Pancreatic Cancer Stem cells: New Direction for Pancreatic Cancer ...

Stem Cell Research

Pancreatic Cancer Stem cells: New Direction for Pancreatic Cancer Treatment
Chenwei Li, Mark J. Hynes, Jie Jing
About the Authors: Chenwei Li received
Abstract
his M.D. degree from Shandong Medical

University in China and a Ph.D. degree
Emerging evidence suggests malignant tumors are composed
from Marshall University in West Virginia.
of a small subset of distinct cancer cells, termed cancer
He completed his postdoctoral training
stem cells. Cancer stem cells have the ability to self-renew
in 2004 at the University of Michigan.
and to also initiate and propagate tumors. Data have been
He joined the Department of Surgery
provided to support the existence of cancer stem cells in
at University of Michigan in 2004 and
human blood cell-derived cancers and solid tissue tumors
started pancreatic cancer stem cell (CSC)
of the breast, prostate, brain, pancreas, head and neck,
research. He is co-founder of OncoStem-
skin, and colon. Furthermore, pathways that regulate
Cell Corporation. Dr. Li was the first to
self-renewal, such as Bmi-1, Wnt, PTEN, Notch and
identify a highly tumorigenic cancer stem
Hedgehog are beginning to be implicated in the regulation
cell population of pancreatic cancer cells
of cancer stem cell self-renewal. Study of human pancre-
expressing the cell surface markers CD44,
atic cancers has revealed a unique subpopulation of cancer
CD24, and ESA. His current research is
aimed at the development of novel thera-
cells that possess the characteristics of cancer stem cells. The
peutic strategies to selectively target the
pancreatic cancer stem cells express the cell surface markers
CSC population, which has been shown in
CD44+CD24+ESA+, and represent 0.5% to 1.0% of
pancreatic and other tumor models to be
the total pancreatic cancer cell population. Along with the
highly resistant to standard chemotherapy.
characteristics of self-renewal and multi-lineage differentia-
He has multiple collaborations with biotech
tion, pancreatic cancer stem cells display up-regulation of
companies on studies testing new anti-
Sonic hedgehog (SHH) and Bmi-1. Dysregulation of these
cancer drugs on pancreatic CSCs; these
pathways in cancer stem cells are believed to be responsible
new therapeutic plans have demonstrated
for the uncontrolled self-renewal of cancer stem cells which
promising results.
generate tumors that are resistant to current radiation and

chemotherapy regimens. Of clinical importance, cancer
Mr. Mark Hynes attended the University
stems cells in several tumor types have shown resistance to
of Michigan. Some of his recent work
standard therapies and may play a role in treatment failure
has included identifying a marker of colon
or disease recurrence. Identification of pancreatic cancer
cancer stem cells, and also, examining the
stem cells and further elucidation of the signaling pathways
transformation from colitis to colon cancer.
that regulate their growth and survival may provide novel
He has many years of experience working
therapeutic approaches to treat pancreatic cancer.
with colon, pancreas, and liver samples

from the clinic in various mouse models of cancer. He is currently testing
Cancer stem cells theory
a Notch pathway blocking antibody as a possible treatment for pancreatic

adenocarcinoma.
The concept that cancers arise from stem cells was

first hypothesized more than 150 years ago[1], and
Dr. Jie Jing has over a decade of experience in drug R&D. Before co-
recent advances in stem cell biology techniques
founding OncoStemCell Corporation he was Director of Business Develop-
ment and Project Management in VenturePhama Group, which is the only
have made it possible to test the cancer stem cell
fully integrated CRO from Drug Discovery to Commerialization in China and
hypothesis. It was first observed that when can-
is also public traded in Hong Kong Stock Exchange. Prior to that he had
cer cells from many different tumor types were
served as Director of Business Development in Crown Bioscience, which is
assayed for their proliferative potential, only a
a leading preclinical CRO company in China focusing on oncology service to
minority of tumor cells showed extensive pro-
advance anti-cancer therapeutics. He has also worked as Director of Asia-
liferative potential.[2] These observations suggest
Pacific Business Development in Symmunity LLC which is a leader in the
that cancers are comprised of a small subset of
rapidly growing market of immune cell cultivation and therapy. He obtained
distinct cancer stem cells with great proliferative
his Ph.D at Tel Aviv University in Israel. He had his postdoctoral training at
potential, and well-differentiated cancer cells have
Stanford University and University of California at Davis. He has authored
very limited proliferative potential. The traditional
15 scientific abstracts and publications.
theory about how tumors develop (shown in
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Fig 1a) is that tumor cells are heterogeneous and most
The existence of human cancer stem cells in other solid
cancer cells retain the ability to proliferate extensively
neoplasm types has since been proven, including brain [5,
to form new tumors. In the cancer stem cell theory (Fig
6, 7], Multiple myeloma [8], prostate [9], ovarian [10], colon [11,
1b), tumor cells are also heterogeneous, but only small
12], pancreatic[13], liver [14] and head and neck [15] cancers.
portion of cancer cells are able to proliferate extensively
Although some cell surface markers seem to define a
and form new tumors. These cells are termed cancer
cancer stem cell in several cancer types (for example
stem cells. Like normal stem cells, cancer stem cells can
CD44 and CD133), it seems that each tumor type pos-
both self-renew and produce differentiated progeny.
sesses a unique combination of cell surface markers that
define the cell subpopulation with the highest tumori-
genic potential (Table I).
Table I. Cancer stem cells have been identified in several types
of human cancer
Cancer type
Surface marker (s)
Reference (s)
Leukemia
CD34+/CD38-
3
Breast cancer CD44+ESA+CD24-/
low
4
Brain cancer
CD133+
5, 6, 7
Fig 1. The cancer stem cell theory. The traditional theory about
Multiple my-
how neoplasms develop is shown in (A), where most tumor cells
eloma
CD138-
8
can proliferate extensively and form new tumors. In the cancer stem
Prostate
cell theory (B), tumor cells are heterogenous, but only cancer stem
cancer
CD44+
9
cells are able to proliferate extensively and form new tumors. These
cells are termed cancer stem cells because like normal stem cells,
Ovarian
cancer
SP cells
10
they can both self renew and produce differentiated progeny. ( Stem
cells, cancer, and cancer stem cells. Nature 2001;414:105-11.)
Colon cancer
CD133+
11, 12

Pancreatic
Dick et al first identified cancer stem cells in acute
cancer
CD44+CD24+ESA+
13
myeloid leukemia in 1997[3], showing that the ability to
Liver
CD133+
14
regenerate human leukemia in non-obese diabetic severe
combined deficiency (NOD/SCID) mice was retained in
Head and
a rare subgroup of cancer stem cells. These cancer stem
Neck
CD44+
15
cells, with cell surface marker phenotype of CD34+/
CD38−, represented only 0.1% of the total cancer cell
population and regenerated a tumor almost identical in
Pancreatic cancer stem cells
appearance to the parent tumor. Tens of thousands of
cancer cells from the same tumors lacking this pheno-
Pancreatic adenocarcinoma is a highly aggressive cancer
type were not tumorigenic. In 2003, Al-Hajj et al. re-
which is usually diagnosed in an advanced state with no
ported that a population of tumor-initiating cells (TICs)
effective therapies. It has the worst prognosis of any
was responsible for the propagation of human breast
major malignancy with 3% 5 year survival rate and is the
cancer [4]. Primary tumor cells expressing a CD44+/CD-
fourth most common cause of cancer deaths per year in
24low were shown to initiate tumors upon transplantation
the United States [16]. This may be due to the fact that ex-
into NOD/SCID mice; all the other tumor cells failed
isting therapies are primarily aimed at targeting the can-
to propagate tumors. These studies indicate that breast
cer cell populations with limited tumorigenic potential.
TICs can undergo self-renewal and differentiate and
A recent study by Li et al. identified the subpopulation
are highly proliferative in a xenogeneic transplantation
of primary human pancreatic cancer cells with CD44
system.
+CD24+ ESA+ surface markers as putative cancer stem

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Stem Cell Research
cells [13]. Pancreatic tumor cells were sorted for the mark-
that recapitulated the primary tumor of origin. They also
ers CD44, CD24, and ESA either individually or in com-
reported an overlap of 14% between
bination and these sorted cells were injected into NOD/
CD44+CD24+ESA+ and CD133+ pancreatic cancer
SCID mice and their tumorigenic potential was assessed
cells. This study raises the question: is there more than
(Table II). Cells expressing all three surface markers
one type of cancer stem cell population in any one
CD44+CD24+ESA+, comprising only less than 1% of
particular cancer type? Wright et al [19] recently reported
all human pancreatic cancer cells, had the highest tum-
that there are two distinct phenotypes of stem cells in
origenic potential. As few as 100 CD44+CD24+ESA+
breast cancer expressing CD44+/CD24– and CD133+,
cells were able to generate tumors, while tumors did not
with no overlap of surface markers depending on the
form in mice until 10,000 CD44–CD24–ESA– were
tumor from which the cancer stem cell populations were
injected into NOD/SCID mice. CD44+CD24+ESA+
isolated. Each stem-cell population behaved similarly
cells demonstrated at least a 100-fold greater tumor-
with equal potency for tumor formation. Further
initiating potential than maker negative cells.
experiments will be needed to verify whether
CD44+CD24+ESA+ and CD133+ pancreatic cancer
Table II. Tumorigenicity of pancreatic cancer cells
cells represent two distinct cancer stem cell populations.
It has been reported that human pancreatic
adenocarcinomas display increased hedgehog pathway
Cell Number
104
103
500
100
activity [20, 21]. In mouse models, transgenic
unsorted
4/6
0/6
0/3
0/3
overexpression of SHH within the pancreas results in
the development of cancer precursor lesions (PanIN
CD44+
8/16
7/16
5/16
4/16
lesions). Li et al [13] reported that expression of the SHH
CD44-
2/16
1/16
1/16
0/16
transcript was increased only about four-fold in bulk and
ESA+
12/18
13/18
8/18
0/18
CD44–CD24–ESA– pancreatic cancer cells when
ESA-
3/18
1/18
1/18
0/18
compared with normal pancreatic epithelial cells, but was
increased 46-fold in CD44+CD24+ESA+ cells (Fig.2).
CD24+
11/16
10/16
7/16
1/16
BMI-1 was also up-regulated in CD44+CD24+ESA+
CD24-
2/16
1/16
0/16
0/16
pancreatic cancer stem cells [22]. Further studies are
needed to determine the role of each these particular
CD44+CD24+ 10/12 10/12 7/12
6/12
pathways and how these pathways may best be targeted
ESA+CD44-
1/12
0/12
0/12
0/12
in patients.
CD24-ESA-
The highly tumorigenic CD44+CD24+ESA+ cells gave
rise to additional CD44+CD24+ESA+ cells as well as
SHH Expression
50
phenotypically diverse non-tumorigenic cells. This
40
indicated that CD44+CD24+ESA+ pancreatic cancer
cells have the ability to both self-renew and produce
30
differentiated progeny. Using in vitro sphere forming
20
old Increase
F
assays, it was observed that single CD44+CD24+ESA+
10
cells form pancreatic tumorspheres, while CD44–CD24–
0
ESA– cells do not [17]. These CD44+CD24+ESA+
ancreas
tumorspheres can be passaged multiple times without
Nontmorigenic
Normal P
loss of tumorsphere forming capability, which represents
CD44+CD24+ESA+
the self-renewal capacity in vitro.

Fig.2 . mRNA expression of Sonic Hedgehog (SHH) genes in
Hermann et al [18] also reported that CD133+ cells in
normal pancreas, nontumorigenic pancreatic cancer cells and highly
primary pancreatic cancers and pancreatic cancer cell
lines distinquish cells with a potent proliferative
tumorigenic CD44+CD24+ESA+ pancreatic cancer cells. To-
capacity.
The CD133+ cells comprised 1% to 3% of pancreatic
tal RNA was isolated and mRNA was quantitated by real-time
adenocarcinoma cells, and as few as 500 CD133+ cells
RT-PCR. (Li et al. Identification of pancreatic cancer stem cells.
injected in immunocompromised mice generate tumors
Cancer Res 67:1030-1037, 2007)

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The origin of pancreatic cancer stem cells
receptor for the ligand stromal derived factor-1, which

mediates cell migration [28, 29]. It was reported that at the
Are these putative cancer stem cells a differentiated cell
invading front of pancreatic tumors, CD133+ pancreatic
within the organ that undergoes de-differentiation and
cancer stem cells also co-express CXCR4.
adopts a stem cell-like phenotype, or are they a normal
CD133+CXCR4– and CD133+CXCR4+ cells were able
stem cell that undergoes malignant change to become a
to form primary tumors equally, but only
cancer stem cell? The origin of cancer stem cells is one
CD133+CXCR4+ cells were able to metastasize [18].
of the most important and interesting question in cancer
Although this study indicated that CXCR4 blockade
stem cells biology. Cancer stem cells possess many
prevented metastasis in this particular tumor model,
features of normal stem cells, such as the ability to
more evidence is needed to confirm the relationship
undergo self-renewal and multilineage differentiation,
between cancer stem cells and metastasis.
resistance to DNA damaging agents, and anchorage-

independent survival. Stem cells are defined by their
Resistance of cancer stem cells to therapy
ability to undergo self-renewal, which is a cell division in

which one or both of the daughter cells remain
Cancer stem cel s from several tumor types have been
undifferentiated and retain the ability to produce another
shown to be more resistant to chemotherapy and
stem cell with the same capacity to proliferate as the
radiation. The cancer stem cel model explains why
parental cell. Researchers have hypothesized that cancer
conventional treatment may result in tumor shrinkage, but
stem cells arise from normal stem cells that have
also why most tumors also recur: because the cancer stem
undergone accumulation of genetic changes until the
cel population survives and regenerates the tumor (Fig 3).
normal stem cells have acquired a malignant phenotype.
Normal stem cells are the longest lived cells in tissues,
and it is thought that these cells are more likely to
accumulate mutations over time and ultimately assume a
malignant phenotype. Studies in both hematologic and
breast cancer support the concept that cancer stem cells
may arise from self-renewing normal stem cells that are
transformed by dysregulation of a self-renewal pathway
[23, 24] Pathways involved in self-renewal in normal stem
cells are found to be dysregulated in human
malignancies. These pathways include the Wnt, Sonic
hedgehog, Bmi-1, PTEN, and Notch pathways. Some
studies suggest that cancer stem cells may arise from
mutated progenitor cells called transit-amplifying cells
that develop the capacity for unregulated self-renewal [25,
26]. Recent data in a genetically engineered mouse model
Fig 3. Cancer stem cells are resistant to conventional therapies.
of pancreatic cancer suggests that pancreatic acinar or
Only treatments that specifically target cancer stem cells will result
centroacinar cells may indeed be the original source of
in cancer cure. (Reya T, Morrison SJ, Clarke MF, et al. Stem
pancreatic cancer [27], which needs to be validated. It is
cells, cancer, and cancer stem cells. Nature 2001;414:105-11.)
unclear if pancreatic cancer stem cells arise from a

mutated stem cell or from a downstream progenitor, or
Observations made with CD34+CD38− cancer stem
de-differentiated cell that has re-gained stem cell-like
cells from leukemia demonstrated that these cancer stem
properties because of genetic alterations
cells were significantly less sensitive to the treatment of

chemotherapy (daunorubicin or cytarabine) than the
Pancreatic cancer stem cells and metastasis
bulk population of leukemic blast cells [30]. This was

accompanied with high expression of multi-drug
Cancer stem cells are thought to be responsible for the
resistance genes and lower susceptibility to apoptosis. In
metastatic spread of cancers. To answer the question if
addition, it has been shown that myeloma cancer stem
pancreatic cancer stem cells are indeed responsible for
cells are more resistant to standard therapies (including
metastasis, Hermann et al.[18] investigated the relationship
chemotherapy and proteosome inhibitors) [8]; and it was
between CD133+ pancreatic cancer stem cells, CXCR4
also reported that the CD 133+ glioblastoma cancer
expression, and metastasis. CXCR4 is a chemokine
stem cells in both primary tumors and xenografts
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increased two- to four-fold after ionizing radiation [31].
cancer stem cells while not affecting normal stem-cell
This enrichment of CD133+ cancer stem cells was due
populations. Specifically targeting the leukemic cancer
to activation of the DNA damage response, protecting
stem cell surface molecule CD44 using a monoclonal
these cells from DNA damaging effects of radiation.
antibody resulted in eradication of human acute myeloid
Todaro et al reported that CD133+ colon cancer stem
leukemic stem cells while sparing normal stem cells in a
cells were resistant to chemotherapeutic agents oxiplatin
xenogaft model [37].
and fluorouracil, mediating by expression of interleukin

(IL)-4 by the CD133+ colon cancer stem cells. Blocking
Recently, Dick et al reported that an anti-interleukin-3
IL-4 enhanced the antitumor efficacy of these
(IL-3) receptor alpha-chain (CD123)-neutralizing
chemotherapeutic agents through selective sensitization
antibody (7G3) specifically targeted acute myeloid
of CD133+ cancer stem cells [32].
leukemia-Leukemia stem cells (AML-LSCs), impaired

human AML cell engraftment and proliferation in
Studies of pancreatic cancer suggest that pancreatic
NOD/SCID mice, and also improved long-term
cancer stem cells may also be resistant to chemotherapy
survival. 7G3 significantly reduced cancer burden in the
and radiation. Shah et al [33] reported that compared to
bone marrow and periphery in mice with established
the parental cells from which they were derived,
AML and inhibited secondary transplantation [38].
gemcitabine-resistant pancreatic cancer cells expressed

an increased level of cancer stem cell surface proteins,
The Clarke group has reported that three microRNAs
including CD44, CD24, and ESA. This was
(miR-200c-141, miR-200b-200a-429, and miR-183- 96-
accompanied by the presence of an epithelial-
182) were downregulated in human breast cancer stem
mesenchymal transition (EMT), and a more invasive
cells, normal human and murine mammary stem cells,
phenotype for the remaining cells. Hermann et al [18]
and embryonal carcinoma cells. In vitro study
demonstrated that CD133+ populations in the L3.6p
demonstrated that miR-200c inhibited the clonal
pancreatic cancer cell line were enriched after exposure
expansion of breast cancer cells and inhibited the
to gemcitabine. Therefore, pancreatic cancer resistance
growth of embryonal carcinoma cells. miR-200c
to standard therapies may be explained by the presence
singnificantly inhibited the ability of normal mammary
of pancreatic cancer stem cells and their insensitivity to
stem cells to form mammary ducts and tumor formation
chemotherapy and radiation.
driven by human breast cancer stem cells in vivo. Effect

of miR-200c on expression of BMI1 might be the
The mechanisms by which cancer stem cells resist DNA
possible mechanism [39].
damage induced by chemotherapy and radiation are

unclear. Others have suggested that some self-renewal
Hoey et al. developed selective anti-human and anti-
pathways (Wnt, Notch) may contribute to cancer stem
mouse DLL4 antibodies targeting the vasculature and
cells resistance to chemotherapy and radiation [34, 35, 36].
stroma in xenograft models derived from human colon

and breast cancers. It was demonstrated that both
Targeting cancer stem cells
blocking antibodies inhibited tumor growth and

combination of the two antibodies was more effective
Treatments targeted specifically at the cancer stem cell
than either alone. Treatment with anti-human DLL4
population may be required to result in an effective
(21M18) inhibited the expression of Notch genes and
treatment of cancer. But when targeting cancer stem
proliferation of cancer cel s. Inhibition of DLL4, either
cells, one must carefully analyze the effects of the
alone or in combination with the chemotherapy
treatment to ensure that the normal stem cells are not
(irinotecan), significantly reduced cancer stem cell
adversely affected. Recent published data suggest that
frequency in xenograft models of human colon cancer [40].
selective targeting of cancer stem cells may be possible

and more effective to treat cancers.
With regard to target pancreatic cancer stem cells, it has

been reported by Mueller et.al [41] that neither sonic
Yilmaz et al [23] reported that conditional deletion of
hedgehog inhibitor cyclopamine nor mTOR blocker
PTEN in adult hematopoietic cells leads to expansion of
rapamycin alone or as supplements to gemcitabine were
leukemic cancer stem cells and depletion of normal
capable of diminishing the pancreatic cancer stem cell
hematopoietic stem cells in mice model. Treatment of
population; only the combined inhibition of both
the mice with rapamycin, which functions to reverse the
pathways together with gemcitabine significantly reduced
effects of PTEN deletion, blocked the development of
the number of pancreatic cancer stem cells both in vitro
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and in vivo. This data indicates that combined inhibition
Even though there may still be a long journey ahead
of sonic hedgehog and mTOR signaling together with
before real benefits and profits are realized, many
gemcitabine may be effective in eliminating pancreatic
biotech and pharmaceutical companies have already
cancer stem cells. The cancer stem cell theory indicates
started to discover and develop new therapies targeting
that the goal of therapy should be to identify pancreatic
cancer stem cells. There are no currently approved drugs
cancer stem cell population and target it. Future research
specifically targeting cancer stem cells. However, a
should focus on understanding the role of WNT, BMI1,
number of early-stage candidates are in development
North, PTEN, Sonic hedgehog and other pathways in
and others are planned. Over 30 companies or
regulating the self-renewal of pancreatic stem cells and
commercially-based research groups are involving in the
to identify specific receptor or bio-markers of these
discovery and development of candidate antibodies and
cells. Pancreatic cancer stem cell studies will lead to
reagents targeting cancer stem cells. These include
improved diagnostics and a possible treatment of
Genentech Inc, GlaxoSmithKline, OncoMed
pancreatic cancer.
Pharmaceuticals and others. Currently there are close to

30 developmental programs relating to the therapeutic
It has become clear that a great deal of cancer research
targeting of cancer stem cells, include new therapies
will focus on cancer stem cells in the near future, and
targeting pancreatic cancer stem cells. Thus far, only
next critical step is to translate these scientific findings
three companies have reported clinical results of patients
into clinical benefits for patients. Targeting cancer stem
in studies using drugs thought to target cancer stem cells.
cells will ultimately lead to significant advancements in

cancer therapy.
Cancer stem cell research is not without its sceptics, and

questions remain which cancer stem cell theory must
Drug discovery
answer. However, cancer stem cell research has

provided new tools to study tumor formation and
Many different strategies are being explored and
metastatic spread, and the outcomes of several clinical
considered to therapeutically target cancer stem cells
trials now in progress will continue to attract significant
including the targeting of surface proteins (markers),
interest from both the scientific and industrial fields.
signaling pathways (Hedgehog, Notch, Wnt etc), the

stem cell niche environment, viruses targeting cancer
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