# Breast Cancer Biology: The Multifaceted Roles of Mesenchymal Stem Cells

Authors: Shyam A. Patel; Andrew C. Heinrich; Bobby Y. Reddy; Balaji Srinivas; Nicole Heidaran; Pranela Rameshwar
Journal: Journal of Oncology
 (2008)

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## Abstract

Recent upsurge in the interest of breast cancer metastasis is partly attributed to the discovery of novel, yet unclear, mechanisms of breast cancer interaction with sites of distant metastasis such as the bone marrow microenvironment. In this review, we discuss the significance of the interactions between breast cancer cells and cells of the bone marrow. This is a subject of intense research studies aim to provide new methods of treatments and perhaps the identification of new drug targets. This review also discusses the role of inflammation and the bimodal function of the transforming growth factor-β signaling pathway in the process of tumorigenesis. We bring attention to future prospects in breast cancer research, including the role of microRNAs in cancer quiescence in the bone marrow and the application of microRNAs to basic science discoveries in oncology. Finally, we discuss the cancer stem cell hypothesis, which is not a new idea, but has resurged with investigative questions.


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## Body

## 1. Introduction

Breast
cancer, despite the subject of intense investigations, remains the most common
cancer among women in the United
States
and the second leading cause of
cancer death among this group. Each year, over 44 000 females die from breast
cancer [1]. The current long-term prognosis for breast cancer is not favorable,
and there remains a great deal of room for improvement in treatments, which
could be derived from research [2]. Efforts to detect breast cancer early,
although successful, do not guarantee survival [3]. This indicates that either
more sensitive methods are needed to detect breast cancer, or it is important
to understand the very early events of breast cancer biology.The
brain, bone, liver, and lungs are preferred sites of metastasis. Metastases
have been reported to occur even in the absence of a primary tumor, signifying
the perilous nature of this process, a subject that is revisited later in this
review [4]. Metastasis to bone results in both physical and physiological imbalances
such as lytic lesions and hypercalcemia [5]. Fractures, compression of the
spinal cord, and reduced quality of life are the ultimate outcomes of bone
metastasis [5]. Recent improvements in chemotherapy for advanced breast cancer
treatment, although to be credited, have shown limited success, as chemotherapy
fails to target quiescent breast cancer cells in the bone marrow [2].The
phenomenon of breast cancer cell quiescence in the marrow cavity has received
attention, and several mechanisms of dormancy, as well as tertiary metastasis
from the bone marrow, have been proposed [6]. Pathological triggers such as
infection can promote release of both lymphocytes and cancer cells from the
bone marrow. This suggests that infection can lead to tertiary metastasis of
breast cancer. Although research studies have been conducted to understand the
complex interplay between breast cancer cells and the bone marrow
microenvironment, the mechanism remains unclear, but the significance of this
disease process merits in-depth research studies.


## 2. The Cancer Cell/Bone Marrow Interface: Molecular Interactions

Molecular
mechanisms of bone marrow interactions with breast cancer cells have been
addressed [3]. The role of stromal cell-derived factor 1α (SDF-1α) has been given considerable
attention. Bone marrow stromal cell expression of SDF-1α is a key consideration to understand breast
cancer cell entry and integration into the bone marrow. In the region of the
endosteum, SDF-1α expression from stromal cells interacts with
the chemokine receptor 4 (CXCR4) [3]. SDF-1α-CXCR4 interactions have also been
linked to the interface between the periphery and bone marrow cavity, thereby
bringing this chemokine-receptor pair as relevant to the entry of breast cancer
cells into bone marrow. Knockdown of SDF-1α in breast cancer cells resulted in reduced
efficiency to cancer cell entry into bone marrow [3]. Following exogenous
supplementation of SDF-1α, contact between these cells was rescued, emphasizing
the critical role of SDF-1α in the breast cancer cell/bone marrow microenvironment
[3].Since
both breast cancer cells and hematopoietic stem cells express the CXCR4
receptor, it is possible that both the endogenous hematopoietic stem cells and
the cancer cells can compete for “docking” to the stroma cells. During
quiescence, the breast cancer cells themselves protect bone marrow destruction
by decreasing the expression of SDF-1α, which would allow the hematopoietic
stem cells to interact with stromal cells rather than the cancer cells,
explained in Figure 1 [3].Figure 1
Model of bone marrow and cell
migration patterns by breast cancer cells. Breast cancer cells entering the
bone marrow with mesenchymal stem cells aiding the entry of the cancer cells are shown. The figure also shows the
migrations of cancer cells to other distant organs. Although mesenchymal stem
cells might have roles in the migration of other organs, this mechanism by
which this occurs is unclear.We
now turn out attention to the neurokinin 1 (NK1) receptor because it has been
closely implicated in breast cancer interaction in the bone marrow. The
interaction between SDF-1α and CXCR4 is regulated by the NK1 receptor, a
seven-transmembrane G-protein-coupled receptor (GPCR) that has been implicated
in hematological and solid malignancies [7]. The NK2 receptor has a somewhat
different function and suppresses hematopoiesis [8]. The NK1 and NK2 receptors
demonstrate reciprocal regulation and have opposing functions in normal cells [9].The
NK1 receptor is constitutively expressed in neural tissue but inducibly
expressed in bone marrow cells and breast epithelial cells [10, 11]. The NK1
receptor interacts with peptides belonging to members of the tachykinin family.
The tachykinins are encoded by the preprotachykinin-1 (Tac1) gene of which the major product is the
undecapeptide substance P [12]. The Tac1 gene also produces the decapeptide neurokinin A, neuropeptide K, and
neuropeptide-γ. These products function in cell secretion and vasodilation [10].
Interactions between peptides of Tac1 and NK1 are involved in hematopoietic regulation, depending on the interacting
peptide or the signaling receptor [10]. In nontumorigenic MCF12A breast cells,
activated nuclear factor-κB (NF-κB) has been shown to suppress Tac1 expression level in the presence of
high levels of SDF-1α [12]. Thus, the NK1 receptor offers a valuable
pharmacologic target in diseases such as breast cancer, neuroblastoma, and
hematological malignancies [7].Recent
investigations on the mechanisms of breast cancer cell metastasis to the marrow
cavity have implicated a central role forTac1.
This gene appears to have an integral role in the molecular interaction between
breast cancer cells and mesenchymal stem cells, which the cancer cells
encounter upon entering the bone marrow cavity [12]. Tac1 appears to regulate this interaction by regulating the
expressions of SDF-1α and CXCR4 on both the cancer cells and mesenchymal stem
cells. These recent findings are interesting as they could lead to future
studies to define a new method of treatment by targeting the SDF-1α-CXCR4 interactions, and also to target the Tac1 gene. Such treatments could be
possible in the near future due to the availability of CXCR4 antagonists [12].
In summary, we propose that Tac1 contributes to breast cancer cell metastasis and integration into bone marrow
stromal compartment [9]. Additionally, Tac1 manages the transition of breast cancer cells into a quiescent phenotype in the
marrow cavity.Recent studies suggest that
particular breast cancer cell subset shows preference for the bone marrow and this preferred site
could be at an early stage of the disease, perhaps prior to clinical detection [6].
At this early phase, if the cells undergo quiescence, they are supported by the
bone marrow microenvironment and are likely to resist chemotherapy. It would be
difficult to ignore the presence of mesenchymal stem cells at the abluminal
region of blood vessels in bone marrow since they could identify avenues of
treatment [6]. In addition to being able to facilitate coupling with cancer
cells, mesenchymal stem
cells also exert immune suppression so that the cancer cells can evade
immune clearance. Thus, it is understandable why the cancer cells in bone
marrow would have advantages to evade detection and protection from the innate
immune system [6]. The next section selects TGF-β to discuss how this cytokine facilitates
breast cancer cells to be established in bone marrow.


## 3. Genes Linked to Various Stages of Breast Cancer in Bone Marrow: Relevance to Resident Stem Cells

The
spectrum of effects of TGF-β in breast cancer biology is vast, yet somewhat
ambiguous. In the early stages of breast cancer growth, TGF-β functions as a
tumor suppressor due to its antiproliferative effects [13, 14]. In later stages,
TGF-β promotes cancer cell proliferation and metastasis, thereby functioning as
an oncogene [13]. This bimodal function has been attributed to changes in the
responsiveness of cancer cells to TGF-β. Thus, during the early stage of breast cancer
development, the cells are sensitive to TGF-β, whereas the malignant cancer
cells, as well as other carcinomas, lose this sensitivity [13]. With regards to
mechanism, the TGF-β/SMAD signaling pathway has been attributed to
the inhibition of breast cancer cell proliferation [13]. TGF-β also alters the microenvironment and immune
responses that may provide favorable conditions for cancer maintenance [15].The promotion of apoptosis by TGF-β
has been linked to its interactions with the Survivin gene, which is a member of the inhibitor of apoptosis
(IAP) family. TGF-β can downregulate the expression of Survivin at the level of gene transcription, resulting in apoptosis
[14]. Evidence suggests that TGF-β downregulates Survivin via activin-like kinase 5 (ALK5) in an SMAD2- and
SMAD3-dependent manner [14].Experimental studies suggest that altered
levels ofSurvivin cause changes in the
receptiveness of cells to TGF-β, and also other cytokines responsible for
inducing apoptosis [14]. These findings could be significant for combating cancer,
since regulating Survivin levels
could make breast cancer cells more susceptible to the apoptotic-inducing
affect of TGF-β.TGF-β has the ability to arrest the cell cycle
progression in G1 phase via the pRb tumor suppression mechanism, thereby preventing
the S phase entry and breast cancer cell proliferation [16]. However, under the
regulation of c-myc, breast cancer
cells become less susceptible to the effects of TGF-β [16]. Point mutations have been identified in
the TGF-β receptor 1 (TGFR1) in breast cancer
cells [13]. In contrast, mutation in the SMAD family is rarely associated with
breast cancer [13]. Whereas limited expression of the type 2 TGF-β receptor in other cancers has been accredited
to point mutation, in breast cancer it is due to the unresponsiveness to the
ligand TGF-β [13]. Both the receptor and its intracellular
signaling components are critical for regulating cell proliferation. In
addition to these properties, TGF-β forms networks with oncogenes such as c-myc to modulate expression of other
genes linked to tumorigenesis such as Tac1 [13]. TGF-β exerts its inductive effects on Tac1 via c-myc [16]. An interesting study demonstrated that TGF-β levels were significantly decreased in
cocultures of breast cancer and bone marrow, unlike insulin-like growth factor [16].
Taken together, these extensive findings indicate that the TGF-β signaling pathway provides a valuable target
for anticancer efforts.Recent reports uncovered
homology between the seven-transmembrane
receptor, NK1, and the hematopoietic growth factor inducible neurokinin-1 type
(HGFIN), also referred to as nmb [7, 17]. This finding is relevant
because both NK1 and HGFIN have been
linked to tumorigenesis, including breast cancer [7]. HGFIN is a type I transmembrane glycoprotein that maps to the short
arm of chromosome 7 and shares structural homology to the NK1 receptor and
murine Osteoactivin [7]. Based on the homology between HGFIN and the NK1 receptor, it would be logical for one to presume
common functions by these two membrane proteins in cancer biology. However,
their roles are contrasting. While NK1, in its truncated form, exerts oncogenic
properties, HGFIN shows tumor
suppressor roles [7].HGFIN can
interact with the major Tac1 peptide,
substance P [17]. HGFIN and its
murine analog, Osteoactivin, exert various functions [17]. The evidence
supports a tumor suppressive role of HGFIN.
Its expression has been reported in lowly aggressive melanoma as compared to
the highly aggressive melanoma [17]. The suggestion is that the role of HGFIN in melanoma may be attributed to
its homology with the melanocyte-specific protein pMEL17 [17]. In breast cancer
cells, HGFIN suppresses their growth and migration [17].Similar to most tumor suppressors,HGFIN has also been linked to the potentiation of tumor formation
but suppresses cell invasiveness. Overexpression of its homolog, Osteoactivin,
has been associated with increased metastatic ability and osteolytic lesion
formation in 4T1 murine breast carcinoma [5]. The transcription factor, p53, binds
to multiple sites in the 5′ flanking region of HGFIN [16]. The limited role of HGFIN/Osteoactivin warrants future research
into its link to cancer. Information on this gene has just begun as its
involvement in cancer biology could be linked to the NK receptor gene family as well as the Tac1 gene. The genes highlighted in this section have been
associated with the biology of hematopoietic and mesenchymal stem cells [6].
Thus, these genes need to be addressed when the biology of breast cancer is
studied in bone marrow with the inclusion of the two major bone marrow resident
stem cells.


## 4. microRNAs: Breast Cancer Link

Recent research in the field of
oncology, especially breast cancer, has focused on the concept of microRNAs
(miRNAs). The technology of miRNA analyses has been employed to study the
regulation of gene expression. These novel nucleotides have been implicated in
cancer, myogenesis, differentiation of neurons, and stem cell renewal [18].
miRNAs are noncoding RNA molecules that are extensively processed before
exerting their effects on endogenous transcripts [19]. A pri-miRNA is
transcribed and then processed by Drosha and Pasha, resulting in the formation
of a pre-miRNA [20]. Upon nuclear export of the pre-miRNA, it is processed in
the cytosol, forming an miRNA-induced silencing complex (RISC), in which the
miRNA binds to the 3′ untranslated region (UTR) of endogenous messenger RNAs [20].
Thus, miRNAs exert their effect at the translational level and are valuable in
regulating gene expression. Unlike RNA interference, the RISC that is
associated with miRNAs does not lead to degradation of the complex but instead
leads to inhibition of endogenous message expression [20]. To date there are
>500 miRNAs in the human genome [20]. The Tac1 gene, which is linked to breast and other cancers [18], could
be suppressed by translational inhibition [18]. Tac1, described above, regulates breast cancer cell interaction
with the mesenchymal stem cells [12]. Thus, miRNAs against Tac1 may affect quiescence of breast cancer cells in the marrow
cavity [12]. Three miRNAs have been found that may bind to Tac1: miR-130a, miR-206, and miR-302a [17].In addition to breast
cancer, miRNAs have been implicated in the disease processes of lung cancer,
colorectal cancer, and diffuse large B cell lymphoma [19]. An expression
profile of miRNAs has been identified for pancreatic adenocarcinoma, including
miR-221, miR-376a, miR-301 [19]. Dysregulation of miR-124 and miR-137 occurs in
glioblastomas [20]. These findings represent only a fraction of our current knowledge
of miRNA involvement in malignancy, yet much remains to be discovered.In addition to their role in
malignancies, miRNAs are also involved in stromal cell interaction with
hematopoietic stem cells (HSCs) and the neural-hematopoietic-immunological system.
Production of hematopoietic regulators including cytokines, neuropeptides, and
neurotransmitters is involved in HSC functioning. Additionally, stromal cells
are adaptive in their ability to respond to the aforementioned regulators [8].
Furthermore, miRNAs have been proposed to serve as the link between cancer and
chronic inflammation (see Inflammation
and Carcinogenesis), although the precise role of miRNAs in these biological
processes is unclear.


## 5. Inflammation and Carcinogenesis

The
bridge between carcinogenesis and chronic inflammation has been under
investigation. It has been suggested that chronic inflammation can promote the
formation of cancer due to increased resistance to apoptosis and increased
proliferation of the affected cells [21]. Furthermore, reactive oxygen and
nitrogen species which are induced by the inflammation process damage vital
components of the target cell such as DNA, lipids, and protein [21]. Such
damage has often contributed both directly and indirectly to malignant cell transformation.
Also, the abnormal or overexpression of cytokines and other proinflammatory
regulators, as well as molecules integral in intermolecular communication, promotes tumor
proliferation [21]. Many cytokines commence the angiogenesis process and therefore
the cancer-stromal cell communication [21].Tumor
necrosis factorα(TNF-α), a proinflammatory cytokine, has multiple
roles in the development of cancer. Whereas it is potentially destructive to
tumor vasculature when expressed in high concentrations, it can also facilitate
tumor cell growth, including growth of breast cancer cells [21]. Mice deficient
in TNF-α or its receptor show resistance to
carcinogenesis, suggesting the oncogenic potential of TNF-α [21].Interleukin-6 (IL-6) is also a proinflammatory
cytokine and an acute phase reactant [22]. Specifically, IL-6 regulates the
expression of antiapoptotic genes and mediates cell cycle progression [22].
Elevated IL-6 levels have been liked to the pathogenesis of cancer [22]. Treatment
with anti-IL-6 results in reduced expression of the antiapoptotic protein
Mcl-1, suggesting that IL-6 controls Akt-dependent survival signals [22].The role of IL-2 in cancer cell
anergy has been demonstrated. IL-2 has been shown to stimulate
activation-induced cell death (AICD) as well as the proliferation of regulatory
T (Treg) cells [23]. Treg cells harbor a CD4+/CD25+
phenotype and are classified into at least two types: Foxp3+ Treg cells utilize granzyme A to induce cell apoptosis, and Tr1/Th3 Treg cells utilize granzyme B [24]. Treg cells can suppress effector T
cell function and autoimmunity [25]. The mechanisms of Treg-mediated
immune suppression involve contact-dependent delivery of inhibitory signals
resulting in cancer cell anergy [26].In addition to its
effects on Treg cells, IL-2 has also been shown to promote the
maturation of cytotoxic T lymphocytes (CTLs) to mature cells expressing CD44
and granzyme B [23]. A more complete comprehension of the consequences of these
signals on CTLs is integral in the pursuit of a more effective method of
adoptive immunotherapy. When activated by IL-2, CTLs have the capability to
lyse tumor cells [23]. For this reason, IL-2 has been used to generate T cells
to treat cancer by cell transfer techniques [23]. Additionally, IL-2 promotes
CTL activation and proliferation [23]. In clinical cases, administration of
IL-2 has led to cancer regression [23].On the other end of the interleukin
spectrum, IL-21 negatively regulates the effects of IL-2 (Figure2). This demonstrates
the antagonistic relationship that exists between the affects of IL-2 and IL-21
on CTLs with respect to cancer. IL-21-primed T cells were found to have the
strongest antitumor response, but only in a small percentage of trials. Thus,
the antitumor potential of IL-21 could be promising in future applications. Such
findings are vital to adoptive immunotherapy and its implications in cancer.
The potential for immune-related therapy in the treatment of cancer merits
further investigation into the interplay between IL-2 and IL-21 [23].Figure 2
Granzyme B in cancer targeting. Granzyme B expression is increased
as CTLs mature. While CD44 is moderately expressed in the early stages of CTL
maturation, its expression increases during the maturation process. A mechanism
by which antigen priming with IL-2 and IL-15 increases granzyme B induction is shown. In contrast, IL-21
is shown to cause opposing effect [22].In addition to the anticancer
potential of IL-21, another member of the type I cytokine family, IL-15, has
also been shown to have antiproliferative effects. IL-2 and IL-15 both promote
antigen-specific cytolytic activity [23]. Despite the vast number of reports on
T-cell signaling, the network and intracellular pathways triggered by T cell
activation need further investigations.The link between inflammation and
stem cell in breast cancer biology is most evident in the recent studies
demonstrating the anti-inflammatory effects of mesenchymal stem cells [27, 28].
Although mesenchymal stem cell therapy is not currently a target for cancer,
further basic science research into their role in inflammation and cancer may
provide insight into molecular processes governing the link between cancer and
inflammation.


## 6. Cancer Stem Cells: New Discoveries on a Traditional Idea

The classical model for cancer is based on stochastic
events that occur in a cell [1]. This model holds that a series of mutations
can lead to cell transformation [1]. The development of chemotherapy agents has
largely been based on this model. Recently, the concept of the cancer stem
cells (CSCs) has received much attention, yet the pioneering work on the
concept of the CSCs was made as early as 150 years ago. Dr. James Till helped
define the term stem cell and,
together with Dr. Ernest McCullough, coined the term cancer stem cell on the basis that cancer might arise from stem
cells. The CSCs hypothesis is based on the identification of a unique
population of stem cells in the bone marrow [29]. Among other reasons, the
observation of a heterogeneous population of cells in tumors such as
glioblastoma multiforme accounts for continued interest in the theory [30].CSCs are tumorigenic multipotential cells
with dysregulated self-renewal properties [31]. Upon division, one daughter
cell retains stemness and the other becomes committed to a lineage [31]. The
CSC fraction typically constitutes 1–5% of the tumor
size [32]. They function in initiation, maintenance, growth, and metastasis of
tumors [33, 34]. CSCs, like other stem cells, provide continuous source of
cancer cells with limited life span, analogous to cancer progenitors. The
hypothesis holds that tumors arise from developmentally arrested stem cells
harboring mutations, and such characteristics promote tissue repair and
organogenesis [30]. They demonstrate slow cycling and indefinite ability to
renew themselves [30]. They can proliferate limitlessly and are more resistant
to chemotherapy and apoptosis than somatic cancer cells [35]. The resistance of
CSCs to chemotherapy and radiation is the basis for heightened interest in
research endeavors in the CSCs hypothesis [30].Evidence is gradually accumulating
on the CSCs hypothesis, as numerous malignancies with stem-cell-like properties
have been identified. A fraction of rat glioma cells have been found to be
CD133+ cells with stem cell characteristics [36]. Gliomas contain 10-fold
greater levels of CD133+ cells than normal tissue, suggesting properties of
stemness in tumors [37]. CSCs have also been identified for medulloblastomas
and oligodendrogliomas [29]. A recent report demonstrated that only CD133+
medulloblastomas and gliomas can generate tumors, with as few as 100 cells being
able to recapitulate a tumor [35]. Squamous cell carcinoma of the oral cavity
has been shown to be positive for the stem cell markers Oct-4, Nanog, Nestin,
CD117, and CD133 [33]. These aforementioned findings are just a few pieces of
evidence supporting the CSC hypothesis.The putative breast carcinoma stem
cell has received much attention. Normal stem cells of the breast can give rise
to ductal epithelia, alveolar epithelia, and myoepithelia [1]. The multilineage
differentiation and self-renewal properties of stem cells are evident in cells
expressing CD24 and integrins β1 and α6. The breast CSCs phenotype is
CD44+/CD24−/lin-, and as few as 200 cells of this phenotype can generate a
tumor in NOD/SCID mice [1]. The same study demonstrated that 20 000 breast cells without
this phenotype were unable to recapitulate a tumor, suggesting the significance
of cancer cells with stem-like properties [1]. HER2 overexpression has been associated with increased expression
of the stem cell marker aldehyde dehydrogenase (ALDH) [32]. Furthermore,
fractions of stem cell progenitors in breast tumors increase in the presence of HER2 overexpression [32]. ALDH has
been suggested as a stem cell marker that may give insight into
characterization of CSCs [38].Current chemotherapeutic treatment
for cancer typically reduces tumor burden without eliminating all the cancer
cells. To date, the classical cancer model has been the foundation for advances
in cancer treatment. However, the high level of resistance of tumors to chemotherapy
lends much support to the CSC model [1]. Multiple characteristics of CSCs
account for resistance to chemotherapy and radiation, including lack of a
targetable phenotype and specific oncoprotein expression, high level of MDR1 expression, and slow cycling rate [32].
Cell-based therapy involving T cells has been proposed for the targeting of
CSCs. T cells have been shown to eliminate tumors by directly targeting
tumor-associated antigens [39]. For practical purposes, however, a T-cell-based
regimen is difficult to administer and fails to fit into the conventional
pharmacology model [39].The significance of the CSC theory
is evident from many perspectives, such as survival analyses. Triple-positivity
for Oct-4, Nanog, and CD133 in oral squamous cell carcinoma renders the poorest
prognosis of all squamous cell carcinoma patients [33]. These findings indicate
the lethality of the CSC and merit attention to CSCs as a future target for
cancer chemotherapy. By eliminating the centrally located multipotential cell
characterized by dysregulation of self-renewal ability, the source of
maintenance and growth of tumors would be terminated.From a pharmacologic standpoint,
methods are currently being devised to suppress CSCs. For instance, an
alkylating agent used in chemotherapy for glioblastoma multiforme fails to
affect CSCs that are inherently resistant [40]. The use of chloride channel
antagonists, however, has shown to induce apoptosis of these CSCs [41]. The use
of monoclonal antibodies to target CSCs has been proposed based on the ideas
that antibodies can interfere with cancer cell signaling pathways, assist in
the delivery of anticancer agents, and facilitate an immune response to tumors [34].
This approach is beneficial because it attempts to specifically target CSCs and
to efficiently destroy the tumor while exerting minimal damage to healthy
cells. Monoclonal antibody therapy for CSCs may thus improve prognoses [34].
Clearly, much room for pharmacological therapy against CSCs exists.


## 7. Outlook: Courses of Action to Combat Breast Cancer

The link between the
chronic inflammation process and cancer growth will continue to be investigated
in order to fully understand the possible functions of the various interleukins
as they would relate to preventing cancer cell proliferation. Future prospects
include harnessing IL-2-induced maturation of CTLs to induce apoptosis in
cancer cells. Also, there is a possibility of using IL-21-primed mature CTLs as
a form of external treatment as it has been shown that they have strong
antitumor properties. TGF-β could also be a significant player in future
treatments of breast cancer. Harnessing its capability to arrest the cell cycle
progression would be a monumental step in the combating cancer. The
anti-inflammatory properties of mesenchymal stem cells may be of value in the
future of breast cancer therapy, as sites of inflammation facilitate cancer by
preventing apoptosis and promoting cellular proliferation [21]. Clearly, prospects
for the future in oncology research are vast.



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