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Journal of Drug Targeting
ISSN: 1061-186X (Print) 1029-2330 (Online) Journal homepage: https://www.tandfonline.com/loi/idrt20
Engineering mesenchymal stem cells: a novel
therapeutic approach in breast cancer
Razieh Heidari, Neda Gholamian Dehkordi, Roohollah Mohseni & Mohsen
Safaei
To cite this article: Razieh Heidari, Neda Gholamian Dehkordi, Roohollah Mohseni & Mohsen
Safaei (2020): Engineering mesenchymal stem cells: a novel therapeutic approach in breast
cancer, Journal of Drug Targeting, DOI: 10.1080/1061186X.2020.1775842
To link to this article: https://doi.org/10.1080/1061186X.2020.1775842
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REVIEW ARTICLE
Engineering mesenchymal stem cells: a novel therapeutic approach in
breast cancer
Razieh Heidari
a
, Neda Gholamian Dehkordi
b
, Roohollah Mohseni
c
and Mohsen Safaei
a
a
Department of Medical Biotechnology, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran;
b
Department of Molecular Medicine, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran;
c
Clinical
Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
ABSTRACT
Breast cancer is one of the most prevalent and deadliest cancers among women in the world because of
its aggressive behaviour and inadequate response to conventional therapies. Cellular and gene therapies
based on mesenchymal stem cells (MSCs) represent promising treatment strategies for multiple diseases,
such as cancers. MSCs are multipotent adult stem cells with important features for cell therapy, such as
tissue homing to injured sites, their differentiation potential, their capacity of secreting plenty of trophic
factors, and low immunogenicity. The quite easy isolation of these cells from various types of tissues are
associated with no ethical concern when dealing with foetal or embryonic stem cells. The MSCs exhibit
both pro and anti-oncogenic properties. However, genetic engineering of MSCs and nanoparticles is being
employed as a means to solve some of these problems and improve the antitumor properties of these
cells. The tumour-homing ability of MSCs and their exosomes to tumour niches have made them as a
promising vector for targeted delivery of therapeutic agents to tumours site. The present study investi-
gated MSCs specifications, pro- and anti-oncogenic properties of MSCs in breast cancer, and reviewed tar-
geted breast cancer therapy via engineered MSCs, likely as potent cellular vehicles.
ARTICLE HISTORY
Received 1 April 2020
Revised 25 May 2020
Accepted 26 May 2020
KEYWORDS
Mesenchymal stem cells;
breast cancer; tumour
homing; targeted drug
delivery vehicle; genetic
modification
Introduction
According to the statistics, more than seven million people died
of cancer around the world. It is estimated that the number of
new cancerous patients will greatly increase. As the most preva-
lent malignant neoplasm, breast cancer in women is associated
with more than one million new cases per year, which could be
the primary reason for death among women aged 45–55 years.
This type of disease has been the second major cause of death
typically induced through cancer. The occurrence of breast cancer
is approximately 1 in 8 women, which most of the time, it is
necessary for complete tissue removal, chemotherapy, radiother-
apy, and hormone therapy [1,2].
Breast cancer is classified based on the various subtypes, and it
extremely heterogeneous in terms of prognosis, degree of metas-
tasis, and disease progression, which makes it hard to treat [3]. In
this regard, treatment can be conducted based on combined
therapeutic methods containing endocrine and targeted therapy,
radiotherapy, chemotherapy, and surgery. Nevertheless, such tech-
niques may have undesirable consequences, such as locating
problems to tumour sites, dispersed nature of the disease, and
toxicity [4]. As a unique therapeutic strategy, cell therapy is used
for various diseases, such as cancer [5]. Migration of mesenchymal
stem cells (MSCs) to sites of tissue injury and tumours may occur
after systemic treatment. Since the identification of the MSCs has
been the tumour-oriented homing ability of MSCs, studies have
shown that they have application for tumour-directed migration
and have a high potential for cancer therapies including, a prom-
ising vector for therapeutic agent delivery to tumours and
metastatic niches. Thereby, a unique investigation field has been
inspired to achieve effective cancer therapy by the use of engi-
neered MSCs [6–8].
MSCs’features have made them one of the excellent candi-
dates in cell therapy and tissue engineering of various diseases,
such as autoimmune diseases, ischaemic diseases, and neuro-
logical disorders. Moreover, 700 MSC-based clinical trials verified
the high therapeutic potential of these cells. Application of MSCs
in cancer study is also developing to find ways to enhance various
malignancies treatment [9,10].
Adipose-Derived Mesenchymal Stem Cells (AD-MSCs) were in
use as part of the fat grafting technique first defined by Coleman
in 1997 long before their characterisation, and it is the most com-
mon procedure in post-oncological breast reconstruction [11].
Various studies by Gentile et al. [12,13] demonstrated that the Fat
graft enhanced with adipose-derived stem cells (FG-e-ASCs) leads
to increased survival of a fat graft in breast hypoplasia patients.
FG-e-ASCs may enhance the preservation of fat grafts by increas-
ing vasculature and through secreting growth factors that pro-
mote fat survival. AD-MSCs are located in the Stromal Vascular
Fraction (SVF) of adipose tissue, which has a heterogeneous col-
lection of mesenchymal cells [14]. AD-MSCs have some benefits as
opposed to other MSCs such as higher proliferative ability, slower
doubling time, and senescence in vitro. They are harvested by
non-invasive methods and can produce a higher cell density than
cord-blood MSCs and bone marrow MSCs [11]. In the last few
years, in addition to the potential of AD-MSCs in regenerative sur-
gery, their role has been examined in promoting tumour develop-
ment, metastatic potential, and invasiveness across different
CONTACT Mohsen Safaei mohsensafayi@yahoo.com, st-safaei.m@skums.ac.ir Department of Medical Biotechnology, School of Advanced Technologies,
Shahrekord University of Medical Sciences, Shahrekord, Iran
ß2020 Informa UK Limited, trading as Taylor & Francis Group
JOURNAL OF DRUG TARGETING
https://doi.org/10.1080/1061186X.2020.1775842
pathways. The definition of a ‘double-edged sword’for MSCs is
due to the simultaneous existence of harmful and favourable
aspects of this cell in cancer [15].
Genetic modification of MSCs is efficient and provides long-
term gene expression without changing their MSC phenotype.
According to these properties, MSCs can deliver anti-cancer agents
to tumours applying specifically as cellular vehicles. So far, MSCs
genetically modified for loading with chemotherapeutic drugs or
drug-loaded nanoparticles. In this regard, oncolytic viruses and
MSC-derived membrane microvesicles (MVs) are employed as
promising carriers in tumour-specific targeting within the antitu-
mor agent delivery. This approach can improve the accumulation
of the suitable concentration of antitumor factors at tumour sites,
especially for solid tumours and tumours that are not often
accessible directly [8].
Mesenchymal stem cells and some of its features
MSCs are widely identified by the self-renewal ability and plastic
adherence, and these cells can be isolated and identified from
many tissues including, bone marrow, dermal tissue, adipose tis-
sue, amniotic fluid, intervertebral disc, different dental tissues,
cord blood, and human placenta [16]. MSC surface markers are
positive for CD29, CD44, CD73, CD90 and CD105, and negative for
CD14, CD34, CD45, and human leukocyte antigen (HLA)-DR. Long-
term cultured human mesenchymal stem cells (hMSCs) have con-
fronted with no severe abnormality in the specific media.
Immunomodulatory characteristics of MSCs caused secretion of
cytokines and immune receptors and provided the regulation of
microenvironment in host tissue [17]. A clinical study of cellular
therapy also necessitates determining MSC immunomodulatory
properties. Accordingly, host compatibility and MSC incorporation
are significantly concerned recently for transplantation and cell
therapy. Co-stimulatory molecules, including CD40, CD80, and
CD86, along with the weak expression of MHC-I and MHC-II defi-
ciency, debilitate MSCs in providing a remarkable alloreactivity,
which these properties protect MSCs from the lysis induced by
natural killer (NK) cells. The reduced response of MSC therapy may
be due to the enhanced alteration of T-helper 2 (Th2) (T helper
cells) response to Th1 cellular immune response which presum-
ably diminish autoimmune disease response through modulation
of interferon (IFN)-cand interleukin IL-4 levels in effector T-
cells [18,19].
Cell-based therapies challenge homing as the cell transfer pro-
cess towards the site of injury. Multipotent MSCs support immu-
nomodulation and homeostasis by migrating towards inflamed or
injured tissue in response to various bioactive molecules, cyto-
kines, chemokines, and growth factors. Tumours similar to the
injury site, have recruited MSCs in their tumour microenvironment
(TME) by producing endocrine and paracrine signals that seem
like a ‘wound that never heals’[20]. MSC migration can be con-
ducted influentially under the effect of matrix metalloproteases
(MMPs). Such migration would also be promoted by using inflam-
matory cytokines, such as TNF-a, TGF-1 b, and IL-1b, through upre-
gulating MMP levels. Many adhesion molecules and receptors,
which involve in the MSC migration process, are expressed by this
stem cell, particularly with the participation of the chemokine
receptor type 4 (CXCR4) and its binding protein stromal-derived
factor 1-a(SDF-1a)[21,22].
Toll-like receptors (TLRs) are seemed to influence MSCs and
their immunomodulation contribution; TLRs respond to so-called
danger signals obtained from molecules that produced by tissue
injury or also microbial invasion (including dsRNA, LPS, endotoxin,
and heat shock proteins). Innate immune effector cells were inves-
tigated to express a number of about 10 human TLRs [23].
Waterman et al. suggested the MSC polarisation based on TLR sig-
nalling, which can be represented as two functionally different
MSC1 and MSC2 when stimulating human MSCs derived from
bone marrow cells with TLR4 and TLR3, respectively. Although
antitumor effects represented by MSC1 cells, tumour growth, and
metastasis have been promoted by MSC2 cells, in this regard, the
enhancement of TLR3 and TLR4 expression in the breast tumour
epithelium was proved to be related to an enhanced risk of dis-
ease relapse [24]. A wide variety of studies have provided evi-
dence of diverse degrees of potency for MSCs, often identified as
‘paracrine’effects. These effects are observed when cells release
stimulating factors at many potential levels for tissue recovery
processes such as endogenous stem/progenitor cells stimulation,
extracellular matrix remodelling, suppression of vulnerable cells
apoptosis, and stimulation of new blood vessel formation [25].
In terms of in vitro differentiation potential, hMSCs can be dif-
ferentiated into all three ectoderm, endoderm, and mesoderm lin-
eages with various diverse by initiating lineage differentiation
through providing proper growth and media supplements. MSCs
can favourably treat inflammatory, autoimmune, and chronic dis-
orders with regards to their characteristics such as multilineage
potential, immunoregulatory effects, homing ability, and ability to
secrete anti-inflammatory molecules [17]. Potentially, MSCs have
been validated to be appropriate candidates in gene therapy of
some diseases such as cancer. Interestingly, MSCs’innate tropism
has caused an efficient migration to malignant sites, specifically
for the cellular delivery of antitumor agents such as IFNs, cyto-
kines, or prodrugs [26]. For the reasons described above and in
the following, we believe that MSCs could have an influential role
in cancer treatments, including breast cancer in the future
(Table 1).
MSCs and breast cancer: a double-edged sword
Nowadays, MSCs have become one of the most remarkable tools
for tumour treatment because of their specific features, i.e. a ten-
dency for tumour cells. The responses of these cells would be
applied through their secretion [39]. Although MSCs may lead to
negative consequences in cancer progression or metastasis inhib-
ition [40,41], the Secretion of MSCs may lead to various effects
and activities. Also, MSC can migrate into injured sites and reform
the damaged sites via secretome. Additionally, since secretome
helps MSCs to sense the inflammatory response, it would be vital
in investigating MSCs’antitumor properties [42,43].
It is believed that cancer treatment with MSCs would be a dou-
ble-edged sword because many reports show that tumour pro-
gression can be triggered by MSCs [44]. Owing to complex
responses of MSCs to tumour cells with various mechanisms, they
should be necessarily identified before considering clinical applica-
tions [45]. Although it has been shown that paracrine and endo-
crine signalings are the cause of MSCs migration to tumour sites,
they might also have anti- and pro-tumorigenic properties, as
investigated in several studies. Tumour progression activities of
MSCs were proved to be supported by tumour proliferation stimu-
lation, angiogenesis, metastasis, motility, drug resistance, cancer
stem cells (CSCs) generation, tissue invasion, and epithelial-to-
mesenchymal transition (EMT). On the other hand, some papers
represented MSCs’inhibitory effects on the cancer progression
through suppressing signalling pathways, apoptosis induction, ini-
tiating cell-cycle arrest, and enhancing monocytes and granulo-
cytes infiltration [3,46–49].
2 R. HEIDARI ET AL.
Table 1. Engineered mesenchymal stem cell MSCs used in the models of breast cancer.
Type Mechanism Factor and Function Vector Tumour model Effect on tumour References
Genetic modification
of MSCs
Gene overexpression TRAIL: induces apoptosis Lentiviral vector Nude mice LVss Subcutaneous
(breast) Metastasis (breast)
A reduction in tumour growth
and metastases
Loebinger et al. [27]
IFN-b: induces differentiation Lentiviral vector Mouse models Syngeneic
Tumour Model
A significant reduction in
tumour growth
and Metastasis
Ling et al. [28]
IL-18: reduces tumorigenesis,
induces apoptosis
Lentiviral vector MCF-7 and HCC1937 cells A significant reduction in
proliferation, migration, and
invasion of the cancer cells
Liu et al. [29]
IL-12: anticancer Lentiviral vector 4T1 breast cancer cells in vivo A reduction of tumour
progression in mice
Eliopoulos et al. [30]
Oncolytic virus Destroy tumours by viral
replication
Recombinant adenovirus
serotype 5
Metastasis breast cancer A significant reduction in
tumour growth
Stoff-Khalili et al. [32]
Orthotopic breast, lung,
ovarian cancer.
Enhanced the survival of
tumour-bearing mice
Hakkarainen et al. [33]
suicide gene Immunoapoptotin e23sFv-Fdt-
tBid: Induces apoptosis
Lentiviral vector Mouse models of orthotopic
and metastatic
breast cancer
Improved local accumulation
of engineered MSCs in the
tumour site. Improved anti-
tumour efficacy
Cai et al. [34]
modified MSC-derived
exosomes
suicide gene CYP2B6TM-RED: induces
apoptosis in present CPA
Lentiviral vector MDA-MB-231 cell line Induce of tumour cell death Altanerova et al. [35]
Gene overexpression miR-379: tumour suppressor Lentiviral vector Metastatic breast cancer
(in vivo & in vitro)
A reduction in tumour growth
and metastases
O’Brien et al. [36]
nanodrug-loaded MSC DOX-LDGI Nanoparticle
loaded MSC
Doxorubicin: induces apoptosis
gold nanorods: light-
responsive
iron oxide: induce CXCR4
upregulation on the MSCs
Nanoparticle Triple-negative breast
cancer (TNBC)
Enhanced accumulation of
nanoparticles in the tumour
Xu et al. [37]
DOX-polymer conjugates
loaded MSC
Doxorubicin: induces apoptosis Nanoparticle Pulmonary metastasis from
breast cancer
A reduction in tumour growth
and metastases
Yao et al. [38]
JOURNAL OF DRUG TARGETING 3
Some studies indicated that the use of MSCs for breast cancer
treatment could be lead to contradictory results and tumour-sup-
pressive effects (Table 2). In contrast, some others exhibited their
tumour-promoting effects (Table 3). In this regard, Ullah et al.
showed that MSCs participate in breast cancer chemoresistance
via a CD9 dependent mechanism. They produced a new hybrid
cell-contained tumour (DP-HCC1806: BMMSCs) and after isolating
new hybrid cells from harvested tumours, was used for injection
into the mammary fat pad of NOD/SCID mice. They also produced
xenograft tumours being smaller in size with resistance towards
chemotherapy drugs (e.g. 5-fluorouracil and doxorubicin [DOX]) in
comparison with tumours obtained only from HCC1806 cells [3]. It
has been indicated that hMSCs from bone marrow cells are cap-
able of increasing the tumour volume, enhancing the oestrogen
sensitivity, promoting hormone-independent tumour growth, and
changing progesterone receptor expression. Moreover, hMSC rep-
resented more oestrogen response near to fourfold compared to
controls. According to the reports of Dittmer et al., hMSCs
involved in cell–cell adhesion while increasing the migration of
breast cancer cells through disintegrin and metalloprotease-10
Table 2. The efficacy of mesenchymal stem cell (MSCs) in the suppression of breast cancer.
Tumour development/type Effect on the tumour Mechanism of effect Reference
MDA-MB-231 in vitro Suppressing Inhibit cancer cell growth With effect on cell morphology, proliferation, cycle,
gene expression, migration, and cell death
Gauthaman et al. [50]
In vivo (mice) using MDA-MB-231 Suppressing Suppress breast cancer tumorigenesis through direct cell-cell contact and
internalisation
Chao et al. [51]
MDA-MB-231 in vitro Suppressing A co-culture model of breast cancer and bone marrow-derived human
mesenchymal stem (HMSC-bm) cells inhibited the growth of breast cancer
cells and entered the bone marrow at early stages. Through Down-
regulation of NK1R-Tr.
Zhou et al. [52]
MDA-MB-231 and T47D in vitro Suppressing Mesenchymal stem cells inhibit breast cancer cell migration and invasion
through secretion of tissue inhibitor of metalloproteinase-1 and -2.
Clarke et al. [53]
In vivo (mice) using MDA-MB-231 Suppressing HUC-MSCs can inhibit breast cancer progression by inducing tumour cell
death and suppressing angiogenesis
Leng et al. [42]
N-Nitroso-N-methyl urea-
induced tumours
Suppressing Placental MSCs effect on the growth of primary tumours and in the
development of new tumours in a preclinical model of mammary tumours
Vegh et al. [31]
MDA-MB-231 Suppressing Intravenous injection of CRAd loaded hMSCs into mice with established MDA-
MB-231 pulmonary metastatic disease homed to the tumour site and led
to extended mouse survival compared to mice treated with CRAd alone.
Stoff-Khalili et al. [32]
MDA-MB-231 and MCF-7 Suppressing HUC-MSCs inhibited the growth of breast cancer cell lines, and primary breast
cancer stem cells (CSCs) in a dose-dependent manner via cell cycle arrest
and induction of tumour cell apoptosis
Ma et al. [54]
MCF-7 cells Suppressing Co-culture studies showed that MSCs had cytotoxic effects on MCF-7 cells Mirabdollahi et al. [39]
Table 3. The efficacy of mesenchymal stem cell (MSCs) in the promotion of breast cancer.
Tumour development/type
Effect on
the tumour Mechanism of effect Reference
DP-HCC1806: BMMSCs a new
hybrid cell
promoting Resistance to chemotherapy drugs Ullah et al. [3]
MCF-7 cell line promoting Increase tumour volume, enhance oestrogen sensitivity, promote hormone-
independent tumour growth, and alter progesterone receptor expression
Rhodes et al. [56]
MCF-7 cell line promoting Interfere with cell–cell adhesion and enhance migration of breast cancer cells by
activating ADAM10
Dittmer et al. [55]
MCF-7 cell line promoting MSC derived exosomes promoted migration of the breast cancer cell line. Lin et al. [57]
MCF7 cells- in vivo promoting Promote cancer proliferation and enhance mammosphere formation partially via
EGF/EGFR/Akt pathway
Yan et al. [58]
MDA-MB-231 MCF-7, T47D, P815
murine mastocytoma, and K562
myelogenous leukaemia
promoting MSCs Protect Breast Cancer Cells through Regulatory T Cells (Tregs) Patel et al. [59]
MCF-7, MDA-MB-231, HMLR, and
MDAMB- 435
promoting The breast cancer cells stimulate the chemokine CCL5 (also called RANTES) from
MSCs, which then acts in a paracrine fashion on the cancer cells to enhance
their motility, invasion, and metastasis
Karnoub et al. [60]
MDA-MB-231 and MCF-7 promoting HUC-MSC extracellular vesicles significantly enhanced the proliferation, migration,
and invasion of the cells in vitro through the activation of the ERK pathway
and promoting the epithelial-mesenchymal transition (EMT) of the breast
cancer cells
Zhou et al. [61]
breast cancer cells promoting The mechanical stimulus of ECM stiffness and the chemical cue of TGFbboth play
a critical role in the activation of MSCs and the promotion of breast cancer
progression
Ishihara et al. [62]
Two independent syngeneic FVB
mammary tumour cell lines, PyMT-
Luc and 17L3C-Luc
promoting Mesenchymal Stem Cells promote mammary cancer cell migration in vitro via the
CXCR2 receptor
Halpern et al. [63]
MCF-7 cell line promoting The hMSCs promote proliferation and migration on the ER-positive human breast
carcinoma cells mediated through ER-SDF-1/CXCR4 crosstalk
Rhodes
et al. [64]
4 R. HEIDARI ET AL.
(ADAM10) activation, which cleaves E-cadherin. Currently, E-cad-
herin is recognised as an essential protein participating in cell-cell
adhesion of MCF-7 spheroids [55,56].
Effects of human umbilical cord mesenchymal stem cell-derived
extracellular vesicles (hUC-MSC-EVs) have been investigated on
migration, proliferation, and invasion of human breast cancer cells.
These studies have reported the successful generation and identi-
fication of both hUC-MSCs and hUC-MSC-EVs. Based on the
results, treatment of human breast cancer cell lines, (MDA-MB-231
and MCF-7), within a medium containing hUC-MSC-EVs, has sub-
stantially increased the migration, proliferation, and invasion of
the cells in vitro through the ERK pathway activation. This men-
tioned medium has reduced E-cadherin expression and increased
N-cadherin expression, leading to the EMT promotion in breast
cancer cells [61].
In vitro, umbilical cord Wharton’s Jelly-derived MSC-conditioned
medium has an inhibitory effect on breast adenocarcinoma, osteo-
sarcoma cell migration, and ovarian carcinoma by inducing apop-
tosis and suppressing angiogenesis [50]. The effect of hUMSCs
was investigated on CSCs in vitro by Ma et al. The results indi-
cated that the growth inhibition of hUCMSCs in breast cancer cell
lines, including MCF-7 and MDA-MB-231, as well as primary breast
CSCs, are dose-dependently. This mechanism is presumably associ-
ated with inducing tumour cell apoptosis and cell-cycle arrest
[54]. Co-culture studies also suggested cytotoxic effects of MSCs
and their secretomes on MCF-7 cells; also, these cytotoxic effects
were dose-dependently mediated with apoptosis induction with
an IC50 of 10 mg/mL [39].
A dose-dependent effect was suggested for developing these
different manners; hMSCs presumably prevent tumour growth at a
lower number of tumour cells, while promoting the tumour
growth at higher numbers of cells [55]. The interaction between
stem cells and cancer cells can be obtained directly or indirectly.
Therefore, the MSC migration towards the site of inflammation
develops a cellular interaction, which arises from both directly
(through a gap junction, membrane receptors, and nano-tubes)
and indirectly (via soluble structures and factors such as cytokines
and growth factors). The action of secreting endocrine and para-
crine signals can trigger MSCs to stimulate nearby cells with pro-
and/or anti-cancer activities. Sequentially, cancer cells can stimu-
late MSCs until developing abnormal tumour-associated pheno-
types [65]. The use of different tissue sources, the variability of an
individual donor, and injection times for MSCs in any experiment
may affect this discrepancy [42,50–53]. There are numerous path-
ways for the interaction between MSCs and tumour cells, which
potentially support or suppress tumour growth. Moreover, incon-
sistent reports on investigating the interaction of MSCs and
tumours have proposed the heterogeneity factor in MSCs to be
likely an influential agent. So far, the investigation of over 1000
MSC-treated patients showed no evidence of tumour formation
for many indications [66].
The therapeutic application of MSCs for cancer may be a prob-
lem by contradictory results describing both anti- and pro-tumour
effects in preclinical studies. An explanation for the conflicting
reported data showing that presumably a number of factors
affecting the interaction between MSCs and cancer cells, including
cancer type, their origin, pre-treatments, and various experimental
conditions that may interfere [15]. Nevertheless, the latest MSC-
based therapies bring new hope to cancer patients by showing
highly effective anti-cancer treatments in a personalised manner
and also, with the help of genetic engineering techniques.
Genetic engineering of MSCs is being employed as a means to
solve some of these problems and improve the antitumor proper-
ties of these cells.
The therapeutic potential of engineered MSCs in
breast cancer
Genetic modification of MSCs
Genetic modification of MSCs emphasises introducing different
beneficial genes with antitumor properties, such as tumour-sup-
pressed genes, suicide gene/enzyme prodrug systems, as well as
interleukins and proapoptotic proteins (Figure 1). Genetically
modified MSCs were recruited to regulating peptide and protein
expression of tumour cells’in the tissue environment [67,68]. The
successful transfection of MSCs relies on transfection methods.
Physical and chemical methods (nonviral), as well as viral vectors,
are used for the delivery of beneficial genes to MSCs. Non-viral
methods, such as electroporation, nucleofection, sonotransfection,
as well as cationic polymers and liposomes, have low immunogen-
icity and high packaging capacity for genetic material. However,
the use of them is limited because of their low efficiency for trans-
fection, transient gene expression, their possibility of disrupting
cellular and nuclear membranes, and chemical agents-induced
toxicity. Because of the limitations and low transfection ability of
nonviral methods, viral vectors, including retroviruses, lentiviruses,
adeno-associated viruses, adenoviruses, and baculoviruses, were
used to improve the delivery of genes. Albeit high transfection
ability and stable gene expression for viral vectors, clinical applica-
tions of them are limited because of oncogenic transformation
and induction of immune responses [67]. The CRISPR/Cas system
is a new strategy for introducing the genes of interest in MSCs
with high efficiency, which these novel methods are also being
used to manipulate MSCs genetically [69,70].
Amara et al. introduced cellular vehicles’delivery based on
MSCs for the suicide gene CYP2B6TM-RED. MSC transduction was
conducted with lentiviral particles, and ex vivo genetically engi-
neered MSCs express CYP2B6TM-RED stably. Obtained results
showed that CYP2B6TM-RED-MSCs leads to bioactivation of cyclo-
phosphamide (CPA) and spoil adjacent tumour cells bystander
effect. Expression of CYP2B6TM-RED with intratumoral injections
of MSCs to the mice in the presence of CPA has totally extermi-
nated tumours in 33% of samples without the risk of recurrence
within six months after the treatment. Thus, the combination of
tMSCs-CYP2B6TM-RED and CPA can be considered as a promising
treatment for solid tumours like breast cancer [71].
Moreover, Cai et al. developed a dual-targeting plan for the
incorporation of the tumour-tropic MSC delivery with the immu-
noapoptotin and HER2. For clinical usage, anti-HER2 antibodies
were employed because of HER2 overexpression in many types of
tumours such as breast cancer. While intact monoclonal antibod-
ies and antibody–drug conjugates accompanied by limitations in
clinical application, some studies have proposed the use of anti-
HER2 single-chain antibodies (scFv) for preclinical procedures.
Immunoapoptotins is an scFv-fused therapeutic with the induction
of apoptosis in tumour cells. Immunoapoptotin-engineered MSCs
were systematically administered and confirmed the local accumu-
lation of which in syngeneic mouse models reconstituted with
human HER2 having metastatic and orthotopic breast cancer. The
immunoapoptotin secretion from MSCs has applied a more signifi-
cant antitumor effect in comparison to the purified immunoapop-
totins. Herein, immunoapoptotin-armored MSCs provide a
motivational design of dual-targeting delivery systems for a wide
variety of cancer types [34].
JOURNAL OF DRUG TARGETING 5
Ling et al. investigated engineered MSCs, which suppress
breast cancer growth through IFN-bsecretion besides dramatic
reduction in metastases in hepatic and pulmonary tumours by
inactivating Stat3. The inefficiency of using recombinant IFN-bfor
cancer treatment would be due to its short half-life, while MSCs
have specifically been engrafted into breast cancer sites of fully
immunocompetent mice, produce high levels of IFN-bat tumour
sites to influence tumour growth before degradation of this pro-
tein. Significant concentrations of IFN-binduce apoptosis in cancer
cell lines through inhibition of Stat3 signalling [28]. IL-18 is a cyto-
kine with multiple functions (such as inducing the Th1-type cyto-
kines production), which is involved in the antitumor activity of
cytotoxic T-cell. After the lentivirus transduction of MSCs, MSCs
secreted IL-18 protein stably. Genetically manipulated MSCs repre-
sented in vitro suppression in growth, invasion, and migration in
HCC1937 and MCF-7 cells [29]. Primary murine MSCs were effi-
ciently modified by lentiviral systems along with being incorpo-
rated into collagen-based matrices for the IL-12 local delivery
through the generation of neo-organoids. IL-12 gene-modified
MSCs with local action on 4T1 breast cancer cells showed slower
tumour progression in mice [30].
Modified MSC-derived exosomes
Exosomes are released by various cells. They are extracellular
vesicles (EVs) and influential in the cross-talk between cells with a
size of 40–100 nm. Exosomes contain biologically active proteins
and genetic materials, such as mRNA and microRNA (Figure 1).
The use of MSCs-derived exosomes has been a potentially curative
therapy approach in targeting tumours because of their tumour-
tropic behaviour [72]. The therapeutic effect of yeast cytosine
deaminase-uracil phosphoribosyltransferase suicide fusion gene
expression (yCD-UPRT-MSCs) released exosomes was proved to be
positive in human breast adenocarcinoma cells MDA-MB-231. The
retrovirus transduction of MSCs was also performed for the yCD-
UPRT MSCs. Engineered MSC-produced exosomes contain the sui-
cide gene’s mRNA, are released in the conditional medium.
Tumour cell growth was inhibited when cell line treated with con-
ditional medium containing exosome in the presence of 5-fluoro-
cytosine (5-FC). Through an exosome’s dose-dependent manner,
the death of tumour cells happens as a result of the prodrug 5-FC
intracellular conversion to 5-fluorouracil by endocytosed exosomes
[35]. In this regard, Brien et al. reported engineered MSC-derived
exosomes with a tumour suppressor microRNA. Exosomes
secreted from engineered MSCs, are enriched by miR-379. Cell-
free exosomes were systematically administered, representing
therapeutic impacts for the in vivo therapy of metastatic breast
cancer [36].
MSCs as oncolytic virus delivery vehicles
Internalizing oncolytic virus to MSCs was examined being a safe
delivery method of oncolytic viruses onto the tumour microenvir-
onment. For the oncolytic virus-loaded MSCs therapy, genetically
modified oncolytic viruses are replicated in MSCs and MSCs
released viral particles into the neighbouring tumour. Viral par-
ticles spread within a tumour microenvironment and eliminate the
cell tumour through direct oncolysis of cells, as well as disrupting
the tumour microenvironment without causing damage to normal
tissues (Figure 1)[73]. Oncolytic virus-loaded MSCs were consid-
ered in the lung model of breast cancer metastasis. The design of
conditionally replicative adenovirus-based agents (CRAds) cause
Figure 1. Engineered mesenchymal stem cells (MSCs) and tumour cells interaction as an MSC-based approach for cancer therapy. Interestingly, MSCs can accumulate
at the site of tumours. Genetic modification of MSCs is aimed towards enhancing different cellular processes such as oncolytic viruses, tumour suppressor, immune-
modulating agents, nanodrugs, and miRNAs and other non-coding RNAs (regulators of gene expression). Figure created with BioRender.
6 R. HEIDARI ET AL.
an enhancement in tumour infectivity and specificity in providing
CAR-independent tropism and CRAd E1A gene, under tumour-
selective promoter CXCR4, via incorporating the human adeno-
virus serotype 3 knob domain (Ad5/3). For a SCID mouse xeno-
graft model (MDA-MB-231 breast cancer metastases in the lungs),
CRAd-loaded hMSCs were intravenously injected to the lungs,
which reduced the tumour burden. The hMSC-based viral delivery
has caused an enhancement in the oncolytic effect, as well as
increasing the survival of tumour-bearing animals while suppress-
ing the growth of pulmonary metastases. These results confirmed
that hMSCs might be an effective carrier for CRAds delivery to
many distant tumours, i.e. metastatic breast cancer [32]. The
obstacles of using serotype 5-based adenoviruses intravenously in
cancer gene therapy would be due to hepatic uptake by Kupffer
with varying low expression patterns of receptors in the tumour
cell. To improve the protection of oncolytic adenoviruses, thera-
peutic approaches were achieved via MSCs based on various cells.
Modified adenoviruses can bind to alternative receptors with high
expression on cancer cells to enhance specificity and/or efficacy.
Hakkarainen et al. suggested that MSC infection might be con-
ducted through replicating designed capsid-modified adenovi-
ruses. Efficacy of virus-loaded MSCs has been investigated in
breast cancer and ortho-topic lung tumours through tumour-hom-
ing ability, biodistribution, and tumour-killing. MSCs’infectivity
was also enhanced significantly via virus targeting into integrins
and heparan sulphate proteoglycan. In vivo, intravenously adminis-
tered MSCs demonstrated primarily lungs’homing, and the virus
releases into the progressed orthotopic lung and breast tumours,
resulting in increased survival and therapeutic efficacy. Based on
the results, MSCs have been suggested to be a potent tool for the
improvement of bioavailability and oncolytic virus delivery into
tumours for the cases of human trials [33].
MSCs as anti-cancer drug delivery vehicles
Nanotechnology has exhibited high potential for the detection,
prevention, and treatment of cancer. An excellent strategy for
drug delivery systems via nanoparticulate is Tumour-targeted
delivery, enabling that therapeutic factors to selectively targeting
tumour cells/tissues and decreasing toxicity to normal cells
[74,75]. Nanotechnology recently proposes new solutions in cancer
therapy via providing the engineered nanomedicines and can
resolve the problems of drug instability, solubility, and low circula-
tion half-life, and can co-deliver various drugs, particularly to the
target site [74]. To overcome these purposes, targeted drug deliv-
ery employing nanoengineered cells with cancer homing ability
has emerged as a useful strategy. Due to the tumour tropism,
integration in the tumour stroma, and their immune-excellent
nature, MSCs can be utilised as a delivery vehicle for therapeutic
and imaging factors, such as drug-conjugated nanoparticles [76].
Drug resistance is one of the main obstacles in cancer chemo-
therapy resulting from long-term drug use due to insufficient
tumour selectivity of anti-cancer drugs (Figure 1). MSCs, as anti-can-
cer drug delivery vehicles, could open new ways of therapeutic
drugs’targeted delivery to tumour sites directly, and it is because
of some features such as tropism to the tumour site and relative
resistance to cytotoxic chemotherapeutic drugs [77]. The paclitaxel-
primed cells are obtained, when MSCs are exposed to paclitaxel
drug causing drug incorporation in MSCs. The anti-cancer effects of
these cells were exhibited in a dose-dependent manner [78].
However, MSCs have limitations to be chemotherapeutic car-
riers because drug efflux transporters may be overexpressed, e.g.
P-glycoprotein (Pgp). Currently, nanotechnology garners attention
to improve cell therapeutic applications with the aid of MSCs. The
utilisation of a nanoparticle for loading of chemotherapy drugs
effectively protects MSCs from direct interaction with toxic drugs
and formation efflux transporters on MSCs [78,79].
MSCs, loaded with a light-responsive plasmonic-magnetic
hybrid nanoparticle, were employed for the treatment of triple-
negative breast cancer (TNBC), which efficiently caused the cancer
cell growth inhibition and active accumulation, as well as con-
trolled drug release improvement in tumour sites. TNBC was char-
acterised by the lack of overexpression in oestrogen and
progesterone receptors, as well as HER-2. The LDGI nanoparticle
contains lipids, DOX, gold nanorods, and iron oxide nanocluster is
biocompatible that can be uptaken into the stem cells efficiently
while maintaining cellular functions. Accordingly, iron oxide nano-
particles induced CXCR4 upregulation on the MSCs for in vitro and
in vivo migration of cancer cells.
Drug release happened upon light irradiation and disassembly
of hybrid nanostructures in stem cells. Light irradiation induces
secretion of microvesicles containing LDGI from MSCs, which
results in the facilitated entrance of LDGI to cancer cells.
Therefore, the tumour homing ability of MSCs-LDGI was confirmed
after systematic delivery by the intensified accumulation of nano-
particles into the tumour tissue [37].
Yao et al. established an innovative delivery system of nano
drug-loaded MSCs for the systematic treatment of pulmonary
metastasis from breast cancer. Loading DOX-polymer conjugates
in MSC, which reserve MSCs’stemness and tumour-tropic poten-
tial with a large number of DOX conjugates and excellent stability
of drug loading. In vivo studies indicated that loaded MSCs were
mainly confirmed to be located and stayed in the lung for a long
time at the situation of the foci of metastatic tumours, which sig-
nificantly inhibit tumour growth [38].
One of the limitations of Photodynamic therapy (PDT) for can-
cer treatment is the difficulty in the accumulation of photosensi-
tizer (PS) in the tumours. Cao et al. used porous hollow silica
nanoparticles (SiO2 NPs) for loading non-toxic PS, purpurin-18
(Pp-18) into MSCs in MCF-7 breast cancer cells line and in vivo
breast cancer cells PDT. Silica nanoparticles are a naturally porous
biocompatible material for loading Pp-18 into the pores. Pp-18 is
a PS with low cytotoxicity in the absence of light, and it may be
activated by a red light with greater tissue penetration depth
than other visible lights. The result was confirmed that the tumour
affinity of the MSCs did not change after PS-SiO2 NPs uptake by
MSCs and MSCs retain in the tumours. The irradiation of red light
in the tumour site generates cytotoxic reactive oxygen species
(ROS), the increase of ROS level is key for inhibiting tumour
growth in PDT [80].
Saulite et al. established nanoengineered MSCs for delivery of
the quantum dot (QD) as an imaging agent to the metastatic cell
line MDA-MD-231 and non-metastatic cell line MCF7 of breast can-
cer in 3 D co-culture model. 3 D culture model of MSCs was cre-
ated after MSC cell seeding on poly (2-hydroxethyl methacrylate)
(poly HEMA)-coated plates. QDs uptake by MSCs in serum-free
conditions efficiently and released from MSCs in a 3 D co-culture.
QD uptake efficiently by MDA-MB-231 compared with MCF7 cells.
These results suggested, nanoengineered MSCs could be consid-
ered as vehicles for the nanoparticle delivery to metastatic breast
cancer cells [76].
Conclusion and future perspectives
MSCs have a suppressive or promotive effect on the development
of breast cancer (Tables 2 and 3). The use of different tissue
JOURNAL OF DRUG TARGETING 7
sources, various individual donors, and MSCs injection time in
each experiment and on the other hand factors such as hetero-
geneity, cancer type, pre-treatments, and different experimental
conditions may affect this discrepancy. MSCs are examined in sev-
eral experimental studies representing the anti-oncogenic poten-
tial of MSCs (Table 1) when loaded with chemotherapeutic drugs
and/or modified with therapeutic genes. Hence, the therapeutic
agent delivery approach would be promising in delivering MSCs
to the tumour sites. MSC-based delivery systems, because of
intrinsic tropism at tumour niche, have been considered as an
attractive research option to improve targeted drug delivery in
cancer; however, there are still challenges in using these cells as
vesicles. The role of MSC in cancer progression or suppression is a
controversial issue and needs further investigation. Issues such as
viral transfection immunity, incompetence non-viral methods, and
a suitable dose of therapeutic agents for delivery to cancer cells
are limitations that must be answered. Currently, the treatment of
breast cancer is puzzling because of chemotherapy resistance, par-
ticularly in some subtypes such as ER-negative cancers and in
metastatic stages. The MSCs indicate a high potential in the ther-
apy of breast cancer, as they constitute an excellent vehicle for
the transfer of anti-cancer therapeutics to the tumour sites; also,
they have high abilities to repair tissue.
MSCs have been tested in pre-clinical models as vectors for
breast cancer therapies such as anti-cancer drug delivery, drug-
loaded exosomes, oncolytic virus delivery vehicles, nanoparticles,
etc. Other than that, more clinical trials are necessary to assay the
efficacy and safety of such new strategies. It seems that the inter-
action between MSCs and cancer cells to improve the clinical
safety of MSC-based therapeutic approaches should be well
known. In the future, engineering MSCs to selectively deliver the
anti-angiogenic molecules and circular RNA (circRNA) could be
promising in breast cancer.
Ethical approval
This article does not contain any studies with human participants
or animals performed by any of the authors.
Author contributions
All authors collected and analysed relevant literature, then drafted
the manuscript, and critically revised the manuscript for content,
finally read and approved the final manuscript.
Disclosure statement
The authors report that there are no conflicts of interest.
ORCID
Razieh Heidari http://orcid.org/0000-0002-8085-8386
Neda Gholamian Dehkordi http://orcid.org/0000-0003-
1033-5237
Roohollah Mohseni http://orcid.org/0000-0001-9759-0876
Mohsen Safaei http://orcid.org/0000-0003-1504-5490
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