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75]

Review Article

Therapeutic approaches targeting cancer

stem cells
ABSTRACT Yunzhi Pan1,
Increasing studies have demonstrated that most tumors consisted a subpopulation of cells with stem cell properties, known as cancer Sai Ma1,
stem cells (CSCs). Accumulating evidence indicated that CSCs may be critical driving force for several types of cancer. Hence, it Kaiyue Cao2,
was necessary to develop therapeutic approaches specifically targeting CSCs. In this review, first, the biological properties of CSCs Sufang Zhou3,
were introduced, including the self‑renewal and differentiation, high tumorigenesis and invasiveness, resistance to chemotherapy Aiqin Zhao3,
and radiotherapy, genetic and epigenetic variations. Meanwhile, CSCs‑targeted therapeutic strategies were summarized, including Ming Li1,
targeting cell surface markers, signaling pathways, CSC niches, differentiation therapy, and drug resistance for CSCs. Furthermore, Feng Qian1,
clinical trials on anti‑CSCs therapies supported the efficacy of these therapies, as well as their combination with conventional Chuanwu Zhu1
chemotherapy and radiotherapy. CSCs could be significantly eradicated, eventually resulting in inhibited tumor growth, metastasis, and 1
The Affiliated
recurrence. Thus, selectively targeting CSCs with various agents may be a novel and promising therapeutic strategy against cancer. Infectious Diseases
Hospital of Soochow
University, Suzhou,
KEY WORDS: Anti‑cancer stem cells therapy, biological properties, cancer stem cells 2
Tianjin First Center
Hospital, Tianjin, 3The
People’s Hospital of
SND, Suzhou, China
INTRODUCTION Currently, global researchers have made great
efforts to understand biological properties of For correspondence:
In the past decades, the anticancer treatment CSCs and develop correspondingly therapeutic Dr. Zhu Chuanwu,
The Affiliated
has made considerable progress, but tumors approaches targeting CSCs. Infectious Diseases
remained refractory mainly because of recurrence Hospital of Soochow
or drug resistance. Conventional tumor therapies, BIOLOGICAL PROPERTIES OF CANCER STEM CELLS University, Suzhou
including chemotherapy and radiotherapy, mainly 215007, China.
aimed to decrease the tumor burden thus making E‑mail: zhuchw@126.
Clarifying biological properties of CSCs would
com
limited efficacy in fighting cancers. Increasing bring tremendous value for exploring targeted
evidence suggested that tumors were composed of therapies. Based on numerous studies, there were
phenotypically and functionally diverse populations several characteristics, which may be significant
of neoplastic cells. Furthermore, of which, the cell to CSCs‑targeted therapeutic strategies.
subpopulation with stem cell properties – cancer
stem cells (CSCs) were closely related to cancer Self‑renewal and differentiation capacity
development, metastasis, and resistance to Like normal stem cells, CSCs showed the ability
therapy.[1‑3] Hence, CSCs have been considered as the of self‑renew. However, unlike normal stem cells,
potential target or drug receptors in the treatment CSCs would be strictly influenced by both internal
of malignancy. and external factors while the balance could not
be maintained, leading to hyperproliferation and
The CSCs theory was initially proposed by Moore even metastasis.
et  al. in 1973. [4] In a study on acute myeloid
leukemia, CSCs were first identified.[5] According to The differentiation potential was another
the hypothesis, CSCs have been a small proportion important property of CSCs both in vitro and Access this article online
of cancer cells with powerful tumorigenesis ability, Website: www.cancerjournal.net
self‑renewal capacity, as well as chemotherapy and This is an open access journal, and articles are distributed under the terms of the DOI: 10.4103/jcrt.JCRT_976_17
radiotherapy resistance.[6] In addition, different Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which PMID: ***
studies demonstrated that CSCs were successfully allows others to remix, tweak, and build upon the work non‑commercially, as
Quick Response Code:
long as appropriate credit is given and the new creations are licensed under the
isolated from a multiple of solid tumors including identical terms.
breast, colon, prostate, and brain cancers [Table 1]. For reprints contact: reprints@medknow.com

Cite this article as: Pan Y, Ma S, Cao K, Zhou S, Zhao A, Li M, et al. Therapeutic approaches targeting cancer stem cells.
J Can Res Ther 2018;14:1469-75.

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Pan, et al.: Biological properties of CSCs and anti‑CSCs therapies

in  vivo. To analyze the differentiation features of CSCs, a Resistance to chemotherapy and radiotherapy
series of studies demonstrated that CSCs showed phenotypic Currently, acquired multi‑drug resistance almost invariably
characteristics or corresponding markers. For example, occurred in advanced and metastatic solid tumors, leading to
liver CSCs could differentiate into cancer cells containing disease progression and death. Increasing studies demonstrated
alpha‑fetoprotein, albumin, CK8, CK18, CK7, and other that many cancers were resistant to chemotherapy and
markers.[7] radiotherapy, and the existence of proliferatively quiescent
CSCs would be one reason. Molecular mechanisms on
High tumorigenesis and invasiveness chemotherapeutic and radiotherapy resistance included
One of the most distinctive characters of CSCs was the high high expression of ABC transporters, enhanced DNA damage
tumorigenesis and invasiveness. Reportedly, injection of as response, a hypoxic niche, apoptosis evasion, and so on.[10,11]
few as 100 CD133 + brain CSCs in nonobese diabetic, severe
combined immunodeficient mouse would produce a tumor Genetic and epigenetic variations
that could be serially transplanted, whereas injection of Genetic and epigenetic factors of CSCs were complicated.
105 CD133‑cells engrafted without causing a tumor.[8] As For example, loss‑of‑function mutations of adenomatous
the most common malignancy in women, breast tumors polyposis coli (APC) and gain‑of‑function mutations of K‑Ras
were composed of phenotypically diverse populations were both common abnormalities in colon cancer. CSCs would
of breast cancer cells. The tumorigenic cells as CD44 (+) be activated with K‑Ras mutations, contributing to colorectal
CD24 (−/low) Lineage (−) were identified and successfully tumorigenesis and metastasis in CRC cells harboring APC
isolated. The tumors could be formed in mice with as mutations.[12]
few as 100 cells with this phenotype, whereas it failed to
form tumor with tens of thousands of cells with alternate Taking above‑mentioned factors into consideration, there
phenotypes.[9] The capacity of tumorigenesis was different were several characters of CSCs which raised the tremendous
in other CSCs [Table 1]. potential for therapeutic approaches targeting CSCs.
Comparison of biological properties between CSCs and normal
Table 1: Markers used for the identification of cancer stem stem cells has been summarized [Table 2].
cells in different cancers
Cancer type CSC markers Transplanted TARGETED THERAPIES AGAINST CANCER STEM CELLS
cells
Lung CD133+ ND
In the past decades, numerous therapeutic strategies for
Sca‑1+CD45‑PECAM‑CD34+ ND
Colon CD133+ 500 eradicating CSCs have been proposed [Table 3]. In general, the
EpCAMhighCD44+ 200 core idea could be envisaged: Eliminating the CSCs themselves
ALDH ND by either killing or differentiating them and disrupting niche
Liver CD90+CD45‑ 5000
Breast CD44+EpCAM+CD24‑Lineage‑ 1000 signaling.
CD44+CD24‑ALDH1+ 20
Ovarian CD44+CD117+ 100 Therapeutic approaches targeting cell surface markers
CD133+ 500
Prostate CD44+CD133+ ND
Various cell surface and transmembrane proteins were expressed
Pancreatic CD44+CD24+EpCAM+ 100 by CSCs, including CD44, CD47, CD123, EpCAM (CD326),
CD133 500 CD133, IGF receptor I, and proteins in the Notch and Wnt
Brain CD133 100 signaling pathways.[13] Monoclonal antibodies (mAbs) against
CD15 1000
Melanoma ABCB5 100000 above‑mentioned proteins have been demonstrated to exhibit
AML CD34++CD38‑ ND significant anti‑CSCs activity in mice with human cancer
CD44+ ND xenograft or in clinical studies.
Head and neck CD44 5000
Skin CD34 1000
Mesenchymal SP 100 Notably, H90, a mouse IgG1 mAb against human CD44, has
CSC=Cancer stem cells, AML=Acute myeloid leukemia been the first mAb targeting CSCs. H90 inhibited proliferation,

Table 2: Biological properties of cancer stem cells and normal stem cells
Items Normal stem cells Cancer stem cells
Self‑renewal ability a. Highly proliferative potential a. Abnormal cell proliferation
b. Under the strict control of body b. Carcinogenicity
c. Regeneration and repair of adult tissue
Differentiation capacity a. A tissue composed of a heterogeneous population a. Heterogeneous cancer cells
b. Organ development b. Differentiation failure
Resistance Increased discharge of toxic substance Drug resistance
Metastasis and invasion Migration and homing Tumor metastasis
DNA repair system Activated DNA repair system Defective DNA repair mechanisms

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Pan, et al.: Biological properties of CSCs and anti‑CSCs therapies

Table 3: Targeted therapies against cancer stem cells appeared to be a promising strategy for eliminating CSCs in
Drugs Reference future cancer treatment.
Therapeutic approaches targeting cell surface markers
H90 (anti‑CD44) [14,15]
Therapeutic approaches targeting signaling pathways
P245 (anti‑CD44) [16] The strongest evidence to date were that the cell signaling
H4C4 (anti‑CD44) [17] pathways such as Notch, Hedgehog (Hh), and Wnt/β‑catenin
GV5 (anti‑CD44R1) [18] played important roles in cancer development. In most cases,
RO5429083 (anti‑CD44, targets a glycosylated [19]
extracellular constant domain of CD44) inappropriate activation of signaling pathways stimulated
BsAb (anti‑CD3/anti‑CD133) [21] proliferation, restricted differentiation, and prevented apoptosis.[23]
OMP‑21M18 (anti‑DLL4 humanized monoclonal antibody) [22] Hence, blockade of aberrant signaling pathways may provide a
Therapeutic approaches targeting signaling pathways further avenue for the cancer therapeutic strategy targeting CSCs.
The notch pathway
γ‑secretase inhibitors [24] The notch pathway
DLL inhibitors [26]
The hedgehog pathway
Notch pathway was associated with CSCs in various cancers.
Cyclopamine [30,31] CSCs in the breast cancer, medulloblastoma, and glioma,
GDC‑0449 (also known as vismodegib) [32,33] could be eliminated with inhibitors of γ‑secretase, the
IPI269609 [34] protease required for Notch cleavage and activation, such
The Wnt/β‑catenin pathway
Dkk1 [40,41]
as Gamma‑secretase inhibitors (GSIs).[24] However, GSIs were
relatively nonselective drug and the Notch inhibition in
Therapeutic approaches targeting CSC niches
intestinal stem cells were associated with dose‑limiting gut
Sunitinib [43]
Bevacizumab [44] toxicity (secretory diarrhea). Highly specialized mAbs that
Sorafenib [45] specifically antagonized Notch ligands and receptors provided
PX‑478 (oncothyreon), topotecan, and digoxin (target [46] single‑target specificity. [25] With anti‑Delta‑like 4 ligand
the HIF pathway) (DLL4, a membrane‑associated Notch ligand) antibody, either
Differentiation therapy alone or in combination with the chemotherapeutic agent
ATRA [47,48] irinotecan, the frequency of CSCs (Ep‑CAM+/CD44+/CD166+)
OSM [49]
could be reduced.[26] SiRNA targeted to Notch4 rather than
BMPs [50]
Notch1 was more effective in suppressing breast cancer
Therapeutic approaches targeting overcoming drug resistance
in CSCs
recurrence.[27]
ABC transporters
Verapamil (P‑gp inhibitor) [51] The hedgehog pathway
CDF [52] Activation of the Hh pathway was involved in the maintenance
ALDHs and tumorigenesis of CSCs in many tumors including multiple
DEAB [53]
myeloma, myeloid leukemia, colorectal cancer, gastric cancer, and
Other therapeutics
glioma.[28,29] Hence, several targeting therapies were developed
Metformin [54] on this basis. Cyclopamine, an antagonist of the Hh co‑receptor
Telomerase inhibitors [55]
Natural compounds [56,57] Smoothened (SMO), could decrease CSCs proportion, or even
CSCs=Cancer stem cells, DLL=Delta‑like ligand, ATRA=All‑trans retinoic acid, eliminate CSCs and induce tumor regression in some cancer
OSM=Oncostatin M, BMPs=Bone morphogenetic proteins, CDF=Difluorinated types, such as pancreatic cancer and brain cancer.[30,31] In addition,
curcumin, ALDHs=Aldehyde dehydrogenases, DEAB=Diethylaminobenzaldehyde,
HIF=Hypoxia‑inducible factors studies demonstrated that GDC‑0449 (also known as Vismodegib),
an orally active SMO antagonist, presented bioavailability in basal
induced terminal differentiation, and mediated apoptosis cell carcinoma,[32] and brain cancer.[33] In the case of pancreatic
tumor xenografts, the proportion of ALDHbri CSCs could be
in human myeloid leukemia cell lines.[14,15] Other anti‑CD44
reduced with IPI269609, the SMO inhibitor.[34]
mAbs such as P245, H4C4, GV5, and RO5429083 might show
pronounced effects on eliminating CSCs in some cancers.[16‑19]
The combined Hh pathway inhibitor‑targeted treatments
An anti‑CD133 mAb‑induced specific, dose‑dependent cytotoxic
and other therapeutic strategies have attracted general
effects in CD133(+)‑glioblastoma cells.[20] BsAb was a chemical attention.[35,36] For example, a combination with cyclopamine
heteroconjugation of an anti‑human‑CD3 mouse IgG2a and gemcitabine or a triple combination with cyclopamine,
mAb (OKT3) and an anti‑human CD133 mouse IgG1 mAb. BsAb rapamycin, and chemotherapy could effectively diminish
was able to effectively and specifically kill human CD133 (high) the number of pancreatic CSCs to be virtually undetectable
pancreatic (SW1990) and CD133 (high) hepatic (Hep3B) cancer levels in vitro and in vivo.[37,38]
cells in co‑culture experiments in vitro.[21] Encouraging data
have revealed that mAbs against DLL4 were effective in The Wnt/‑catenin pathway
eliminating CSCs.[22] From the above, it was possible that Aberrant activation of the Wnt/β‑catenin pathway in
therapeutic approaches targeting cell surface markers CSCs was closely associated with tumorigenesis in many

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Pan, et al.: Biological properties of CSCs and anti‑CSCs therapies
tissues. An antibody specific to frizzled7, a Wnt receptor,
depleted clonogenicity, and tumorigenicity in tumors.[39]
Dickkopf‑1 (Dkk1), a major secreted Wnt signaling antagonist,
bound to the low‑density lipoprotein receptor‑related
protein‑6 (LRP6), an essential co‑receptor for canonical Wnt
signaling.[40,41] Recently, Salinomycin, an antibiotic potassium
ionophore, has been reported to inhibit breast CSCs and target
the Wnt pathway by blocking the phosphorylation of LRP6.[42]
Therapeutic approaches targeting cancer stem cells niches
Various factors involved in the tumor microenvironment
including cancer‑associated fibroblasts, endothelial cells,
angiogenic vascular cells, cancer cells, and inflammatory
cells. All these factors have made a direct influence on
CSCs properties. The humanized mAb (Sibrotuzumab) have
provided good clinical benefits for non‑small cell lung cancer,
which blocked the activity of fibroblast activation protein α
expressed by carcinoma‑associated fibroblasts.[43] Meanwhile,
anti‑angiogenic therapies have also been studied in preclinical
and clinical trials, such as anti‑vascular endothelial growth
factor antibodies and tyrosine kinase inhibitors.[44,45] The
application of anti‑inflammatory drugs in cancer prevention
and treatment was also supported with clinical and
experimental data.[46] Thus, the specialized microenvironment
seemed to be a crucial target for CSCs elimination.
Differentiation therapy
Increasing cases suggested that tumor growth would be
unsustainable if CSCs were induced to differentiate. All‑trans
retinoic acid (ATRA), a natural compound derived from
vitamin A, has been considered as a potent differentiating
agent. ATRA was extensively applied in eliminating CSCs
from glioblastomas, and head and neck cancer.[47,48] Oncostatin
M, an interleukin 6‑related cytokine, was reported to
induce the differentiation of liver CSCs, from hepatoblasts
to hepatocytes.[49] Bone morphogenetic proteins (BMPs),
among which BMP7 elicited the strongest effects, triggered
differentiation and reduced CSCs in human glioblastomas.[50]
Therapeutic approaches targeting overcoming drug
resistance in cancer stem cells
Currently, many researchers have strived to propose
therapeutic approaches targeting drug resistance in CSCs.
Verapamil, a classical P‑glycoprotein inhibitor, was able to
enhance the chemo‑sensitivity of CSCs in squamous cell
cancers.[51] Difluorinated‑curcumin, a novel analog of the
dietary ingredient of Curcumin, could be an effective treatment
strategy for preventing chemo‑resistant CSCs. These effects
were associated with the down‑regulation of ABCG2.[52] In
addition, the sensitivity of traditional anti‑cancer treatments
could be enhanced with the down‑regulation of ALDH in some
cancer types, such as liver cancer and breast cancer.[53]
Other therapeutics
In addition to the above‑mentioned targeting therapeutics,
there were other therapeutic strategies proposed in recent
1472
years such as metformin, natural compounds, telomerase
inhibitors, oncolytic viruses, MicroRNA, and interferon. In
a study from Hirsch et al., low doses of metformin inhibited
cellular transformation and selectively killed CSCs in four
types of breast cancer with genetic diversity.[54] Imetelstat, as
a telomerase inhibition, has been applied in clinical treatment
for breast cancer, non‑small cell lung cancer, multiple myeloma,
and chronic lymphocytic leukemia.[55] Some natural compounds
including sulforaphane, epigallocatechin gallate, quercetin,
curcumin, berberine, gamma‑tocotrienols (gamma‑T3), and
parthenolide, showed biological activities in CSCs‑targeted
anti‑tumor therapies.[56,57]
CLINICAL RESEARCH
As described above, worldwide researchers have devoted
to exploring new anti‑CSCs drug, although there are many
challenges and difficulties to overcome. According to
ClincalTrials.gov., numerous anti‑CSCs compounds have been
already completed different phases of testing and successfully
entered human clinic trials [Table 4].
CONCLUSION AND FUTURE EXPECTATIONS
Although there has been still controversy regarding the
origin and certain features of CSCs, it was undoubted that
CSCs showed stem‑cell characteristics and were resistant to
chemotherapy and radiotherapy. Hence, therapies targeting
CSCs bring new hopes for future anti‑tumor treatment.
Based on the current knowledge, CSCs‑targeted therapies
mainly aimed at controlling cell proliferation and growth,
unable to eradicate the tumor cell mass. Chemotherapy and
radiotherapy may bring better therapeutic response on the
tumor bulk. Hence, it was noted that targeting any single
molecular pathway or cell type could not realize efficient
anticancer efficacy, neither avoiding the acquisition of resistance
to treatment. A combination of classical chemotherapy and
radiotherapy with novel therapies targeting CSCs may exert
better therapeutic effects than that of single therapy.
Clinical and experimental data demonstrated that cancer
therapy was effective only when CSCs could be completely
eradicated. Unfortunately, the currently reported innovative
therapies were not highly specific for CSCs. One potential
reason may be that the differences among various cell
populations in tumors were difficult to find, and there were
several signaling pathways involved in the regulation of both
CSCs and normal stem cells. Another reason may be that cancers
could be triggered by several oncogenic mutations or there
could be multiple mutations in CSCs. Due to the complexity,
it was critically important to further improve our knowledge
and understanding on CSCs properties and tumorous biology.
In general, therapeutic approaches targeting CSCs have
great significance on the cancer treatment, but there are still
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Pan, et al.: Biological properties of CSCs and anti‑CSCs therapies

Table 4: Potential anti‑cancer stem cells drug in clinical studies

Drug Disease treated Research stage Reference or websites
IPI‑926
IPI‑926 Neoplasms The Phase 1 clinical http://clinicaltrials.gov/ct2/show/
trial (NCT00761696) NCT00761696?term=IPI926&rank=4
IPI‑926 plus cetuximab Recurrent head and The Phase 1 clinical http://clinicaltrials.gov/ct2/show/
neck cancer trial (NCT01255800) NCT01255800?term=IPI926&rank=6
IPI‑926 plus Pancreatic cancer, The Phase 1 clinical http://clinicaltrials.gov/ct2/show/
FOLFIRINOX adenocarcinoma trial (NCT01383538) NCT01383538?term=IPI926&rank=5
IPI‑926 plus Metastatic The Phase 1b/2 clinical http://clinicaltrials.gov/ct2/show/
gemcitabine pancreatic cancer trial (NCT01130142) NCT01130142?term=IPI926&rank=2
Demcizumab Nonsmall cell lung The Phase 1 clinical http://www.clinicaltrials.gov/ct2/show/
cancer trial (NCT01189968) NCT01189968?term=NCT01189968&rank=1
Cancer stem cell vaccine Pancreatic cancer The Phase 1 and phase 2 http://clinicaltrials.gov/ct2/show/
clinical trial (NCT02074046) NCT02074046?term=cancer+stem+cell&rank=1
Lung cancer The Phase 1 and phase 2 http://clinicaltrials.gov/ct2/show/
clinical trial (NCT02084823) NCT02084823?term=cancer+stem+cell&rank=2
Liver cancer The Phase 1 and phase 2 http://clinicaltrials.gov/ct2/show/
clinical trial (NCT02089919) NCT02089919?term=cancer+stem+cell&rank=4
Nasopharyngeal The Phase 1 and phase 2 http://clinicaltrials.gov/ct2/show/
cancer clinical trial (NCT02115958) NCT02115958?term=cancer+stem+cell&rank=3
Epithelial ovarian The Phase 1 and phase 2 http://clinicaltrials.gov/ct2/show/
cancer clinical trial (NCT01334047) NCT01334047?term=cancer+stem+cell&rank=15
Chronic lymphocytic The Phase 1 clinical http://www.clinicaltrials.gov/ct2/show/
leukemia trial (NCT00458679) NCT00458679?term=NCT00458679&rank=1
Glioblastoma, brain The Phase 1 and phase 2 http://www.clinicaltrials.gov/ct2/show/
tumor clinical trial (NCT00846456) NCT00846456?term=NCT00846456&rank=1
Bevacizumab Breast cancer The Phase 2 clinical http://clinicaltrials.gov/ct2/show/
trial (NCT01190345) NCT01190345?term=cancer+stem+cell&rank=8
RO5429083 (anti‑CD44 Neoplasms The Phase 1 clinical http://www.clinicaltrials.gov/ct2/show/
monoclonal antibody) trial (NCT01358903) NCT01358903?term=NCT01358903&rank=1
Reparixin Breast cancer The Phase 2 clinical http://clinicaltrials.gov/ct2/show/
trial (NCT01861054) NCT01861054?term=NCT01861054&rank=1
Gemcitabine, Metastatic The Phase 2 clinical http://clinicaltrials.gov/ct2/show/
nab‑paclitaxel, GDC‑0449 pancreatic cancer trial (NCT01088815) NCT01088815?term=NCT01088815&rank=1
Metformin Colon cancer The Phase 1 clinical http://clinicaltrials.gov/ct2/show/
trial (NCT01440127) NCT01440127?term=cancer+stem+cell&rank=11
Mithramycin Lung cancer The Phase 2 clinical http://clinicaltrials.gov/ct2/show/
Esophageal cancer trial (NCT01624090) NCT01624090?term=cancer+stem+cell&rank=13
Mesothelioma
Gastrointestinal
neoplasms
Breast cancer
MK‑0752 plus docetaxel Breast cancer The Phase 1 and phase 2 http://clinicaltrials.gov/ct2/show/
clinical trial (NCT00645333) NCT00645333?term=cancer+stem+cell&rank=20
Trastuzumab plus Breast cancer The Phase 3 clinical http://clinicaltrials.gov/ct2/show/
doxorubicin and trial (NCT00004067) NCT00004067?term=NSABP‑B‑31&rank=2
cyclophosphamide

several issues requiring extensive investigations in the future. REFERENCES

For example, how do we find new markers with optimal
specificity and sensitivity? What are the exact mechanisms of
therapeutic strategies targeting CSCs? How do we combine
these new CSCs‑targeted agents with conventional chemo‑ and
radio‑therapies to achieve better efficacy? Approaches for
solving these issues will ultimately contribute to improving the
efficacy of targeted therapeutic strategies for the eradication
of CSCs.
Financial support and sponsorship
The clinic medical center of infectious diseases in Suzhou
(SZZX201508).
Conflicts of interest
There are no conflicts of interest.
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