating that treatments, such as erties of CSCs to learn how they can be overcome. In
well as overexpression of claudin-1, vimentin, β-catenin, chemotherapy and radiation, can increase the proliferation with stem cell properties, damaging the deoxyribonu-
addition to being treatment-resistant, CSCs prefer a cleic acid (DNA) could cause the cell to become malig-
ZEB1, Slug, and Snail.22 These drug-resistant cells also of CSCs. Investigations are underway into the molecular hypoxic environment. They don’t need much oxygen to
exhibited an aggressive tumor phenotype, including higher signaling pathways involved in tumor cell repopulation. The nant. However, if the DNA is damaged in a cell with no
survive and can remain dormant for quite some time. stem cell properties, the cell dies because it has a limited
motility, invasion potential, tumor formation potential, small subpopulation of CSCs in gastroesophageal and other Research that improves our understanding of these
and metastatic capacity.22 Furthermore, the drug-resistant solid tumors may be a rational treatment target. number of life cycles. If, for example, DNA damage
characteristics may ultimately lead to depletion of CSCs occurs in 100 cells but only 1 of them is a stem cell,
in the tumor. that cell will survive with the DNA damage and eventu-
References ally accumulate more damage and become cancerous.
1. Centers for Disease Control and Prevention. Global cancer statis- 12. Liu Y, Yang R, He Z, Gao WQ. Generation of functional organs
Q Why is the concept of targeting CSCs so
attractive?
tics. [Link] 2012. from stem cells. Cell Regen (Lond). 2013;2:1.
Q What should practicing oncologists know

A
Accessed July 6, 2015. 13. Bjerknes M, Cheng H. Multipotential stem cells in adult mouse today about CSCs?
 Dr Wicha: A mutation that is driving a cancer
2. Crew KD, Neugut AI. Epidemiology of upper gastrointestinal gastric epithelium. Am J Physiol Gastrointest Liver Physiol.
sometimes is also driving the CSC. A good

A
malignancies. Semin Oncol. 2004;31:450-464. 2002;283:G767-G777.
14. Barker N, Huch M, Kujala P, et al. Lgr5(+ve) stem cells drive example is human epidermal growth factor receptor  Dr Wicha: Practicing oncologists will start seeing
3. National Cancer Institute. Surveillance, Epidemiology, and End
Results Program (SEER). SEER Stat Fact Sheets: Stomach Cancer. self-renewal in the stomach and build long-lived gastric units in 2 (HER2) in human breast cancer. HER2 is a very more clinical trials of CSCs and immunotherapies.
[Link] Accessed vitro. Cell Stem Cell. 2010;6:25-36. potent driver of breast CSCs, and we think that’s why The key is to follow very closely the results of these
August 3, 2015. 15. Singh SR. Gastric cancer stem cells: A novel therapeutic target.
HER2-targeted therapies have been so successful. How- clinical trials because oncology is moving at a quicker
4. Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones Cancer Lett. 2013;338:110-119. pace than we’ve ever seen before. I think we’re going
DL, et al. Cancer stem cells−perspectives on current status and 16. Schepers A, Clevers H. Wnt signaling, stem cells, and cancer ever, in some cancers where the epidermal growth factor
of the gastrointestinal tract. Cold Spring Harb Perspect Biol. receptor (EGFR) appears to be important, the benefit to see advances in the CSC area, with the potential for
future directions: AACR Workshop on cancer stem cells. Cancer
Res. 2006;66:9339-9344. 2012;4:a007989. of EGFR inhibitor therapies appears to be short-lived. achieving much more durable responses. I would also
5. Han L, Shi S, Gong T, Zhang Z, Sun X. Cancer stem cells: thera- 17. Quante M, Wang TC. Inflammation and stem cells in gastrointes- This may be because we’re selecting clones that are resis- encourage practicing oncologists to participate in these
peutic implications and perspectives in cancer therapy. Acta Pharm tinal carcinogenesis. Physiology (Bethesda). 2008;23:350-359.
tant to those therapies, but also because the stem cells trials as members of cooperative groups.
Sin B. 2013;3:65-75. 18. Sims-Mourtada J, Izzo JG, Apisarnthanarax S, et al. Hedge- Understanding CSCs may help us to develop new
6. Wong DJ, Segal E, Chang HY. Stemness, cancer and cancer stem hog: an attribute to tumor regrowth after chemoradiotherapy in those tumors don’t depend on HER2 signaling but
and a target to improve radiation response. Clin Cancer Res. rather different pathways. approaches to cancer prevention. Some interven-
cells. Cell Cycle. 2008;7:3622-3624.
7. American Cancer Society. Stomach cancer: survival rates for stom- 2006;12:6565-6572. tions, like weight reduction, diet, and exercise, may
Dr Ajani: Another aspect to consider is that if we affect stem cells through inflammatory mediators, like
ach cancer, by stage. [Link] 19. Xu ZY, Tang JN, Xie HX, et al. 5-Fluorouracil chemotherapy of
cer/detailedguide/stomach-cancer-survival-rates. 2015. Accessed gastric cancer generates residual cells with properties of cancer can target CSCs effectively, we may reduce the tumor interleukin (IL)-6 and IL-8. We know that IL-6 is an
August 11, 2015. stem cells. Int J Biol Sci. 2015;11:284-294. burden in patients. We may not be able to eradicate the important driver of breast CSCs. Women with breast
8. Shiozaki H, Sudo K, Xiao L, et al. Distribution and timing of 20. Ajani JA, Wang X, Song S, et al. ALDH-1 expression levels tumor, but we can certainly reduce the tumor bulk. A cancer who either lose weight or undergo an active exer-
distant metastasis after local therapy in a large cohort of patients predict response or resistance to preoperative chemoradiation in tumor with fewer stem cells could become indolent.
with esophageal and esophagogastric junction cancer. Oncology. resectable esophageal cancer patients. Mol Oncol. 2014;8:142-149. cise intervention program lower their levels of inflam-
That’s what we hope we can do. matory cytokines, such as IL-6, by 50%.
2014;86:336-339. 21. Choi YJ, Kim N, Chang H, et al. Helicobacter pylori-induced
9. Elimova E, Shiozaki H, Wadhwa R, et al. Medical manage- epithelial-mesenchymal transition, a potential role of gastric Dormancy of cancers is also an issue. In diseases like
ment 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 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 tras-
Q Do you think that all cancers will be shown to
have CSCs as the key player?
estrogen receptor–positive breast cancer, cancers can
recur after 15 or even 20 years, and molecular analyses
cancer-molecular and clinical dimensions. Nat Rev Clin Oncol.
2013;10:643-655.
11. Passegué E, Jamieson CHM, Ailles LE, Weissman IL. Normal and
tuzumab in gastric cancer cells is associated with activation of
IL-6/STAT3/Jagged-1/Notch positive feedback loop. Oncotarget.
2015;6:5072-5087.
A  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
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?
leukemic hematopoiesis: are leukemias a stem cell disorder or a cancers. At one end of the spectrum are hematologic We think that these are dormant CSCs. Normal stem
reacquisition of stem cell characteristics? Proc Natl Acad Sci USA.
2003;100(suppl 1):11842-11849.
malignancies, where it looks like maybe 1 of 1,000 or 1 cells can sit for long periods and become active only
14 after damage is sustained; CSCs may act the same way. Dr Ajani: Oncologists in the community need to be NOTES: 15
This may be why a cancer recurs 1 or 2 years after a aware of the ramifications of treating stem cells and
woman has a great trauma, like losing a spouse or being non–stem cells. Certain cancers behave like an organ.
Oncology Times • November 10, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions

Oncology Times • November 10, 2015 • Cancer Stem Cells: Current Perspectives, Future Directions
involved in an accident. This might not be a coincidence For example, when skin is injured, normal adult stem
and may be related to dormant CSCs, which can be cells are animated and cause the skin to heal. They
found on biopsies in the bone marrow and may present repopulate and maintain the skin. The same phenom-
during times of extreme stress and inflammation. If that’s enon occurs with cancer. When CSCs are injured by
the case, it tells us that stress reduction and exercise are chemotherapy, they will also automatically repopulate.
important, and that potentially there may be new ways Further, in patients with colon cancer, it has been
in the future of administering a therapy and eradicating shown that if all the CSCs are killed, some of the non–
these dormant CSCs. This is just speculation at this stem bulk tumor cells will reformulate and transform
stage, but it’s exciting to think about the possibilities. into CSCs.
In addition, many of the practicing oncologists are Most clinicians tend to focus on the non–stem cells
members of cooperative groups. They will start seeing when treating cancer. We use cytotoxic drugs against
many more cancer stem cell trials be added, along with this proliferative group of cells and sometimes we have
immunotherapy trials, giving them many more options success, but most of the time they produce only a tran-
for their patients who may be appropriate candidates. I sient effect. Treatment success will occur when CSCs
would highly encourage practicing oncologists to partici- and non–stem bulk tumor cells are treated in unison.
pate in these trials. That is where we need to go.

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Cancer Stem Cells: 

The Promise and The Potential
A Seminars in Oncology Supplement

Despite advancements in
Jaffer A. Ajani, MD Howard S. Hochster, MD
treatment modalities, many
The University of Texas Yale School of Medicine
patients with cancer experi-
ence tumor recurrence and MD Anderson Cancer Center New Haven, Connecticut
metastasis at regional or Houston, Texas
distant sites. Evolving under-
standing of tumor biology Shumei Song, MD, PhD Ira B. Steinberg, MD
has led to the hypothesis that The University of Texas Boston Biomedical
tumors possess a stem cell– MD Anderson Cancer Center Cambridge, Massachusetts
like subpopulation known Houston, Texas
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 Published April 2015
initiation, heterogeneity, Cancer Stem Cells: 
therapy resistance, recur-
rence and metastasis, and
The Promise and The Potential
the potential for [Link]
effectively treating patients
by targeting these cells.

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