Recent advances in regenerative medicine strategies for cancer treatment

Abstract

Cancer stands as one of the most leading causes of death worldwide, while one of the most significant challenges in treating it is revealing novel alternatives to predict, diagnose, and eradicate tumor cell growth. Although various methods, such as surgery, chemotherapy, and radiation therapy, are used today to treat cancer, its mortality rate is still high due to the numerous shortcomings of each approach. Regenerative medicine field, including tissue engineering, cell therapy, gene therapy, participate in cancer treatment and development of cancer models to improve the understanding of cancer biology. The final intention is to convey fundamental and laboratory research to effective clinical treatments, from the bench to the bedside. Proper interpretation of research attempts helps to lessen the burden of treatment and illness for patients. The purpose of this review is to investigate the role of regenerative medicine in accelerating and improving cancer treatment. This study examines the capabilities of regenerative medicine in providing novel cancer treatments and the effectiveness of these treatments to clarify this path as much as possible and promote advanced future research in this field.

Full text

Biomedicine & Pharmacotherapy 141 (2021) 111875
0753-3322/© 2021 Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Review
Recent advances in regenerative medicine strategies for cancer treatment
Vahid Mansouri
a
,
f
, Nima Beheshtizadeh
b
,
c
,
f
,
*
, Maliheh Gharibshahian
d
,
f
, Leila Sabouri
f
,
Mohammad Varzandeh
e
,
f
, Nima Rezaei
g
,
h
,
i
,
**
a
Gene Therapy Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
b
Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Iran
c
School of Engineering, Faculty of Science and Engineering, Macquarie University, Sydney, NSW 2109, Australia
d
Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
e
Department of Materials Engineering, Isfahan University of Technology, Isfahan 84156-83111, Iran
f
Regenerative Medicine group (REMED), Universal Scientic Education and Research Network (USERN), Tehran, Iran
g
Research Center for Immunodeciencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
h
Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
i
Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientic Education and Research Network (USERN), Tehran, Iran
ARTICLE INFO
Keywords:
Cancer treatment
Regenerative medicine
Tissue engineering
Cell therapy
Gene therapy
ABSTRACT
Cancer stands as one of the most leading causes of death worldwide, while one of the most signicant challenges
in treating it is revealing novel alternatives to predict, diagnose, and eradicate tumor cell growth. Although
various methods, such as surgery, chemotherapy, and radiation therapy, are used today to treat cancer, its
mortality rate is still high due to the numerous shortcomings of each approach. Regenerative medicine eld,
including tissue engineering, cell therapy, gene therapy, participate in cancer treatment and development of
cancer models to improve the understanding of cancer biology. The nal intention is to convey fundamental and
laboratory research to effective clinical treatments, from the bench to the bedside. Proper interpretation of
research attempts helps to lessen the burden of treatment and illness for patients. The purpose of this review is to
investigate the role of regenerative medicine in accelerating and improving cancer treatment. This study ex-
amines the capabilities of regenerative medicine in providing novel cancer treatments and the effectiveness of
these treatments to clarify this path as much as possible and promote advanced future research in this eld.
1. Introduction
Regenerative medicine and its sub-disciplines, as emerging elds, try
to address various medical challenges. Regenerative medicine is an
approach to restore normal function and health to the organs and pa-
tients, commonly directed towards utilizing various stem cells. In recent
years, several regenerative approaches were used to ght against can-
cers. Although considering the broad range of other treatments that
could be counted as a subset of regenerative medicine, we encounter
many innovative, FDA-approved products for previously-known incur-
able disorders along with a mass of promising therapeutics in the eld of
cell and gene therapy [1].
Abbreviations: AAVs, Adeno-associated vectors; APC, Antigen-presenting cells; ADA, Adenosine deaminase; CAR T Cell, Chimeric antigen receptor T cells; CAFs,
Cancer-associated broblasts; CSCs, Cancer stem cells; CRISPR, Clustered regularly interspaced short palindromic repeats; CNT, Carbon nanotube; DMD, Deschene
muscular dystrophy; DCs, Dendritic cells; ESCs, Embryonic stem cells; ECM, Extracellular matrix; HA, Hyaluronic acid; HSCs, Hematopoietic stem cells; GVT, Graft-
versus-tumor; ICM, Inner cell mass; iPSCs, Induced pluripotent stem cells; LLC, Lewis lung carcinoma; MMP, Matrix-metalloproteinase; MSCs, Mesenchymal stem
cells; MPLA, Monophosphoryl lipid A; MSR, Mesoporous silica microrods; NK cells, Natural killer cells; NSCs, Neural stem cells; NPs, Nanoparticles; PAD, peripheral
arterial disease; PTT, Photothermal therapy; PDT, Photodynamic therapy; P I:C, Polyinosinic: polycytidylic acid; PAA, Polyacrylamide; PEG, Polyethylene glycol;
PLG, Poly(D,L-lactide-co-glycolide); PCL, Polycaprolactone; PLGA, Poly (lactic-co-glycolic acid); SCID, Severe combined immunodeciency; SMA, Spinal muscular
atrophy; SMN1, Survival motor neuron 1; scFv, Single-chain variable fragment; TME, Tumor microenvironment; TCRs, T-cell receptors; 3D, Three-dimensional; 2D,
Two-dimensional; VEGF, Vascular endothelial growth factor.
* Corresponding author at: Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of
Medical Sciences, Iran.
** Correspondence to: Children’s Medical Center Hospital, Dr. Qarib St, Keshavarz Blvd, Tehran 14194, Iran.
E-mail addresses: N-Beheshtizadeh@Razi.tums.ac.ir, nima.beheshtizadeh@hdr.mq.edu.au (N. Beheshtizadeh), Rezaei_Nima@tums.ac.ir (N. Rezaei).
Contents lists available at ScienceDirect
Biomedicine & Pharmacotherapy
journal homepage: www.elsevier.com/locate/biopha
https://doi.org/10.1016/j.biopha.2021.111875
Received 8 May 2021; Received in revised form 23 June 2021; Accepted 28 June 2021

Biomedicine & Pharmacotherapy 141 (2021) 111875
2
One of these challenges is to provide effective treatments for cancers
with fewer side effects [2]. Increasing our knowledge of the cancer tissue
structure and function makes regenerative medicine scientists more
effective and purposeful in providing treatment alternatives. Technol-
ogies related to cell engineering and cell therapy, as well as scaffolds and
biomaterials, are two major categories that underlie many approaches
[3–5]. Depending on the issue, they can be used separately or in com-
bination to solve the challenge [6,7].
Cancer is one of the most leading causes of death worldwide, and one
of the biggest challenges in treating it is developing better ways to
predict, diagnose, and eradicate tumor cell growth [8–10]. Although
various methods, such as surgery, chemotherapy, and radiation therapy,
are used today to treat cancer, this disease mortality rate is still high due
to the numerous shortcomings of each of these methods [8].
Surgical removal of the tumor is one of the most common methods
used to treat cancer for patients with early stages and small tumors. In
this method, due to vascular invasion, tumor spread and metastasis, and
new tumor formation after tumor resection, subsequent recurrences
occur, which has made this method efcient for only a small number of
patients [11–14].
This method usually requires secondary radiation therapy, which
itself is associated with many problems. Since high doses of radiation
therapy are used to treat cancer, the surrounding healthy cells are also
damaged. Side effects of radiation therapy depend on radiation location
and sometimes continue for several weeks or months after treatment.
Common side effects include fatigue, hair loss, and the possibility of
secondary cancer, dryness, itching, blisters, and other skin problems
[15–18].
Chemotherapy is useful for patients with advanced and metastatic
stages. Most chemotherapy drugs, including Sorafenib, Lenvatinib, and
Regorafenib, have anti-inammatory and anti-proliferative properties
[19]. They increase a patient’s life expectancy and delayed cancer
progression. Since cancer cells grow so fast, the action mechanism of
these drugs is to affect fast-growing cells. The problem with this function
is the effect of chemotherapy drugs on healthy fast-growing cells, such as
hair follicles, oral cells, and cells of the reproductive system. Side effects
of these drugs, such as diarrhea, anorexia, high blood pressure, weight
loss, skin reactions, and hair loss, limit their use [20–23].
Accumulation of cells’ genetic mutations causes them to overgrow
and form tumors [24]. Tumor cells come into close contact with the
stroma, while genetic alteration in these cells causes the stroma to
change, leading to the development of an environment called TME
(tumor microenvironment), which helps cancer survive and progress
[25].
Interactions among tumor cells and stromal cells in various forms,
including cell-cell communication or paracrine and endocrine connec-
tions, cause structural and functional changes that lead to tumor sur-
vival and growth [25,26]. During their continuous expansion and
proliferation, tumor cells reach a stage where they lack oxygen and need
to form a vascular network. Studies show that hypoxia has no role,
although genetic changes caused by tumor cells cause overexpression of
angiogenesis. Nevertheless, angiogenesis occurs early in the develop-
ment of tumors [26].
Tumor cells secrete FGF, which calls broblasts to the site, and in
turn, metaplasia and become tumor and endothelial cells. Tumor-
associated broblasts modify tumor ECM by producing a specic
collagen content [26,27]. Also, tumor cells secrete chemokines, leading
to the accumulation of monocytes, neutrophils, and regulatory lym-
phocytes. This cell inltration in tumors occurs from the early stages of
tumor growth and is inuenced by tumor-secreting factors such as
TGF-B, IL 4, 10, other exosomes, and cytokines. Taken together, this cell
complex with the existing ECM, which is the result of their interactions,
creates a tumor prole, or TME, in-situ [26]. Studies showed that there
are at least six types of TMEs in tumors [24,28]. TME also varies at
various tumor sites, tumor growth stages, and even between different
patients [24].
Attempts to decipher the complexities of TME have led to the
development of new approaches to estimating the specic expression
proles of that type of tumor-associated cells, immune cells, and tumor
stroma. Targeting non-cancerous TME cells without considering the
cancer cells causes the TMEs to rell after treatment [24,29].
The only exception reported is immunotherapy, which includes
checkpoint therapies and has produced dramatic therapeutic effects.
There are several essential points in this treatment method. The rst is a
more understanding of the basis for activating and inhibiting immune
and stromal cells, although we have reached an acceptable under-
standing of T cells. The next item is to use biomarkers-based therapy [24,
30]. Given the high heterogeneity of TME, the development of reliable
biomarkers to guide targeted TME therapies will be essential to achieve
clinical efcacy. Finally, the use of hybrid approaches is recommended.
Despite the signicant and lasting effect of immunotherapy, most
cancer patients do not currently benet from it. It is recognized that
combination therapy is essential for improving the immune response
[24]. Therefore, it is essential to further identify TME as a tool for
developing new approaches to cancer treatment [26].
Among these, one of the most comprehensive approaches to target
therapy is the use of various regenerative medicine approaches,
including targeted drug delivery, anti-metastatic and restorative scaf-
folds, and preclinical modeling for the development of new drugs can be
considered with the concepts of TMEs.
Using different approaches, including gene therapy, cell therapy, and
tissue engineering, regenerative medicine can participate in the treat-
ment of cancer and understanding of cancer biology (Fig. 1). In addition
to the traditional application of tissue engineering scaffolds in encour-
aging the restoration of tissue structure and function of lost tissue due to
the architecture and materials used in them, they play a signicant role
in the development of cancer tissue in our body or as an immune system
adjuvant factor and be effective in modulating the immune system
[31–34].
Generally, research in the regenerative medicine applications in
cancer treatment refers to the multiple major elds, including stem cell
transplantation to recover immune system, production of cancer-specic
T cell from induced pluripotent stem cells (iPSCs), stem cells as vector
carrying therapeutic to tumors, cancer stem cells and vaccines for can-
cers, and cancer microenvironment and tissue engineering [35].
The majority of attempts in regenerative therapy, such as gene
therapy and cell engineering, cell therapy, and tissue engineering scaf-
folds, have reached from the bench to the bedside. Although regenera-
tive medicine suffers from major challenges in cancer treatment, several
clinical trials resulted in the commercialization of approved products
available in the market. Despite all the successes and failures in utilizing
available products, future perspectives, including the vaccination and
Fig. 1. Various approaches in regenerative medicine participate in the treat-
ment of cancer.
V. Mansouri et al.

Biomedicine & Pharmacotherapy 141 (2021) 111875
3
research in microenvironment modication, were widened. Finally, the
goal is to bring fundamental and laboratory research to effective clinical
treatments. Proper interpretation of these researches will help to reduce
the burden of treatment and illness for patients. The purpose of this
review is to investigate the role of regenerative medicine in accelerating
and improving cancer treatment. This study examines the capabilities of
regenerative medicine in providing new cancer treatments and the
effectiveness of these treatments to clarify this path as much as possible
and help advance future research in this eld.
2. Novel advanced therapeutic strategies, based on regenerative
medicine approaches
2.1. Gene therapy and cell engineering
Gene therapy corresponds to transferring genetic materials into cells
to induce new features or manipulate the characteristics of the cells
[36]. Gene therapy is considered a novel therapeutic method compared
to other regenerative medicine facilities [37]. However, the number of
gene therapy applications is emerging since the rst gene therapy was
done in 1990 [38]. The primary elds that gene therapy has entered are
cancers and genetic disorders, contributing to more than 90% of the
clinical trials in this eld [39].
Generally, therapeutic gene therapies include transferring genetic
materials into cells to reverse an abnormal condition or induce a new
feature. This approach can use different strategies according to the ge-
netic problem, such as addition, edition (repair), and deletion/knockout
(inactivation) [40]. Sometimes gene therapy is used to add a normal and
functional copy of an allele to make the gene expression higher. For
example, adding a human clotting factor IX allele produces a higher
amount of blood coagulation factor XI in hemophilia type B [41].
Sometimes gene therapy is used to add a modied allele into the cells to
show new features, such as the widely used chimeric antigen receptor
(CAR) T cells [42].
Also, gene therapy is used to repair/edit a mutation or defective
allele, such as editing the survival motor neuron 1 (SMN1) gene in spinal
muscular atrophy [43]. Moreover, gene therapy is used for inactivating
abnormal or defective genes. For instance, using siRNA (anti-sense oli-
gonucleotides) to degrade TTR mRNA and decrease TTR protein pro-
duction in the treatment of hereditary transthyretin-mediated
amyloidosis [44].
Noteworthy the fact that incorporating and employing two actions of
the mentioned mechanisms is possible. The examples for these ap-
proaches include silencing the mutated allele and simultaneously
introduce a normal copy of the allele. This approach was used for dis-
eases in which an abnormal product interferes with the normal function
of the patient, such as thalassemia [45] and sickle cell disease [46]. Also,
clustered regularly interspaced short palindromic repeats (CRISPR)
could act as a new valuable tool regarding these mechanisms [47].
Vectors are one of the essential factors in transferring genetic ma-
terials. Commonly there are two types of vectors, including viral and no-
viral vectors [48]. Various vectors with their specic characteristics
have been using for various applications. The most common vectors are
viral vectors, which can effectively transfer their gene into their host
cells. Genes responsible for replicating, assembling, or infecting the
virus are substituted with therapeutic genes to make them
replication-decient, specic, and safe therapeutic viral vectors [49].
Retroviruses and Adeno-(associated)-viruses are the most common
viral vectors, allowing for stable viral genome integration [49].
Although retroviral vectors only infect dividing cells, lentiviral vectors,
as a complex type of retroviral vectors, can also infect non-proliferating
cells, result in their extensive usage [50]. Adenovirus vectors have a
high transgene expression and the ability to infect various quiescent to
proliferating cells. Therefore, they have a high reputation for use as
oncolytic viruses and viral vaccines.
Among viral vectors, Adeno-associated vectors (AAVs) are one of the
best candidates and widely-used in-vivo applications. AAVs can infect
both dividing and non-dividing cells and contribute to the life-long
expression of the transgene. Besides, it contains no virulence genes
preventing an undesirable immune reaction. Due to their low integra-
tion frequency, their risk of insertional mutagenesis is low [40,51].
Non-viral vectors are the most straightforward route of delivering
genetic material, are less popular, mainly due to their off-targets and risk
of degradation. The traditional form of non-viral vectors are Plasmids,
DNA, and RNAs (siRNA and miRNA) [52]. The rst two are used for the
gain of function to replace or to substitute a specic genetic function in a
target cell, and the last one is used for loss of function for reducing the
expression of endogenous genes in a sequence-specic manner purpose
[52].
Plasmids have currently entered the market as a vector in the form of
Neovasculgen, which consists of a plasmid DNA encoding Vascular
endothelial growth factor (VEGF) under the control of a CMV promoter
for treatment of atherosclerotic peripheral arterial disease (PAD) [53].
Two major methods for transferring genetic materials into the cells
include ex-vivo and in-vivo gene therapy. The rst one, ex-vivo gene
therapy, involves laboratory-based transduction of cells. After harvest-
ing specic cells either from the patient (autologous) or a donor (allo-
geneic), a vector is used to carry the therapeutic gene into the cells. The
transduced cells are then returned to the patient after possible activation
or expansion [54]. In-vivo gene therapy involves vector delivery into a
patient without any cellular vehicle so that the gene transfer process
takes place inside the body [55]. By ex-vivo gene transferring, we could
specically target the obtained appropriate cells; also, the ability to
select and rene the cells of interest before transplantation enables us to
incorporate weaker vectors and ensure the cell’s desired characteristics
[56].
However, ex-vivo genetic manipulation of cells requires a high-tech
laboratory, strong-background researches, and advanced equipment.
Unlike ex-vivo gene therapy, the in-vivo method needs much fewer
laboratory works since the vector is directly administered into the body,
and the rest is done inside [57]. After the entrance of the vector into the
body, based on the injection route and vector tropism and specicity (e.
g., specied tropism in some AAV vectors and usage of target
tissue-specic promoters), the vector would infect the desired cells and
transformed it using one of the aforementioned strategies. The direct
administration of the products cuts the necessary in-vitro process for
manufacturing the personalized products and enables the product to be
prepared off-the-shelf, therefore fasten up the treatment process.
However, this method is limited to accessible tissues. In-vivo gene
manipulation is the primary method of gene therapy, when cells cannot
be isolated from the body or are unable to live a long time in ex-vivo.
Also, in-vivo gene therapies often target long-lived non-mitotic cells
(e.g., retinal cells), in which non-integrative (episomal) gene transfer
could be safely expressed for years [58]. However, non-specic cell
targeting and a higher risk for immune reactions have limited the use of
this method [54]. The most common vector used for in-vivo gene ther-
apies is AAVs, which their minimal immunogenicity along with effective
gene transfer, especially in non-dividing cells, makes it the pioneer of
current gene therapy vectors. Several current gene therapy products
used the in-vivo method for gene delivery, including Spinraza, Zolge-
nesma (for SMA) and Luxturna (for retinitis pigmentosa) [58]. It should
be noted that clinical trials from 2010 to 2020 were rather equally used
the in-vivo and ex-vivo methods; however, it seems that in-vivo gene
therapies would excel in the future, even in gene therapy of cancers
[58].
To this date, There are several gene therapy products indicated for
cancer treatment, including Gendicine® (2003, indicated for head and
neck cancer), Oncorine® (2005, indicated for nasopharyngeal carci-
noma), Rexin-G® (2007, indicated for Soft tissue sarcoma and osteo-
sarcoma), Imlygic® (2015, indicated for melanoma), and ve CAR T
cells, which are discussed in the next sections, naming Kymriah® (2017,
indicated for relapsed B cell acute lymphoblastic leukemia), Yescarta®
V. Mansouri et al.

Biomedicine & Pharmacotherapy 141 (2021) 111875
4
(2017, indicated for relapsed or refractory large B cell lymphoma),
Tecartus® (2020, indicated for relapsed/refractory mantle cell lym-
phoma), ABECMA® (2021, indicated for multiple myeloma) and
BREYANZI® (2021, indicated for relapsed or refractory (R/R) large B-
cell lymphoma).
Gendicine®, the rst gene therapy product approved for clinical use
[59], was shown acceptable safety and efcacy in treating head and
neck cancer, primarily when used in combination treatments with
radiotherapy. Approximately 93% of patients with head and neck
squamous cell carcinoma had clinical response compared to 79% when
radiotherapy was used alone [60]. Oncorine®, the rst oncolytic virus
product approved for clinical use, was designed against solid cancers
and used safely for glioma, head and neck, pancreatic, and ovarian
cancers; however, weak efcacy causes its limited use nowadays [59].
Rexin-G®, a pathotropic (disease-seeking) tumor matrix-targeted
retrovector, was rst evaluated for pancreatic cancer [61]. However,
its safety and efcacy were approved in several studies for osteosar-
coma, soft tissue sarcoma, and pancreatic cancer [62,63]. Imlygic®, an
HSV-1 oncolytic virus armed with GM-CSF cassette, showed promising
therapeutic effects on melanoma and also other cancers, either alone or
in combination with pembrolizumab or ipilimumab [64]. About 16.3%
of patients with melanoma receiving Imlygic® got a durable response in
comparison with the control groups just receiving GM-CSF [65]. During
recent years, gene therapy of cancers continued in the form of a new
generation of genetically modied effector cells, called CAR-T cells,
which growing numbers of them were being approved or expanding
their previous indications.
2.2. Cell therapy
Cell therapy corresponds to various cells’ usage to reverse or repair
the diseased state of tissues or organs. Cell therapy can be administered
either locally or systemic and is almost always minimally invasive [66].
Generally, cell therapy started with the rst blood infusion early in the
1940s [67]. Later in the 1950s, it followed with bone marrow trans-
plantation, enabling humankind to utilize different cells’ characteristics
and functions to identify and treat diseases [68].
Cell therapies include a wide range of therapeutics, from cell-based
vaccines to engineered cells, which in recent years showed promising
results, especially in treating hematological cancers [69,70]. Among
different types of cellular therapies, stem cells, chimeric antigen re-
ceptor (CAR)-T cells, and natural killer (NK) cells get the most attention
in cancer treatment (Fig. 2) [71,72].
2.2.1. Stem cells
Stem cells are non-specialized cells with the ability of self-renewal,
unlimited proliferation, and differentiation into various cell types.
They can migrate to the site of cancer cells and play a signicant role in
suppressing and modulating the immune system by secreting multiple
factors, such as growth factors, chemokines, and cytokines [73,74]. By
targeting and destroying primary and metastatic cancer cells, stem cells
reduce tumor volume, increase patient survival, and prevent cancer
recurrence.
The use of stem cells in cancer treatment is one of the newest and
most non-invasive methods for cancer therapy that uses different ap-
proaches for this purpose. Some of the main application of stem cells in
cancer therapy include regeneration of damaged tissues after traditional
treatments, immunotherapy, inducing immune cells, targeting and
destruction of cancer stem cells (CSCs) by stem cell-based-anti-cancer
vaccines, anti-cancer drug screening, therapeutic carriers, and targeted
delivery of oncolytic viruses and nanoparticles [75–78]. Depending on
the stem cells’ types, transplantation method, transplantation time, and
the number of transplanted cells, the efciency of stem cell therapy and
its effect on tumor suppression or tumorigenesis is determined.
The type of stem cells determines the therapeutic potential and how
they function. In general, stem cells have two primary categories of
embryonic (ESCs) and adult stem cells [77]. Neural stem cells (NSCs),
mesenchymal stem cells (MSCs), and hematopoietic stem cells (HSCs)
are some of the adult stem cells that have been studied to treat cancer
[79–81].
ESCs are pluripotent cells that are isolated from the inner cell mass
(ICM) of the embryo. These cells can differentiate into all cells except
placental cells. However, the use of ESCs has some ethical obstacles due
to their primary source of isolation and embryo destruction. Hence,
induced pluripotent stem cells (iPSCs) were introduced [82].
Somatic cells can be reprogrammed through the transferring of Oct
3/4, Sox2, Klf4, and c-Myc, and produce iPSCs [83]. Based on previous
studies, there is no ethical concern about iPSCs, and the lack of immu-
nogenicity in these cells has led to their higher efciency [84,85]. They
can induce a variety of immune cells and anti-tumor-vaccines to target
tumor cells. IPSCs can be used to repair and replace damaged cells with
chemotherapy, surgery, and radiation therapy. These cells are also
useful in evaluating anti-cancer drugs for end-stage patients. Simulta-
neously, iPSCs-based vaccines effectively prevent tumor relapse and
increase immune cells’ proliferation and their secretions [86,87]. These
cells can be efcient in immunotherapy by inducing T and NK cells. The
possibility of teratoma formation and autoimmunity are some major
issues using them [87–89].
NSCs are multipotent stem cells with the expression of classical
markers, such as Sox2 and Nestin. NSCs have the ability to self-renewal
and differentiate into astrocytes, oligodendrocytes, and neurons [90,
91]. They can migrate to tumor sites, and their homing could effectively
deliver anti-tumor therapeutic agents, proteins, enzymes, prodrugs, and
nanoparticles to tumor cells. The migration of these cells to the tumor
site is caused by hypoxia [81,92–94]. These cells can cross the
blood-brain barrier and are particularly useful in the treatment of brain
cancer. Besides, studies show that NSCs are useful for the treatment of
breast [92], ovarian [95], prostate [93], pancreatic [74], and lung [94]
tumors. Isolation and purication of these cells are generally arduous.
Moreover, MSCs are multipotent cells that, like other stem cells,
possess self-renewal capacity and differentiate into different cell types.
They are derived from bone marrow, adipose tissue, placenta, umbilical
cord, peripheral blood, and muscle [96]. These cells have valuable
properties, such as tropism, anti-tumor effects, anti-angiogenic effects,
reduction of tumor cell proliferation, migration, and homing ability at
the tumor site. The CXCL12 / CXCR4 signaling pathway is one of the
signicant ways, which affects the movement of MSCs cells toward the
tumor.
These cells’ secretions can activate the patient’s immune system and
regulate the tumor microenvironment (TME) [97]. MSCs can also
release drugs at the tumor site, deliver therapeutic agents, and regen-
erate cancerous tissues [98–101]. Previous studies showed that MSCs
are effective in treating various tumors, such as the brain [99], mela-
noma [100], breast [102], and lung [101] tissues. However, many
Fig. 2. Various cells in cancer therapy, include stem cells, NK cells, and CAR-
T cells.
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Biomedicine & Pharmacotherapy 141 (2021) 111875
5
studies have suggested dual roles for MSCs in stimulating and sup-
pressing cancer [103,104]. Therefore, the function of MSCs depends on
their origin, the number of them, and the method of cell transplantation.
HSCs are multipotent cells that can form mature blood cells and are
mainly present in the bone marrow [105]. The anti-tumor effects of HSC
transplantation are very signicant in the treatment of hematologic
malignancies. HSCs are also valuable in immunotherapy by introducing
genes encoding CARs and T-cell receptors (TCRs) against the tumor
antigen. Transplantation of these cells in solid tumors can increase
survival by the graft-versus-tumor (GVT) since the new donor T lym-
phocytes react with tumor antigens and stimulate the immune response
against them. Transplantation of HSCs after chemotherapy and radiation
therapy is useful and helps facilitate hematological recovery. The
migration of these cells to the tumor depends on the interaction of
CXCL12 and its receptor CXCR4 [106–108]. Properly adjusting the niche
factors and expressed factors on the cell surface (CXCR4-CXCL12)
binding helps to better homing and stabilizing these cells. CD26 express
in many solid tumors and cells, such as HSCs can cleave CXCL12 and
reduce its activity. By reducing the amount of CD26 via various inor-
ganic and biological inhibitors, CXCL12 binds to CXCR4 and improves
homing. To improve homing, these cells or their target tissue must be
manipulated to create higher levels of chemokines and their receptors
[109].
In addition to the above cells, CSCs are multipotent stem-like cells
possessing self-renewal, unlimited proliferation, differentiation into
other cancer cells, and resistance to chemotherapy drugs’ capabilities.
These cells are the foremost cause of metastasis, progression, and cancer
recurrence [110–112]. There is always a small population of CSCs in the
heterogeneous environment of the tumor. Conventional cancer treat-
ment methods do not destroy these cells, and these cells can initiate
various tumors.
Targeting and killing CSCs is critical to successful cancer treatment.
Since stem cells are adsorbed to CSCs, stem cell therapy and cell-cell
interactions can be used to reduce tumor proliferation, metastasis, and
angiogenesis [111,113]. Besides, to remove these cells, involved signals’
inhibition could be used in CSCs self-renewal, destruction of CSCs
microenvironment, and targeting CSCs surface markers [114,115]. CSCs
in different cancers have various surface markers such as CD44, IL-3R,
CD133, and CD13. For example, since CD13 is a marker of hepatic
CSCs, Haraguchi et al. [116] used anti-CD13 antibodies to suppress
dormant CSCs and prevent their tumorigenicity.
CSCs are located within specic microenvironments capable of
maintaining their phenotype, drug resistance, and facilitating their
metastasis [117]. Therefore, changes in this microenvironment, such as
reduced vascularization, changes in hypoxia, and inhibition of CSCs
growth in this microenvironment, can also prevent the growth of tumor
cells. Besides, various signaling pathways, such as Wnt and Notch1, are
involved in maintaining the basic properties of CSCs and their differ-
entiation and self-renewal, which can be controlled and targeted to help
eliminate CSCs and treat cancer [118].
Another parameter affecting the efciency of cell therapy is the
method used for cell transplantation. Stem cells are usually delivered to
the patient by controlled injection at the tumor site, intranasal, and
using semi-solid substrates and hydrogels. In choosing the trans-
plantation method, the degree of invasion, and the risk for patients, the
type of therapeutic agent, and the location and tumor type are vital
parameters. For instance, intracranial injection is an invasive and non-
repeatable procedure for brain tumors, while encapsulating cells in
different substrates helps to accurately deliver therapeutic agents to the
desired location and increase the success and durability in the treatment
of brain cancer [119,120]. Other factors affecting the anti-tumor or
tumorigenesis function of stem cells are the number of transplanted cells
and the time of transplantation. The insufcient and the excess number
of transplanted stem cells will result in cancer recurrence and teratoma
formation, respectively [121].
Stem cell therapy is usually used in combination with other methods.
According to the general protocol chosen for treatment, the time of cell
entry into the tumor must be carefully estimated. For instance, NSCs that
reach the brain tumor before radiation and Temozolomide (XRT-TMZ)
treatments can increase survival relative to the reverse [121,122].
Besides, various modications can be done on stem cells to increase
their effectiveness in treating cancer. Genetically modied stem cells
can convert non-toxic prodrugs into toxic products by expressing spe-
cic enzymes after transplantation and migration to the tumor site,
causing tumor cells’ death. This method is called Enzyme/prodrug
therapy or suicide gene therapy, which can increase the accuracy of
control over time, place, and amount of drug. Up to now, suicide gene
therapy has entered clinical phases I and II [123].
2.2.2. CAR-T cells
CAR-T cells are one of the prominent successful applications of gene
therapy in immunotherapy. Genetically engineered CAR-T cells were
produced by reconstructing chimeric receptors on T cells using a gene
sequence of monoclonal antibodies that could identify specic mole-
cules, particularly tumor-associated antigens [124]. Moreover, along
with the promotion of CAR-T cells across its generations, they occupy
some intracellular co-stimulatory domain responsible for fully acti-
vating T cells after encountering the specic antigen. The focal gath-
ering of activation and expansion potential of several co-stimulatory
domains in cytotoxic T cells with the specicity of monoclonal anti-
bodies make the CAR-T cells one of the most promising tools to ght
cancers [124]. Fig. 3 shows the cancer therapy procedure utilizing
CAR-T cells.
Car-T cells’ potential anti-cancer effects lie under the incorporation
of two main segments together with a hinge. These two segments
include an extracellular antigen-targeting part, such as a single-chain
variable fragment (scFv), and an intracellular domain featuring helper
co-stimulatory domains triggered by antigen detection. The scFv mod-
ule, with a structure similar to a small part of antibody-containing the
variable segments of heavy and light chain fused with a linker, could
easily be generated against every antigen.
This module is responsible for the specic reactivity of CAR-T cells,
which is inuenced by the antigen’s binding afnity, expression level,
antigen density on the target cell, and epitope proximity [125]. Intra-
cellular domains of CAR are responsible for its potential efcacy and
durability. Incorporating one or more co-stimulatory domains could
enhance CAR-T cells’ inuence while reducing their exhaustion and
improving their persistence. These cells have shown promising results in
treating liquid malignancies, especially CD19-positive cells, contrib-
uting to the approval of two of their leading product-Kymriah and
Yescarta [126]. Recent studies demonstrate that CAR-T cells could also
be impressive in treating solid tumors. It is under discussion whether
their homing in solid tumors is reliable or not [127–129].
2.2.3. NK cells
NK cells are active cells in the innate immune system and are
considered as a part of the lymphocyte family. These cells can respond to
many pathological conditions and are commonly known as controllers of
cancerous microenvironments [130]. For this reason, they have many
functional interactions with T cells from adaptive immunity [131]. In
contrast, natural killer cells do not need antigen-presenting cells for
identication and directly identify tumor cells [132].
In addition to the direct function, NK cells indirectly affect other
immune cells, such as macrophages and dendritic cells, with their
cytokine secretions, such as INF Ɣ and TNF
α
, enhancing the immune
response and further the success of immunotherapy [133]. Therefore, by
increasing the activity of NK Cells, a more robust immune response can
be induced in pathological conditions such as cancer [133].
Researchers are working on NK cell engineering and indirect
methods to strengthen the immune system, including the use of small
molecules, cytokines, and even genetically engineered stem cells
secreting specic cases of cytokines [134]. Stem cells can also
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Biomedicine & Pharmacotherapy 141 (2021) 111875
6
differentiate into NK cells in-vitro conditions and provide ready-use
stocks of such immune cells for research and therapeutic purposes
(Fig. 4a) [135]. However, NK cell response rate depends on interactions
with other immune system cells, such as T cells, dendritic cells, and
macrophages. Type 1 IFNƔ, IL-12, IL-18, and IL-15, are potent activators
of NK cell function [132]. IL-2 has also been shown to stimulate NK cells’
proliferation, toxicity, and cytokine secretion [133].
For achieving more effective immunotherapy, genetically engineer-
ing NK cells and modifying them to identify tumor targets could be
considered novel and accurately potent approaches [136]. NK cells, like
T cells, can be engineered using CARs. The preparation and production
of chimeric antigen receptor-natural killer (CAR-NK) cells as
off-the-shelf products in immunotherapies can increase the access of NK
cells to cancerous microenvironments (Fig. 4b) [133]. NK cell engi-
neering can increase the cytotoxic ability of NK cells and detect tumor
antigens faster and greater. Although studies in this area are still in the
preclinical stages, CAR-NK cells can be considered as a new immuno-
therapeutic approach [136]. Overall, it can be concluded from studies
that a combination of methods should be used in order for immuno-
therapy and its engineering to obtain more effective results in treatment
[137,138].
2.3. Tissue engineering scaffolds
What is known as scaffolds in tissue engineering are the ordered
structures of various materials adapted to the body’s physiological
environment that have been constructed and processed according to the
desired task and application [4]. Various biomaterials have been
approved as scaffolds to regenerate the structure and function of the
specic tissues. The particular physical and chemical properties of these
substances allow their application in the body.
They support cell attachment and migration, differentiation,
increased angiogenesis in the case of need, crosstalk with the sur-
rounding tissues, and integration with them [4,5]. So far, the concept of
tissue engineering scaffolds in cancer therapy has meant using them in
the repair of lesions leftover from surgical treatments and tissue tumor
resection site, adjuvants, targeted drug delivery, immunotherapy, and
in-vitro three-dimensional (3D) modeling.
The most common approach to using scaffolds in cancer therapy, as
in other chronic and degenerative diseases, is to reconstruct the lost
tissues and organs’ structure and function during the disease period and
improve the patient’s quality of life. It is necessary to mention that the
use of scaffolds in cancer treatment is a supportive approach.
Manufacturing and designing various types of bone scaffolds to repair
Fig. 3. Cancer therapy procedure via employing CAR-T cells.
Fig. 4. (a) The potential of iPSC-NK cells as a template for engineering. (b) The preparation and production procedure of off-the-shelf NK cells.
(a) Reproduced with permission from [134].
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Biomedicine & Pharmacotherapy 141 (2021) 111875
7
critical defects are examples of this approach [5,139].
The next approach is to use adjuvants, which have nally evolved
into modern vaccinations [140]. Adjuvants are compounds that stimu-
late the immune system to ght cancer [141]. In other words, they in-
crease the presentation possibility of tumor cells to the
antigen-presenting cells and prevent hiding tumor cells from the im-
mune system [33,141]. Researchers have used a wide range of bio-
materials as adjuvants in cancer immunotherapy, including various
mineral and organic materials, having specic characteristics, such as
size, shape, surface, and molecular weight, affecting immune response
(Fig. 5a) [32,142,143]. These materials are used in combination or
separately; thus, scaffolds made of these materials can stimulate the
immune system against cancer. The activity of immune system cells is a
pre-inammatory spectrum, which can be regulated by the inherent and
designed properties of implanted materials in the body. One of these
characteristics is the material’s size, affecting drug trafcking rate,
uptaking, and exposure to immune stations in the body. Thus, they can
play an essential role in further activating the body’s immune system or
keeping it off. Besides, the shape of the implanted biomaterials and their
surface characteristics also affect the type and manner of immune re-
sponses, and the immune system signaling cascade can be easily
manipulated by deforming the biomaterials. For instance, biomaterials
with rougher levels have been shown to stimulate pro-inammatory and
inammatory mechanisms in the body (Fig. 5b and c).
On the other hand, biomaterials with a higher surface-to-volume
ratio can interact with more immune cells and move structurally later
in the body, stimulating the immune system more than others. Even the
release of by-products from the degradation of implanted biomaterials
and their chemical and physical properties can affect the intensity of
immune responses and how they are performed.
Scaffolds have developed another approach to cancer immuno-
therapy. This treatment’s basis is the specic function of the cancer
microenvironment in regulating the immune system and suppressing it
[6]. Studies have shown that this particular microenvironment has
factors that stimulate myeloid precursor cells to travel to tissues, such as
the lungs and liver, where they differentiate into myeloid-derived sup-
pressive cells [6,146,147]. Therefore, they prepare the body for metas-
tasis and secondary establishment of cells. Such tissues that provide the
conditions for tumor cell metastasis are called pre-metastatic tissue
(Fig. 6) [148,149].
Scaffolds have now been developed that trap tumor cells by simu-
lating such pre-metastatic sites and preventing cell proliferation and
tumor recurrence. These scaffolds are implanted near the primary tumor
site and, if equipped with image-detecting agents, will track tumor
function and initiate tumor recurrence by periodic imaging. Among the
scaffolds used to play this role are Poly (lactic-co-glycolic acid) (PLGA)
and Polycaprolactone (PCL) porous scaffolds, and scaffolds containing
collagen, brin, hyaluronic acid, and alginate [31,150–152].
Using each of these approaches or combining them can be helpful
during the cancer therapy stages, along with other traditional treat-
ments such as surgery, radiation therapy, and chemotherapy [153,154].
However, optimizing the application of these methods in different
conditions and tissues requires simulation in laboratory models.
Scaffolds also are used to upgrade two-dimensional (2D) cultures and
are a branch of 3D culture modeling [7,155,156]. Laboratory models
increase our knowledge of cancer’s evolutionary pathway and lead to
more effective treatments. Scaffolds are also efcient in these areas, with
the body’s 3D environment simulation to prevent information from
being lost and getting research closer to reality. Biomaterials can also
play the carriers’ role for drug, gene sequencing, and stem cell delivery
to cancer tissue and boost direct targeted therapy [3,32,157].
Fig. 5. (a) Intrinsic properties of materials inuence immune
responses. Biomaterials commonly used in the vaccine,
immunotherapy, and tissue engineering approaches present
features including size, shape, surface charge, hydrophobicity,
and molecular weight that modify interactions with the im-
mune system. Confronting components of the innate and
adaptive immune system with scaffolds and biomaterials re-
sults in the formation of the brotic capsule to isolate the
material, differential activation of dendritic cells and macro-
phages, recognition and removal by antibody and complement
proteins, and even manipulating the adaptive immune
response. (b) Particle shape dictates immune cell uptake and
activation. Spherical polymeric particles fabricated from
polystyrene polyethylene oxide that exhibit rough surfaces
(left) were preferentially taken up by macrophages and
induced a pro-inammatory response compared to smooth
particles (right) (Scale bar, 10 mm; inset scale bar, 5 mm). (c)
Electron micrographs of gold nano constructs with spherical
(left), cube (center), or rod-like (right) shapes. Incubating with
dendritic cells, rod-like particles induced inammatory IL-1b
and activated the inammasome, while sphere and cubes
caused secretion of TNF-a (Scale bar, 40 nm).
(a) Reproduced with permission from [32]. (b) Reprinted with
permission from [144]. (c) Reprinted with permission from
[145].
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3. Regenerative medicine in cancer; from bench to bedside
3.1. Clinical trials
Today, gene therapy is used as an emerging treatment for cancers
and genetic disorders. Although gene therapy is considered a way to
treat genetic disorders, cancer gets rst place among the diseases treated
with gene therapy [39]. Cancers constituted a signicant part of the
trials each year from 2016 to 2020 [39]. Among the various cancers,
hematological cancers with broad-expressed tumor-associated antigen
with excellent cell-cell interactions were the most investigated [158].
Moreover, looking at current trials addressing cancer diseases, the ma-
jority of them are in phase I [39]. Although the number of phase II
clinical trials is also high, it seems that few of them reach phase III and
IV. Notably, to this date, there are ve phase-IV trials are focusing on
leukemia and lymphoma, solid tumors, especially prostate cancer [39].
Most genetic disorders, unlike cancers, are congenital, such as
Thalassemia, Deschene muscular dystrophy (DMD), and cystic brosis
[159]. In principle, this group of diseases is based on the transferring
genetic materials’ concept to treat diseases. It rst started in 1985 for
Adenosine deaminase (ADA) deciency resulting in severe combined
immunodeciency (SCID) [160]. Metabolic disorders and blood coag-
ulation disorders accounted for about half of the trials in this group.
Looking in more detail, Hemophilia (either type A or B), DMD, and
retinitis pigmentosa were the most common genetic disorders with the
highest number of clinical trials [161].
Furthermore, cell therapy clinical trials are running in cancer treat-
ment. The main focus of more than 600 ongoing clinical trials is on some
types of CAR T cells. However, CAR T cells targeting hematologic cancer
accounts for more than half of all clinical trials. After then, gastroin-
testinal cancer, nervous system cancer, and breast cancer have the
highest counts, which collectively account for more than three-quarters
of all CAR T cell trials. Most of the CAR T cells used in the trials were
directed against CD19, CD 20, CD30, CD22, EGFR, Mesothelin, and
BMCA [162].
3.2. Approved products in the market
There are currently two FDA-approved CAR T cell-based products for
CD19+B cell acute lymphoblastic leukemia, named Kymriah®
(Novartis, Swiss) and Yescarta® (Kite Pharma, US), which revolution-
ized the use of gene therapy in the eld of cancers [126]. However, the
number of approved products is higher for genetic disorders (ten for
genetic disorders versus six for cancer). To date, approved products for
the various diseases have entered the market, including ADA deciency,
DMD, spinal muscular atrophy (SMA), retinitis pigmentosa, B-Thalas-
semia, and several metabolic disorders, such as Familial lipoprotein
lipase deciency, Homozygous familial hypercholesterolemia, Heredi-
tary Transthyretin Amyloidosis, and Adult Familial Chylomicronemia
syndrome. Table 1 showed the approved gene therapy products along
with their indication and approval year.
Moreover, Table 2 shows the approved cellular products. First
approved cell therapy products dated back to 1998, the year of approval
of the rst gene therapy product [191]. However, unlike gene therapy
products, cellular products are focused on donor hematopoietic stem/-
progenitor cells. Only one product targeted against cancers: Provenge®
(Dendreon, US), whereas others mainly focused on the healing process
in soft tissues such as skin, cartilage, and wounds.
3.3. Current challenges in cancer treatment via regenerative medicine
approaches
Regenerative medicine as a promising emerging interdisciplinary
eld has faced many ups and downs since it was established in the late
90s [204]. At rst, the simplistic nature of replacing tissues with cells
cultured in a matrix raises many hopes for the regeneration and sus-
tainability of tissue and organs. Although tissue engineering worked
well in avascular and tissues with low metabolism, critical issues hamper
its success when applied to more complex tissues. Complex and 3D tis-
sues, unlike their ancestors, need accurate control of cell-cell in-
teractions as a signicant factor for their proper function. Various tissue
components like blood vessels, parenchymal, and non-parenchymal cells
need to be adjusted spatially at microscales. However, tissue
Fig. 6. Pre-metastatic microenvironments formation process.
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Biomedicine & Pharmacotherapy 141 (2021) 111875
9
engineering provides spectacular abilities for basic tissue engineers, but
in the eye of medical practitioners, tissue-engineered products are still
far away from being a reliable choice in clinics. Therefore, regenerative
medicine needs to utilize appropriate strategies to overcome its current
challenges in cancer treatment via regenerative medicine approaches
[205]. Fig. 7 demonstrates the principle challenges of regenerative
medicine in cancer treatment.
•Regulatory issues
The main challenge that regenerative medicine faced nowadays is
regulatory issues. Although regenerative medicine approaches involved
a simple rationale for repairing and restoring body function, it involves a
wide variety of formulations, bio-manufacturing, biological
interactions, unstable nature of products, storage difculty and
personalized mode of utilization and administration. From this point of
view, until the recent last year, categorizing these products in the prior
existing classication cause signicant problems during regulatory
consideration. Innovative regenerative approaches could hardly be put
into any medical drugs or devices categories, requiring a unique regu-
latory review process and authorization.
Applying the current regulatory approach used for other pharma-
ceutical drugs/devices is incompatible with the novel, cutting-edge
nature of regenerative medicine products and prevent considering
comprehensive aspects of these products [206]. Using specic review
guidelines and assessment themes for these drugs in special reviewing
board committees could be one promising way for easing the appro-
priate assessment of investigated products [207].
Table 1
Approved gene therapy products.
No. Trade name (General name) Year of
Approval
Indication Manufacturer Price Refs.
1 Vitravene (Fomivirsen) 1998 cytomegalovirus retinitis in
immunocompromised patients
Isis Pharmaceuticals with
Novartis Ophthalmics
withdrawn [163]
2 Gendicine (Recombinant
adenoviral vector expressing
p53)
2003 Head and neck cancer Shenzhen
SiBionoGeneTech
$387 per injection [164]
3 Macugen (Pegaptanib) 2004 Wet age-related macular degeneration Eyetech Pharmaceuticals
and Pzer. Inc
$765 per dose [165]
4 Oncorine (recombinant human
adenovirus type 5 injection)
2005 Nasopharyngeal carcinoma Shanghai Sunway Biotech – [68]
5 Rexin-G (Mx-dnG1) 2007 Soft tissue sarcoma and osteosarcoma Epeius Biotechnologies $5000 per bag 500,000 $ per
treatment
[166]
6 Neovasculgen
(Cambiogenplasmid)
2011 Peripheral vascular disease and limb
ischemia
Human Stem Cells
Institute
$6600 for treatment course [167]
7 Glybera 2012 Familial lipoprotein lipase deciency Amsterdam Molecular
Therapeutics
over $1.2m per patient [168]
8 Kynamro (Mipomersen) 2013 Homozygous familial
hypercholesterolemia
ISIS Pharmaceuticals $6910 For 1-ml vial [163]
9 Imlygic (Talimogene
Laherparevec)
2015 Melanoma Amgen $65000 per treatment [169,170]
10 Zalmoxis 2016 Restoring the immune system of the
patient after hematopoietic stem cell
transplantation
MolMed SPAA
€
149000 Dec 2017
€
163900 EUR
in Germany: ex-factory price
[171]
11 Strimvelis (Modied
Autologous CD34 +cells)
2016 Severe combined immunodeciency
(SCID) due to ADA deciency
GlaxoSmithKline (GSK) 594,000 euros, or $648000 [172–174]
12 Spinraza (Nusinersen) 2016 Spinal Muscular Atrophy (SMA) Biogen Ionis
Pharmaceuticals, Inc.
$125000 per injection [175,176]
13 Exondys 51 (Eteplirsen) 2016 Duchenne Muscular Dystrophy (DMD) Sarepta Therapeutics $1678 For 2 ml vial [176,177]
14 Kymriah (Tisagenlecleucel) 2017 Relapsed B cell acute lymphoblastic
leukemia
Novartis Pharmaceuticals
Corporation
$475000 Feb 2018 [178]
15 Yescarta (Axicabtagene
Ciloleucel)
2017 Relapsed or Refractory large B cell
lymphoma
Kite Pharma,
Incorporated
$373000 April 2018 [179]
16 Luxturna (Voretigene
Neparvovec-rzyl)
2017 RPE65 mutation-associated retinal
dystrophy
Novartis Inc. $850000 or $425000 per eye [180]
17 Invossa (chondrocytes
transduced with TGF-ß1)
2017 Moderate Knee Arthritis TissueGene (now called
KolonTissueGene)
– [181,182]
18 Onpattro (Patisiran) 2018 Hereditary Transthyretin Amyloidosis Alnylam Pharmaceuticals
Inc.
$345000 per 2 mg/ml [44]
19 Collategene (Beperminogene
perplasmid)
2019 Critical Limb Ischemia AnGes Inc. $18,000 to $27,000 per patient [183]
20 Zolgensma (Onasemnogene
Abeparvovec-xioi)
2019 Pediatric SMA Novartis Inc. Range ($2.125–5.0M/
treatment), the average lifetime
cost/patient is $4.2–6.6M
[184]
21 Waylivra (Volanesorsen) 2019 Adult Familial Chylomicronemia
syndrome
Ionis Pharmaceuticals,
Inc.
€
17381.15 for 1.5 ml vial [185]
22 Zynteglo 2019 Adult transfusion-dependent ß-
thalassemia
bluebird bio, Inc. 1.58 million euros ($1.78
million)
[186]
23 Vyondys 53 (Golodirsen) 2019 Duchenne Muscular Dystrophy Sarepta Therapeutics $1679.90 for 2 ml vial [187]
24 Tecartus (brexucabtagene
autoleucel)
2020 relapsed/refractory mantle cell
lymphoma
Kite, A Gilead Company $373,000 for a one-time infusion [188]
25 ABECMA (Idecabtagene
vicleucel)
2021 Adult patients with multiple myeloma
who have received at least three prior
therapies
bluebird bio, Inc. $419,500 [189]
26 BREYANZI (lisocabtagene
maraleucel)
2021 adult patients with relapsed or
refractory (R/R) large B-cell lymphoma
(LBCL)
Bristol Myers Squibb $410,300 for a one-time infusion [190]
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Biomedicine & Pharmacotherapy 141 (2021) 111875
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•Potential tumorigenesis concerns
This challenge is related to the stem cell therapy eld. Stem cells
used in regenerative medicine approaches share some common
characteristics with cancer stem cells, including self-renewal, dif-
ferentiation, and epithelial to mesenchymal transition capacities,
which raise concerns about their potential ability for tumorigenesis
[208]. There were several conicting results about the tumor growth
promotion or tumor formation of these cells, although the exact
tumorigenesis ability of these cells is still under doubt [209–211].
Also, there is a difference between the rates of malignant transform
of mesenchymal, neural, and hematopoietic stem cells with ESCs and
iPSCs.
Although it has been shown that the long-term rate of malignant
transformation of bone-marrow-derived MSC was about 45% [210],
ESC and iPSCs are less safe for clinical use, and most studies
demonstrated the highly tumorigenic capability of these cells [212].
Therefore, several strategies have been proposed for their ex-vivo
elimination prior to administration [213]. These strategies include
excluding these cells using antibodies targeting their specic surface
biomarkers using cell sorters, forcing them to differentiate into
specic cell lineage expressing certain reporter protein used for their
identication, using toxic antibodies or antibody-guided toxins,
using cytotoxic agents against undifferentiated pluripotent cells,
using prodrugs after incorporating suicide genes, and using novel
DNase expression induction following continuous proliferation
instead of differentiation. Further studies still would be necessary to
comprehensively assess the tumorigenesis potential of these cells and
ways to mitigate it [212,213].
•Public perceptions of gene therapy
Although gene therapy and other regenerative approaches raise
the hope for curing the disease previously known as incurable, there
are some public concerns towards genome editing, transgenic crea-
tures, and regenerative approaches [214]. In general, people support
the benets of gene therapy outweighing its risks, as shown in the
study by Robillard et al. [215], demonstrating a positive attitude
toward gene therapy in almost three-forth of the people in the United
States. However, following the adverse effects of gene therapy seen
in the early clinical trials of ornithine transcarbamylase, deciency
(OTCD) (rst death attributable to gene therapy because of massive
Table 2
Approved cell therapy products.
Category Trade name (Proper name) Year Details Indication Refs.
Adult cell
therapy
Azcel-T (Laviv) 2011 Autologous source of skin broblast cells, First
cellular therapy autologous drug
Aesthetic therapy [192]
Maci (Autologous Cultured Chondrocytes on a Porcine
Collagen Membrane)
2016 – Full-thickness cartilage
defects of the knee under
55 years
[193]
APLIGRAF (tissue-engineered biological wound
dressing mat)
1998 The rst cell contained and matrix composite tissue
analog
wound healing process [191]
Gintuit (Allogeneic Cultured Keratinocytes and
Fibroblasts in Bovine Collagen)
2012 Fibroblast and keratinocyte-containing sheet, the rst
FDA approved cell therapy product for the treatment
of wounds in the oral soft tissue defects, especially
gum surgery
Wounds of the oral soft
tissue defects
[194]
Stem cell
therapy
Clevecord (HPC, Cord Blood) 2016 Unrelated donor hematopoietic stem/progenitor cell Disorders affecting the
hematopoietic system
[195]
Hemacord (HEMACORD (HPC, Cord Blood)) 2011 Unrelated donor hematopoietic stem/progenitor cell,
rst-ever cellular drug approved
Disorders affecting the
hematopoietic system
[196]
Ducord (HPC, Cord Blood) 2012 Unrelated donor hematopoietic stem/progenitor cell Disorders affecting the
hematopoietic system
[197]
HPC, Cord Blood (Clinimmune Labs; University of
Colorado Cord Blood Bank, LifeSouth Community
Blood Centers, Inc; Bloodworks; MD Anderson Cord
Blood Bank)
2012 Unrelated donor hematopoietic stem/progenitor cell Disorders affecting the
hematopoietic system
[198–201]
Allocord (HPC, Cord Blood) 2011 Unrelated donor hematopoietic stem/progenitor cell Disorders affecting the
hematopoietic system
[202]
Immuno-
cell
therapy
Provenge (Autologous Cellular Immunotherapy) 2010 First autologous cell therapy cancer vaccine Advanced prostate cancer [203]
Fig. 7. Principle challenges of regenerative medicine in cancer treatment.
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Biomedicine & Pharmacotherapy 141 (2021) 111875
11
immunological response and multi-organ failure) [216], SCIDX1
(insertional mutagenesis following the insertion of vector upstream
of LMO protooncogene, resulting in the development of T cell acute
lymphoblastic leukemia in 25% of participants) [217,218], public
concerns about the risk and side effects of these approaches, chal-
lenged its sustainable progression. Although nowadays these risks
are better identied and understood and supposed very unlikely in
gene therapy, the situation is better for organ transplantation and
stem cell therapy has given a vast amount of information and
well-identied risks [219]. Finally, despite extensive progression in
the safety of gene therapy vectors and strict regulatory supervision,
strategies should be used to build up the necessary public trust in
these approaches [220].
Establishing a balance between the benets and risks would be one
of the hurdles of gene therapy in the future. Improving the standards
of informed consent, using minimally invasive methods, developing
greater public trust, acquiring appropriate regulatory frameworks,
providing better education of gene therapy to patients and stake-
holders, and personalized discussion about the individual risk/be-
nets of gene therapy, would be the future steps to make gene
therapy more appealing for people to accept.
•Ethical and moral issues
Signicant ethical and moral considerations should be taken for
implementing regenerative medicine approaches. The sense of
interfering with natural or genetic manipulating the natural diversity
for longevity and enhancements faced this eld of treatment with
ethical issues [220]. However, less risky techniques have shown to be
more morally acceptable, demonstrating its close relationship with
treatment risks [221], some other serious issues including germ cell
(versus somatic cell) genetic modication, administration of gene
therapy to children and fetus and the conict of interests for selecting
participants who would be enrolled in high cost, high-risk clinical
trials of gene therapy still under debate [220].
•Implementation
As these products are basically novel, clinicians and specialists
need to be trained to use them. Clinicians should be aware of the
specic methods for decision making, treatment implementing,
monitoring, and expected results of these products to manage the
patients according to a clear clinical workow [222]. Also, necessary
information about the long-term outcomes of these products, which
is essential for advocacy and getting the support of trusts/clinics, is
still relatively scarce. Coupling tissue engineers with clinicians in
centers of excellence could pave the way for this kind of approach
[223].
•Treatment durability
Treatment durability is one of the most essential factors for clini-
cians, especially for cancer treatment in which relapses are common.
Cellular treatment showed promising results in cancer treatment;
however, treatment efciency and durability are still under concern.
Similar to other treatment modalities, like chemotherapy or radio-
therapy, single-agent treatments usually fail to achieve a complete
durable response, encouraging combination treatments [81]. In
combination with immunotherapies or chemo- or radio-therapies,
stem cell-based treatments showed more enhanced durable treat-
ment outcomes [224–226]. Also, scaffolds could be used as cancer
treatment supportive platforms, providing necessary growth factors,
cytokines, and co-stimulatory molecules [212].
•Scalability
Tissue engineering for clinical applications needs further beyond
laboratory-scaled engineered products. They need to have a suitable
size, appropriate transport (vascular) system, good physical speci-
cations according to the host environment, and considerable homo-
geneity across the engineered tissue [205]. In addition, translational
aspects of novel regenerative medicine approaches should be
considered in their development and large-scale manufacturing
[227,228].
•Materials and manufacturing protocols
The interaction between the tissue matrix and the corresponding
cells stresses out the role of a reliable selection of tissue components
in its fully functional state. The tissue component sources like cells or
matrix used for culture or the scaffold material used plays a pivotal
role in the reliability of the regenerative medicine approach [205,
227–229].
•Host toleration
One of the key steps for these approaches is the host toleration
against the engineered products, in which without successful toler-
ation and engraftment, the host body will reject the corresponding
tissue, which results in more consequences. Several strategies for
overcoming this challenge were used, including modulation of the
local immune response, use of a preconditioning regimen that eases
the metabolic shock of going from culture medium to plasma, or
stimulation of angiogenesis [205].
•Costs
Like any novel treatment facilities, such as transplants and ro-
botics, regenerative medicine approaches, including cell therapy,
gene therapies, or tissue engineering, have high up-front costs [230].
Moving towards large-scale manufacturing, off-the-shelf products,
health economic models, insurance coverage could help these
products’ accessibility and affordability [223,231].
4. Future perspectives
4.1. Vaccination
•Biomaterial-based vaccines in cancer treatment
Vaccination is a promising way to treat cancer by recruiting the
patient’s immune system [232]. However, problems associated with
the specied T-cell response to cancer and the low inltration
capability of effector T-cells into tumors remain unsolved. Several
approaches using biomaterials and nanomedicine concepts are
recently pursued to achieve a better outcome in treating cancers
[233,234].
Regarding biomaterial-based vaccines, the inherent
antigen-presenting cells (APC) are recruited by releasing
chemo-attractants, such as GM-CSF, and fed with the specic tumor
antigens and adjuvants [235]. GM-CSF is a promising chemotactic
agent for recruiting dendritic cells (DCs) and inducing MHC-II and
CD86(+) expression [236]. In other words, the biomaterials in the
shape of the scaffold provide an appropriate setting to maturate the
inltrated immature DCs. The resulted DCs migrate to the lymph
node to deliver the antigens to the T-cells leading to the lymphocyte
activation and the specied antitumor reaction [237]. The porous
structure of the biomaterials alongside the sustained-release ability
of cytokines is necessary to design a biomaterial-based vaccine.
Bencherif et al. [238] created an injectable microporous alginate
cryogel and loaded it with CPG-ODN and GM-CSF as adjuvant and
chemoattractant, respectively. The system considerably enhanced
the fraction of CD86+MHCII+cells and the amount of IL-12
in-vitro. Besides, this system signicantly increased cytokines’
levels, including the interleukin family, as proof of successful
vaccination. In the next research, they used tough alginate to
maintain the porous structure post-injection, which has enhanced
the fraction of CD86+and CD11+compared to chemically
cross-linked [239].
Ali et al. [240] assessed several Toll-like receptor agonists com-
bined with GM-CSF in the poly(D, L-lactide-co-glycolide) PLG scaf-
fold for eliminating melanoma cancer. The CpG-ODN,
monophosphoryl lipid A (MPLA), and polyinosinic: polycytidylic
acid (P (I: C)) showed 15, 20, and 23-fold DCs, respectively. More-
over, CPG-ODN and P(I: C) enhanced the migration of the DCs to the
lymph nodes by 10-fold, which is consistent with the anti-cancer
effect [240]. Combining PLG-based vaccines with CTLA-4 and
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Biomedicine & Pharmacotherapy 141 (2021) 111875
12
anti-PD-1 checkpoint antibodies increased their effect against
B16-F10 melanoma cancer [241].
Recently, ceramic-based biomaterials have been introduced in
vaccine cancer therapy [242]. In this way, mesoporous silica
microrods (MSR) mixed with PEI and loaded with CPG, Ovalbumin,
and GM-CSF to form a scaffold-shaped structure following the in-
jection for hosting the attracted DCs [242]. This system was suc-
cessful in DCs maturation and CD8 cytotoxic T-cells activation,
which exerts tumor regression. Additionally, the combinational
approach with anti-CTLA4 shows more tumor growth reduction
versus an alone method [242].
•Stem cell-based vaccine therapy
Similarly, expressed antigens over ESCs and tumors bring the
chance of immunotherapy. Using a whole-cell as a vaccine agent
instead of specied or cell lysate brings the availability of a large
number of known and unknown antigens [243]. This property is
beyond the ability of monoclonal antibodies, which necessitates the
identication of dened antigens. The role of ESCs in inducing an
immune response against tumors was initially reported on the colon
[244] and lung cancers [245]. Zhang et al. [246] showed that the
human embryonic stem cells (H9) and murine mesenchymal stem
cells (IVP-ES1) effectively suppressed cancer in a mouse bearing ID8
ovarian cancer.
Yaddanapudi et al. [247] reported that the synergistic effect be-
tween ESCs and GM-CSF administration decelerated the rate of Lewis
lung carcinoma (LLC) tumor growth. Later, the same group used
GM-CSF bearing exosomes extracted from engineered ESCs to mini-
mize tumor outgrowth [248]. The results showed the activation of
effector CD8+T-cells and a suppressive effect on the migration of
immunosuppressive Treg. Li et al. [249] used a simulated micro-
gravity process on MSCs to increase the Treg cells ratio and apoptosis
mediated by CD8+cytotoxic T lymphocytes. Elevated expression of
MHC I and HSP proteins was consistent with the ultimate immune
response.
As mentioned before, iPSCs are an emerging technology in stem
cell therapy and regenerative medicine. These cells are a suitable
candidate for resolving the ethical problems associated with ESCs
utilization. Therefore, Kooreman et al. [88] injected CpG and iPSCs
in a breast cancer model via activating the cytotoxic and helper T
cells. The immunosuppressive microenvironment made this system
unable to elicit antitumor activity on the melanoma model.
However, tumor manipulation via resection led to B cells and
myeloid cell activation [88]. Combination methods using immune
checkpoint inhibitors (ICI) or radiotherapy with iPSC may syner-
gistically improve the treatment. In this way, Mashima et al. [250]
introduced GM-CSF secreting myeloid cells derived from induced
pluripotent stem cells (iPSC-pMCs) as antigen-presenting cells. The
combination of iPSC-pMC and ICI increased the inltrated cytotoxic
T-cells and NK cells. Most recently, Wang et al. [251] found a similar
gene expression among iPSC derived from human broblast and
cancer stem cells from lung adenocarcinoma. The iPSC and CpG
simultaneous administration signicantly increase effector/cyto-
toxic T-cells, resulting in reduced tumor size.
4.2. Microenvironment modication
The TME is a sophisticated medium in both chemical and mechanical
aspects [252]. The progressive TME stiffens over time due to the per-
manent extracellular matrix (ECM) production and rearrangement
[252]. Also, the tumor’s physical modication leads to malignancy and
progression due to the altered cell-matrix interaction and
epithelial-mesenchymal transition [253,254]. In brief, cell interaction
with matrix conventionally applies using cell surface-expressed pro-
teins, such as integrin, which coordinates with the intracellular cyto-
skeleton [255]. Therefore, the cytoskeleton directly modulates cell
migration, and integrin-dominated mechano-sensing affects cancer cell
invasion [256]. In a study by Peng et al. [257], the stiff polyacrylamide
(PAA) gel represents higher migration owing to the b1-FAK activation
mediated RhoA/ROCK1/p-MLC and RhoA/ROCK2/p-colin pathway in
the breast cancer cell. Epithelial-transition is a hallmark of metastasis
that identies via various mechanisms, such as cadherin-mediated
cell-cell adhesion loss [258]. Surprisingly a meaningful decrease in
E-cadherin content is proved in stiff materials that bring
epithelial-mesenchymal transition [259].
MSCs showed a wide range of results from tumoricidal to metastasis
induction by secreting cytokines in the TME. Moreover, the interplay
among MSCs and cancer cells in the TME produces carcinoma-associated
MSC and regulates their function [260,261]. MSCs protect cancer cells
via interaction with the immune system, modulating their antitumor
effects [262]. Namely, TGF-β1 secretion by MSCs increases the regula-
tory T cells (Tregs) with a diminished amount of antitumor cytokines
[263]. In other words, the MSCs provide the circumstance for the breast
cancer cells’ dormancy.
Also, the dormancy effect of the MSCs on metastatic breast cancer
cells was dominated under exosomes secreted carrying microRNAs is
proved [264,265]. Noteworthy exosomes from MSCs arrange TME by
angiogenesis suppression [266,267] and increased migration [268]. In
contrast, several exosomes from cancer cells regulate the environment
by transforming MSCs into supportive stromal cells [269].
Cholangiocarcinoma-related research has evidenced increased met-
astatic behavior and proliferation in cancer cells mixed with human
umbilical cord-derived MSCs through the Wnt/ β-catenin pathway
[270]. Besides, MSCs secrete several chemokines, such as CCL5, which
activate the AKT/NF-κB pathway and enhance metastasis under
inammation [271]. Also, CCL5 secretion by MSCs was responsible for
enhancing metastasis of the low metastatic breast cancer cells [209].
Breast cancer cells have two main categories, hormone-dependent
and independent; the rst demands hormones in the medium to form
a tumor. However, MCF-7 cells expressing estrogen receptors could form
tumors in assistance with adult human MSCs [272]. This report inten-
sied the role of MSCs as tumoral stromal cells, such as
cancer-associated broblasts (CAFs) and the remained cells for cancer
progression [272].
Studies proved the migration and homing of MSCs into the TME and
used it for targeted delivery [273–275]. Jung et al. [276] showed that
prostate tumors recruit MSCs by releasing CXCL16 chemokine and
inducing their transformation to CAFs. The transformed cells secrete
CXCL12 for increasing the metastatic of prostate cancer cells via
epithelial-to-mesenchymal transition [276]. Several ongoing clinical
trials leverage MSC’s potential for cancer therapy [71]. Also, Table 3
lists the key researches utilizing stem cells in various cancer treatments.
•Nanotechnology and novel methods for TME manipulation
Nanotechnology brings several particular tools for manipulating the
function of the tumor component. For instance, photo-thermal therapy
(PTT) using nanoparticles (NPs) signicantly decreases the tumors’
stiffness, which results in higher immune cell inltration [300]. As
illustrated in Fig. 8a, the carbon nanotube (CNT) content under laser
irradiation affects tumor collagen components’ dissociation. Marangon
et al. [300] demonstrate the role of thermal ablation or mild hyper-
thermia in the presence of CNT on the stiffness and tumor size. On the
other hand, the effect of hyperthermia on increasing the permeability of
tumor vessels is proven [301]. Also, increasing the distance between
collagen bers from 101 ±17 nm in the control group to 133 ±32 nm
in tumors treated with iron oxide under hyperthermia can indicate tu-
mors’ abnormal structure [302]. Irradiation effect on CNTs and tissue
function could be found in Fig. 8b and c.
Furthermore, photodynamic therapy (PDT) acts as a double-edged
sword on the collagen polymer in several tissues. This effect includes
crosslinking of the corneal tissue [303], and degradation upon
matrix-metalloproteinase (MMP) released upon the tumor’s broblasts’
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Biomedicine & Pharmacotherapy 141 (2021) 111875
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Table 3
Utilizing stem cells in various cancer treatment.
Cancer type In-vitro In-vivo Stem cell type Result Note Refs.
Ovarian cancer SK-OV-3 and OVCAR-3 – Adipose derived MSCs
(AMSC)
Exosomes secreted from cancer
cells transforms MSCs to tumor
supportive myobroblast
Overexpression of TGF-β, SDF-1
and
α
-SMA
[277]
Ovarian cancer SK-OV-3 and OVCAR-3 – -Bone marrow derived
MSC (BMMSC)-Tumor
associated MSC
MSC protects cancer cells against
hyperthermia
C-X-C motif chemokine 12 (CXCL
12) induces thermotolerance
[278]
Ovarian cancer SKOV3, CAOV3,
A2780 and ES2
SKOV3 AMSC Cancer cells secretes high levels of
MMP accompanied by
-Increased MMP2 and MMP9
expression in cancer
[279]
ES2
Ovarian cancer SKOV3 SKOV3 Adult BMMSC -Platelet activating factor secretion
by MSC increased the tumor
progression
– [280]
Ovarian cancer SKOV3 SKOV3 Human endometrial
MSC
Enhanced cellular death and
chemosensitivity in-vivo
-Cell cycle arrest, mitochondrial
membrane potential alteration and
decreased AKT signaling
[281]
Ovarian cancer -SKOV3 – Human AMSC Antiproliferation induced via
miRNA exosome
- BAX/Caspase-3/caspase-9 were
upregulated and BCL2
downregulated (Intrinsic
apoptosis)
[282]
–
Ovarian cancer -SKOV3 -SKOV3 AMSC -Increased migration, invasion and
proliferation
- Several proteins such as thymosin
beta 4 X-linked upregulated in
cancer cells
[283]
-HO8910
-ES2
Breast and ovarian
cancer
-TOV-112D -Human umbilical cord
wharton’s jelly MSC
(hUCMSC)
hUCMSC have not transformed to
tumor associated broblast
TAF (TGF-β etc.) were
overexpressed in BMMSC
[284]
-MDA-MB-231 -BMMSC
(Conditioned media)
Mammary cancer Mat B III Rat umbilical cord stem
cells from Wharton’s
jelly
Tumoral regression within 34–38
days
- Apoptosis and antiproliferation
effect was evidenced
[285]
-No sign of recurrence in 100 days
Breast cancer MDA –MB 231 MDA –MB
231
hUCMSC Attenuated tumor growth and
colony formation
-Intravenous injected stem cells
were accumulated in tumor site
[286]
-Manipulated the cell cycles in G2
phase
Breast cancer MCF-7 – Human MSC -Attenuated tumor growth -Wnt pathway inhibition in cancer
cells via MSC secreted dickkopf-1
(Dkk-1)
[102]
Colorectal cancer HT-29 HT-29 Human BM-MSC Increased tumor initiation and
sphere formation
IL-6 secretion by MSC stimulates
tumorigenesis
[287]
Colorectal cancer HCT-8/E11, HCT116,
SW480, HT29,LoVo
and T84
HCT 8/E11 BM-MSC Increased tumorigenesis, survival
and invasion
Neuregulin 1 secretion by MSC
activates PI3K/AKT
[288]
Colorectal cancer HCT116, LS180,
COLO205, HT29 and
SW480
LS180 BM-MSC -EMT induction -Cell-cell transactions through
surface TGF-β
[289]
-Excessive angiogenesis and tumor
growth
Colorectal cancer SW480, LS174T and
HT29
SW480,
LS174T and
HT29
MSC Increased angiogenesis IL-8 mediated increased HUVEC
proliferation and migration
[290]
Colorectal cancer SW480, SW620, HT29,
DLD1 and HCT116
HT29,
SW480, and
HCT116
MSC Somewhat strong CCR5 expression
dominates tumor growth
– [291]
Colorectal cancer HT29, Lovo, SW1116,
and Caco2
HT29 MSC (TNF-
α
treated) -EMT induction CCL5 secretion by MSC targets
CCR1 receptors and activating
CCL5/β-catenin/Slug pathway
[292]
-Enhanced proliferation, migration
and invasion
Colorectal cancer SW48, SW480 and
SW620
SW48 Cancer derived MSC -EMT induction IL-6 secretion mediates IL-6/JAK2/
STAT3 signaling pathway
dominates
[293]
-Promoted invasiveness and
metastatic behavior
Colorectal cancer SW620 – MSC TGF-β1 mediated invasiveness P53 downregulated [294]
Hepatocellular
carcinoma
MHCC97H, MHCC97L
and SMMC-7721 and
HEPG2
SMMC-721,
HEPG2
Cancer derived MSC Promoted proliferation and
invasion
Modulatory effect of S100A4
secretion is evidenced
[295]
Osteosarcoma SaOS-2, MG-63 and
HOS
– BM-MSC -Inducing Mesenchymal to
amoeboid transition
MCP-1, GRO-
α
, IL-6 and IL-8
secretion induced GTPase Rhoa
activation
[296]
(continued on next page)
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Biomedicine & Pharmacotherapy 141 (2021) 111875
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destruction [304]. Moreover, photochemical degradation and mechan-
ical properties alteration of hyaluronic acid (HA) is proved [305]. Due to
the incident laser and the utilized agent characteristics, PDT has various
vascular effects, from increasing permeability to occlusion [306,307].
Notably, there is a similar effect on TME using radio-sensitizers.
The hypoxic niche is the main hallmark of TME and plays a leading
role in cancer therapy resistance [308] and anaerobic
glycolysis-mediated acidication [309]. Routinely, hyperbaric oxygen
and ozone therapy were used to hamper the hypoxia-associated prob-
lems [310,311]. Oxygen carriers based on hemoglobin (Fig. 9a-c) [312]
and peruorocarbons (Fig. 9d-e) [313,314] are the emerging technolo-
gies to alleviate the tumor’s hypoxia. In addition, oxygen-generating
particles which produce oxygen through chemical reactions are quite
an of interest. Peroxide-based materials generate oxygen in a water
environment, catalyzed by catalase enzymes [315]. Most recently,
self-oxygen generators are synthesized, following the electrochemical
Table 3 (continued )
Cancer type In-vitro In-vivo Stem cell type Result Note Refs.
Esophageal
Squamous Cell
Carcinoma
Eca109 and TE-1 Eca109 and
TE-1
MSC β2-Microglobulin mediates EMT
induction
-E-cadherin downregulation [297]
Multiple myeloma U266 and LP-1 – MSC Increased invasion and decreased
drug sensitivity
-CXCL13 secretion [298]
Melanoma B16-F10 B16-F10 MSC -Cell cycle arrest – [299]
-Increases capsase-dependent
signaling
Fig. 8. (a) Effect of hyperthermia on the collagen component
of the tumor. Few intact collagen bers were observed in zones
devoid of CNTs while destructurated collagen bers were
visualized nearby CNTs (circled region). Cell damage evalua-
tion by TPEF and SHG microscopy in response to CNT-
mediated photothermal therapy in tumor slices. Circled re-
gions indicate the presence of CNTs. (b) Without laser irradi-
ation, the integrity of the tissue was observed both in the
presence or absence of CNTs for CNT-injected non-irradiated
control group. (c) Under laser exposure, tissue damage
correlated with the presence of CNTs while the tissue preserved
its integrity in the regions devoid of CNTs for CNT-injected and
irradiated group.
reprinted with permission from [300].
V. Mansouri et al.

Biomedicine & Pharmacotherapy 141 (2021) 111875
15
principles for oxygen generation [316–318]. Therefore, using the oxy-
gen delivery method diminishes the hypoxic niche and diminishes the
acidosis and excessive angiogenesis in tumors.
Leveraging drugs for modifying the TME backs from the crosstalk
between cells and their residing niche. Drugs that act as angiogenesis
inhibitors, such as Axitinib, are the major subgroup that impedes tumor
progression and aggression via selectively inhibiting VEGF [319].
Quercetin, a plant-derived avonoid, remodels the TME to introduce
and retain nanoparticles [319,320]. Honokiol extracted from Magnolia
Ofcinalis acts as a vasculogenic mimicry channels inhibitor, encour-
aging their combination therapy with anticancer drugs [321,322].
Also, curcumin binds to the VEGF receptor and inhibits VEGF release
[323]. Moreover, conventional drugs, such as Aspirin, have recently
gained attention in modulating the tumors [324]. A drug delivery sys-
tem carries a drug to a specic tissue, minimizing the cytotoxicity while
increasing the efcacy [325]. Drugs are encapsulated within the reser-
voir and incorporated into the nanoparticle’s structure, physically and
chemically [326].
5. Conclusion
The concept of regenerative medicine highlights its potential in
treating various diseases through various facilities. The application of
regenerative medicine approaches in cancer treatment widens the hope
avenue of treating severely treatable diseases. Conventional cancer
treatments, such as surgery, chemotherapy, and radiotherapy, do not
entirely eradicate cancer since these methods cannot detect tumor cells
and, in addition to cancer cells, damage normal cells. Several regener-
ative medicine approaches, including cell therapy, gene therapy, and
tissue engineering, provide targeted cancer treatment. These methods
are specic, safer, and more effective than conventional methods. The
course of treatment is shortened, and the need for repeated doses is
eliminated, especially in the gene therapy approach. Scaffolds and tissue
engineering constructions can also be benecial in the targeted delivery
of antitumor drugs on tumor sites and overcome the short half-life of
chemotherapy drugs. Scaffolds can facilitate conventional immuno-
therapies and the proper homing and distribution of immune cells in
tumor sites by adjusting the tumor microenvironment. In addition, they
prevent the erosion of immune cells during the complex process of
immunotherapy due to activating factors loaded on the scaffold. Using
biomaterials to recruit immature antigen-presenting cells and further
direct the T-cell toward cancer cell death shows promising in cancer
therapy. Altering the TME by laser-assisted treatment, radiation ther-
apy, and drug delivery leveraged nanomedicine’s potential. These
methods guide the tumors toward regression by direct or indirect effects
on cancer cells and TME components.
Delivery and selection of appropriate vectors for transgenic expres-
sion in tissues, regulation of optimal therapeutic transgene expression,
and safe and efcient on-site delivery of the product are the most sig-
nicant challenges of gene therapy. Delivering the appropriate dose of
the therapeutic agent, including cell or gene therapy product to the
cancer tissue, trapping the therapeutic agents in organs such as the liver,
and their neutralizing by the treatment system are other signicant
challenges in this way. Furthermore, regulatory issues, proper imple-
mentation and monitoring of treatment, treatment durability, sophisti-
cated manufacturing methods, and the high cost of products are among
the most signicant challenges facing cancer treatment in regenerative
medicine. It is hoped that with the advancement of research in this eld,
the adverse effects of mentioned strategies can be controlled and make it
possible to perform personalized cancer treatments.
Funding
This study was not funded by any institute.
CRediT authorship contribution statement
Vahid Mansouri: Investigation, Conceptualization, Resources,
Visualization, Writing - original draft. Nima Beheshtizadeh: Concep-
tualization, Visualization, Writing - original draft, Writing - review &
editing, Supervision. Maliheh Gharibshahian: Investigation, Re-
sources, Writing - original draft. Leila Sabouri: Investigation, Re-
sources, Writing - original draft. Mohammad Varzandeh: Resources,
Writing - original draft. Nima Rezaei: Conceptualization, Supervision,
Validation, Writing - review & editing, Project administration.
Conict of interest statement
The authors declare that they have no conict of interest.
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