Introduction

Since the start of the twenty-first century, researchers have been interested in the idea of
cancer stem cells, or CSCs. Notably, this year commemorates the 20th anniversary of the first
experimental demonstration of the existence of CSCs (Fulawka, Donizy and Halon et al.,
2014).
It has been demonstrated that cancer stem cells (CSCs), which Bonnet and Dick initially
discovered in acute myeloid leukemia (AML) in 1997, are comparable to normal stem cells in
that they may self-renew and differentiate into different cell types. The study showed that
AML CSCs with the phenotype CD34+ CD38−, which make up between 0.1 and 1% of
tumors, can cause AML in mice. Additional research has demonstrated that CSCs have a
major role in cancer treatment resistance to radiation and chemotherapy. They also have a
higher risk of spreading, which is a significant issue (Kusoglu and Avci et al., 2019). Cancers
are chronic illnesses that pose a major risk to human life. Numerous approaches, such as
surgery, radiation, chemotherapy, and targeted therapy, have been developed to treat cancer.
All of these treatments have contributed to a constant incidence rate of cancer in women and
a slight drop in the cancer death rate in men during the last ten years (2006–2015 and 2007–
2016). However, only certain malignant tumors respond well to conventional cancer therapy
techniques. Metastasis, recurrence, heterogeneity, resistance to chemotherapy and radiation,
and evasion of immunological surveillance are the primary causes of cancer treatment
failure.The properties of cancer stem cells (CSCs) may account for all of these failures (Yang
at el.,2020).

Concept of Cancer Stem Cells:

Tumorigenesis is directly caused by CSCs' potent capacity for self-renewal. CSCs have the
ability to symmetrically split into one daughter cell or two CSCs. In order to overly boost cell
growth and eventually cause tumor formation, CSCs divide symmetrically. Mice with severe
combined immunodeficiency disease (SCID) were given CSCs obtained from the initial
tumor tissue, which subsequently developed into new tumors (Chen et al ., 2011).
A number of regulatory signaling pathways that are important in the self-renewal process,
including the Wnt/β-catenin, Sonic Hedgehog (Hh), and Notch pathways, are also shared by
CSCs and normal stem cells. Furthermore, PTEN and the polycomb family are two more
signaling molecules that are crucial in controlling the formation of CSCs. The key to
comprehending carcinogenesis is the control of CSC self-renewal. Treatment for cancer will
have a clear focus thanks to these findings (Dick et al., 2008). Cells having CSC capabilities
are also commonly referred to as "tumor-initiating cells." Regarding the cells they refer to,
both phrases have the potential to and do generate misunderstandings. They may be produced
from normal stem cells that acquire the genetic hits required for malignant transformation, as
suggested by the term CSC. Although it implies that the tumor-initiating cell is the actual cell
from which the tumor originated initially, the term "tumor-initiating cell" more accurately
represents the experimental evidence currently available. This is probably not the case
because it is well established that the population of tumor-initiating cells, or CSCs, can shift
as the disease worsens (Vermeulen et al., 2008).
Therapeutic strategies targeting cancer stem cells:
Cancer Stem Cells and Intratumoral Heterogeneity:

Tumor tissue diversity is deeply associated to the collapse of traditional anticancer

treatments. Tumors often encompass of genetically copies of cancerous cells, which
established in retort to selection pressure from the tumor microenvironment. In genetically
identical tumor cells the diversity occurred due to the variation in gene expression pattern.
Intratumoral diversity comes from the combination of functional and genetic variation,
making it inherently complex. Normal tissue consists of distinct cell types derived from stem
cells, developing hierarchically through epigenetically regulated gene expression. Similarly,
tumor also shows the similar cellular hierarchy with cancer stem cells having high
tumorigenic and producing progenitor and differentiated cells. Before the CSC theory, tumor
diversity is considered random genetic mutation. Tumor diversity is now considered to result
from the combined contributions of both genetic and epigenetic mechanisms acting in
parallel(Fisher et al., 2013;Gerlinger et al., 2012;Nguyen et al., 2012;Easwaran et al., 2014.
Cancer stem cells have the resistance to redox stress shows "robustness", have the
ability of efficient DNA repair , adaptability to microenvironment, metabolic
reprogramming ,and drug release via ATP-binding cartridge transporters. These traits
contribute in MRD, CSC-enriched lesion that sustain therapy and leads to metastasis and
relapse. Chemotherapy-induced MRD influence CSC enrichment through mechanism such as
metabolic reprograming or signals from apoptotic non-CSCs. Increased CSC markers after
chemotherapy in various cancers highlight their importance in predicting treatment outcomes
and prognosis(Ishimoto et al., 2011;Wu et al., 2015;Maugeri-Saccà et al., 2012;Skvortsov et
al., 2015;Ishimoto et al., 2010;Yoshida & Saya, 2014;Weinberg et al., 2010;Saga et al.,
2014;Dean, 2009;Meads et al., 2009;Creighton et al., 2009;Viale et al., 2014)

The Niche, a Favorable Microenvironment for CSCs:

Normal tissue stem cells are commonly reside in the microenvironment or “niches” made up
of different type of cells, ECM, and many other growth factors. Likely, CNCs are maintained
and growth in niches having endothelial cells, osteoblasts, hyaluronic acid and EMC
molecules. Cancer-associated fibroblasts, and undifferentiated mesenchymal stem cells and
macrophages associated with tumor and immune cells within the tumor stroma act as niches
for CSCs by secreting different growth factors like epidermal growth factor, hepatocyte
growth factor ,transforming growth factor –β,along with pro inflammatory cytokines such as
tumor necrosis factor-α and interleukins like IL-1β and IL-6. This niche activates the NF-kB
signaling pathway, which not supports growth but maintain CSCs to take part in metastasis
and recurrence. For instance, Melanocytic stem cells located in sweat gland secretory portion
in the volar skin helps in development of acral melanoma, which contribute in multiplication
od oncogenic encoding cyclin-D1.It represents that CSCs originate from normal tissue cells
and share their niche(Sato et al., 2011;Rabbani et al., 2011;Guerrouahen et al., 2011;De
Veirman et al., 2014;Jinushi et al., 2012;Hoesel & Schmid, 2013a).
The concept of the microenvironment (niche) is important in understanding the “seed and
soil” theory of tumor dissemination, proposed by Paget, which suggests the site where the
primary tumor determines the metastasis of cancer cells within bloodstream to a pre-
metastatic niche. For example, cancer cells secrete parathyroid hormone-related protein,
influencing bone remodeling and help in entering the cancer cells in the bone marrow. The
phenomenon where metastasized circulating tumor cell CTCs return to the primary tumor site
is known as “tumor self-seeding” , CTCs not only circulate to distant sites but also able to
reach to its origin, as the primary tumor sites provide the acquainted niche and support
factors. CTCs have the ability to modify the niche to favor tumor formation in both the
primary site and distant site (organ).For example, Self seeding is performed by the high
expression of MMP-1, collagenase-1etc(Ribatti et al., 2006;Shiozawa et al., 2011;Yoneda &
Hiraga, 2005;Sun et al., 2005;Norton & Massagué, 2006;Comen et al., 2011;Kim et al.,
2009).

Distant metastasis depend on cancer stem cell theory, involves several steps: cancer cells
detach from the primary tumor site(1).enters into bloodstream (2).circulating as CTCs (3).exit
into distant tissues (4).settle down in pre-metastatic niche to form metastasis (5). Success of
metastasis depends on whether the niche support CTCs

Molecular Mechanisms Underlying Plasticity of CSCs:

CSCs were considered immobile body initially, at hold position at the top of the tumor cell
hierarchy. It is now broadly acknowledge that CSCs becomes dynamic and have reversible
changes influences by their surrounding niche, a concept known as dynamic stemness
model. Epigenomic changes triggered by some factors such as chronic inflammation,
oxidative stress, hypoxic stimulus increase the plasticity of conversion between the CSCs and
non-CSCs.
The dual nature make CSCs help to adopt their niche, but their plasticity also complicate their
clinical detection in vivo(Islam et al., 2015;Csermely et al., 2015;Harris & Best, 1988;Roesch
et al., 2013).A fleeting decrease in the diversity of cancer caused by the treatment has been
observed to reflect the enhancement of CSCs. This amplification occurs not only through the
selection of therapy-resistant CSCs but also through the decrease in the CSCs properties to
non -CSCs. For example, long-term treatment with vemurafenib,a drug that is used to target
the V600E mutation in BRAF protein kinase. This protein is highly oncogenic in the slow-
cycling melanoma cells. Generally, CSCs are dormant and slow-cycling in the unfavorable
conditions. As a result, melanoma CSCs when exposed to the vemurafenib turns less
dependent on the oncogenic BRAF(V600E)-mediated signals helps in adaptive resistance in
tumors to treatment.Acquired resistance to the anticancer therapies is believed to arise
between signaling pathways and reversible epigenomic changes. For the effective treatment
or elimination of CSCs, combined therapies involving two or three molecularly targeted
drugs are used(Roesch et al., 2013).
Cancer Stem Cells in Solid Tumors
According to the cancer stem cell (CSC) hypothesis of tumor growth and progression, a
subpopulation of cells in tumors, similar to those in normal adult tissues, have the ability to
self-renew and produce differentiated offspring. The only cells that may sustain tumor growth
permanently are the stem cells, which make up a small portion of the entire organ, much as in
other tissues. Even though they make up the majority of the tumor's cells and are aggressively
multiplying, the remaining cells are also differentiating and will eventually perish (Ailles and
Weissman et al., 2007). The majority of cancers are solid tumors, and about 80% of all
cancers are epithelial cancers that arise in tissues such as the breast, lung, colon, prostate, and
ovary. Other tumor entities, like glioblastoma multiforme and pancreatic ductal
adenocarcinoma, are less common but have incredibly high death rates. Histology and the
expression of certain markers are typically used to clinically evaluate tumors at the gross
level. This has been used in conjunction with gene expression analysis to define different
tumor subtypes (Hermann et al., 2010).

Diagrammatic representation of cancer stem cells (CSCs) and stem cells. Normal stem cell differentiation and
proliferation are seen in the left panel. The right panel discusses the relationship between CSCs and
carcinogenesis as well as how they may affect cancer treatment.
Solid tumors represent a significant therapeutic barrier and a significant cancer burden. Many
of these tumors demonstrate dormant behavior and treatment refractoriness, which can be
explained by the appealing biological mechanism offered by the cancer stem cell (CSC)
theory. There is mounting evidence that a specific subset of CSCs sustains and organizes a
variety of solid tumors in a hierarchical manner. Although other forms of heterogeneity also
appear to be relevant, mice models of epithelial carcinogenesis have lately provided direct
evidence for the CSC theory. Although preliminary studies suggest that targeted targeting
may be achievable, the clinical relevance of CSCs is still a basic problem (Visvader and
Lindeman et al., 2008).

Therapeutics of Cancer stem cells

Origin of Breast CSCs

For many years, there has been debate in the profession over the ultimate origin of BCSCs.
Whether BCSCs originate from multipotent mammary stem cells (MaSC), are a distinct
progenitor population, dedifferentiate non-stem cells, or a combination of these is still
unknown. The most commonly held belief is that progenitor cells and MaSCs give rise to
BCSCs (Crabtree et al., 2018). Breast cancer is a disease that varies in histology, molecular
makeup, and epidemiology. Based on gene expression studies, there are six molecular
subtypes: basal-like, claudin-low, luminal A and B, normal breast-like, and HER2/ERBB2
over-expressing. Different transformation targets have been proposed as the cause of the
molecular heterogeneity among breast tumors. The various epithelial populations in pre-
neoplastic and normal tissue from bearers of the BRCA1 mutation were investigated by Lim
and associates (McDermott et al., 2010).

Breast Cancer stem cells Markers

Breast CSCs (BCSC) are among the best defined CSCs because they were the first to be
prospectively shown in human solid cancers. such CSCs in other tumor settings, BCSCs have
been enriched using a variety of phenotypic markers (such CD44+CD24−/lowLin−) and
techniques (like the side population, ALDEFLUOR assay, and mammosphere), indicating
that they are also diverse (Velasco-Velazquez et al., 2012). A 477-gene tumorigenic signature
was produced from patient BCSCs, including RPL39 and MLF2, whose silencing in patient-
derived tumor xenografts may result in decreased tumor volume and lung metastases along
with a corresponding drop in the expression of CSC markers. Interestingly, 50% of lung
metastases from breast cancer had mutations in RPL39 and MLF2, according to RNA-Seq
research. The ability of BCSCs to proliferate, invade, and self-renew was improved by the
overexpression of the mutant genes. According to these findings, RPL39 and MLF2 are new
"tumor-initiating" genes that affect lung metastasis and target BCSCs. The differences
between BCSCs and the cell-of-origin of breast cancer have been hotly debated. It's
interesting to note that while the BCSC was first described as having the
CD44+CD24−/lowLin− phenotype, the CD24+/high and CD24−/low cells in certain patient
tumors have different genetic changes, indicating that they came from different sources
(Yang et al., 2014).
Signaling mechanisms controlling the activity of breast cancer stem cells

Signaling Pathways of Breast CSCs

Resistance to treatment and a rise in BCSCs during or after treatment have been linked to the
Notch, Hedgehog, and Wnt pathways. These pathways are essential for both adult tissue
homeostasis and embryonic development (Bozorgi et al., 2015).

Wnt Pathway:

BCSC phenotypic shape, proliferation, migration, chemoresistance, and radioresistance are

all significantly influenced by the Wnt pathway. Through the Snail protein, the Wnt/β-
catenin/TCF4 axis stimulates miR-125b expression and chemoresistance in BCSCs. In
BCSCs, snail increases ALDH activity and CD44 marker expression. LRG5 and the protein
C receptor (ProCr) are powerful BCSC indicators and new Wnt targets. It has been
demonstrated that MMP3 targets Wnt signaling and aids in BCSC maintenance. Nestin is a
type VI intermediate filament protein that increases BCSCs' capacity to metastasize by
favorably targeting the Wnt/β-catenin pathway (Song et al.,2021). In a HER2-overexpressing
mouse model, BCSCs are targeted by PKF118-310 (PKF), a small molecule inhibitor of
Wnt/β-catenin signaling, and Pyrvinium pamoate (PP), an anti-helminthic medication and a
WNT pathway suppressor, which stop the growth of BCSCs and the expression of the
NANOG, SOX2, and OCT4 genes (Farzaneh et al., 2021).

Hedgehog Pathway:
Hedgehog signaling can affect BCSC stemness and cancers through its interaction with the
Smoothened (SMO) protein. A VEGF receptor called neuropilin-2 (NRP2) promotes the
production of α6β1 integrins and glioma-associated oncogene-1 (GLI-1), which aids in the
beginning of BCSCs. GLI-1 speeds up the course of BCSC by encouraging angiogenesis
(Pires et al., 2016). Research indicates that α6β1 integrins can mediate BCSC self-renewal
ability and initiate focal adhesion kinase (FAK) activation. Therefore, an appealing therapy
approach for BC may involve focusing on the VEGF/NRP2, α6β1, GLI1, and FAK signaling
pathways. It has been demonstrated that the isoflavone genistein, which is found in soy
products, inhibits hedgehog downstream signaling and prevents BCSC growth and survival.
Additionally, by inhibiting hedgehog downstream signaling, an aqueous extract of Trametes
robiniophila Murr (Huaier) can reduce BCSC proliferation, growth, and self-renewal (Feng et
al., 2018).

Notch Pathway:

Through JAG-1 and NOTCH-4, the Notch pathway can promote and sustain BCSC invasion,
mesenchymal-like characteristics, and treatment resistance. GAS1 and SLUG are targeted by
NOTCH4, which contributes to the development of BC [104]. The NUMB protein inhibits
the Notch pathway and blocks the cytoplasmic Notch intracellular domain (NICD) in healthy
cells (Wang et al., 2022). According to reports, miR-146a inhibits NUMB activity, initiates
the Notch pathway, and causes BCSCs to develop. Therefore, BCSCs' ability to self-renew
may be weakened by downregulating the expression of miR-146a and miR-146b. A little
cargo protein called MAP 17 (PDZKIP1) stimulates the Notch pathway, inhibits NUMB
activity, and aids in BCSC maintenance.

Important signaling pathways that play a role in the spread and metastasis of breast cancer stem cells (BCSCs).
Origin of Prostate CSCs:

An AR-expressing cell from the luminal compartment is thought to have a longer lifespan
and the capacity to move and form new growth in metastatic areas, according to a common
theory of prostate cancer formation. This opinion is somewhat supported by a thorough
analysis of the genetic alterations found in the few prostate cancer cell lines that are currently
available. For instance, apoptotic suppressors like Bcl2 are often overexpressed, tumor-
suppressor gene activity (like phosphate and tensin homolog–10) is decreased, and
telomerase activation46 lengthens life expectancy (Lang et al., 2009).

Therapy resistance in Prostate CSCs

Some clues on the mechanisms of resistance to therapy can be discovered in the gene
expression patterns of CSCs and amplifying cells. The residual sickness in other cellular
systems is often of a rudimentary nature, different from the more developed cells that were
treated in the initial disease. After castration treatments, the AR-negative, basal phenotype of
the CSCs in prostate cancer offers a convenient explanation for the disease's low residual
level (Maitland et al., 2009).

Therapy Primary Resistance Secondary Resistance

Surgery Residual tumor

Androgen CSCs AR negative Genomic instability

Therapy
Radiotherapy CSCs divide slowly Expression of known radio
resistance gene elevated in CSCs
Chemotherapy CSCs divide slowly Expression of drug resistance
gene including ABC transporters
in stem cells
Immunotherapy Normally directed against Genomic Instability
common $ differentiated cell
antigens not expressed in CSCs
Gene Therapy CSCs not express in common Genomic instability
differentiating cells

Strategies to get removal of Prostate cancer

The risks of focusing on stemness have not yet been evaluated, and therapeutic approaches to
restore or eradicate mutant stem cells are still in their infancy. There was a signal that could
distinguish cancer from benign stem cells as well as TA cells when identifying the
phenotypic variations between normal and malignant stem cells in the prostate (Collins et al.,
2009).
First, assay systems for developing cancer drugs are currently based on a limited number of
cell lines for the majority of tumor types, which necessitates the availability of huge numbers
of cells. Prostate cancer stem cell cultures are not lines and have a short lifespan due to an
insufficient cell supply. Because of their presumed innate DNA instability, long-term culture
will probably result in subclones and variants that are chosen by the culture environment
(Skvortsova et al., 2018).
Second, the tests needed to eliminate the CSCs cannot be assessed by a slowdown of growth
rate or metabolism since fast proliferation is not required in the stem-cell compartment. The
stem cells would develop more quickly and become vulnerable to traditional death if they
were promoted from the stem to the amplifying compartment. The stem cells would also
become vulnerable to other antiandrogen treatments if differentiation from the AR-negative
stem and TA compartments were induced (SLvortsova et al., 2018).
Third, it is possible that the CSCs possess innate resistance mechanisms. Normal stem cells
must possess the highly evolved ability to preserve stem-cell integrity in tissues, and there is
no reason to believe that CSCs will not have done so. The most effective treatments will
ultimately target all of the prostate's cellular compartments, revealing the stem-cell
compartment once the 99% of cells that exhibit the AR-positive luminal phenotype have been
destroyed (Tang and Dubrovska et al., 2018).

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