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6 The Dynamics of Tumor Microenvironment and Therapeutic Targets
The NK cells are incapable of recognizing the target cells specically and count on
stromal cells which trans-presents IL-15 for NK cell activation (Lucas et al., 2007),
and MHC class I polypeptide-related sequence A (MICA) expressing monocytes,
which bind to Fc receptor to enhance antitumor function (Campbell et al., 2017).
This enables not only the complete differentiation and induction of effector responses
but also the ability of the NK cell to form immunological memory, referred to as
“trained immunity,” which was once the signature feature of adaptive immunity.
This trained immunity induces trans-differentiation of normal NK cells to memory
NK (NKm) cells (Cerwenka et al., 2016). Many NKm cells producing IFN-γ, perfo-
rin and granzyme family molecules are detected in the TME, after restimulation (Ni
et al., 2012) but NK and NKm cell dysfunction is noted, leading to the only prolifera-
tion of tumor cells (Cerwenka et al., 2016; Wu et al., 2020). Loss of Tp53 or mutation
in cancer cells is correlated with reduced NK cells in the TME, accelerating cancer
cell immune evasion (Rooney et al., 2015). NK cells are downregulated in primary
lung adenocarcinomas and lung cancer metastases compared with those in normal
lung tissues (Lavin et al., 2017).
The sympathetic nervous system pilots the recruitment of NK cells to the
TME through the β-adrenergic signaling (Cole et al., 2012). The use of β-blocker
(β-adrenergic antagonist) before surgery can improve immune surveillance (Benish
et al., 2008).
1.3.1.1.4 Macrophages
The tumor-associated macrophages (TAMs) and their precursors refer to a plastic
and heterogeneous cell population of the TME comprising up to 50% of the myeloid
inltrate in some solid neoplasms (Cassetta et al., 2019). The elevated degree of
TAM heterogeneity in the TME reects their ability to acquire an entire range of
phenotypic, metabolic, and functional proles in response to environmental agita-
tions, ranging from a pro-inammatory M1-like to an anti-inammatory M2-like
state (Cassetta et al., 2018; Vitale et al., 2019).
In some cancers, TAMs originate from both tissue-resident macrophages and cir-
culating monocytes, and this ontogeny inuences their functional prole (Bowman
et al., 2016). Some TAMS are also derived from embryonic macrophages that were
rested in tissues during development (Zhu et al., 2017). Additionally, the accurate
localization of TAMs within the TME is directly associated with their ability to
support or check tumor progression. Explicitly, the subpopulations of TAMs at the
hypoxic or perivascular areas exhibit pro-angiogenic and immunosuppressive prop-
erties (Laoui et al., 2014), while the TAMs populating invasive tumor front or cancer
cell nests exhibit tumoricidal activity (Yang et al., 2018).
On the one hand, while TAMs provide malignant cells with trophic and nutri-
tional support, thereby promoting disease progression and resistance to therapy,
on the other, these cells mediate antineoplastic effects, especially in response to
pharmacological agents that boost their phagocytic and oxidative functions. Some
TAM subsets correlate with poor disease outcome by favoring oncogenesis, vascu-
larization, disease progression despite immunosurveillance (immunoevasion), and
resistance to treatment (Gentles et al., 2015), while other TAM populations exert
tumoricidal functions and support (rather than counteract) the efcacy of various
anticancer therapies (Mantovani et al., 2015; Vitale et al., 2019).
7Tumor Microenvironment
TAMs are essentially involved in the initiation and maintenance of chronic
inammation, which is associated with tumorigenesis and tumor progression under
the effect of TAM-derived pro-inammatory cytokines (Grivennikov et al., 2010).
This chronic inammation is provoked and maintained by the feed-forward networks
formed between TAMs and cancer cells, which may also be associated with mucosal
barrier defects and complex interactions with the microbiome (Cassetta et al., 2018).
TAMs also play key role in suppressing adaptive antitumor immunity (DeNardo et al.,
2019). For instance, TAMs express raised levels of immune checkpoint ligands, like
PD-L1, PD-L262, and VISTA63, which suppress T cell activities. TAMs can recruit
regulatory T cells (Treg) and facilitate their expansion in the TME resulting in sup-
pression of T cell immunity (Noy et al., 2014). TAMs promote angiogenic switch
(induction of a tumor vasculature mandatory for tumor growth and expansion), by
delivering critical pro-angiogenic factors like vascular endothelial growth factors
(VEGF), which strengthen the recruitment and activation of endothelial and other
associated cells necessary for generation of vascular networks (Bergers et al., 2003;
Lin et al., 2006). Furthermore, a subset of TAMs, expressing angiopoietin-1 receptor
TIE2 (TIE2+) gather around tumor blood vessels, regulating angiogenesis (Lewis
et al., 2016). It is predicted that metastatic cancer cells invite bone marrow (BM)
derived monocytes, which later differentiate into TAMs once erupted from blood
vessels. Extremely invasive cancer cells secrete prominent levels of CCL2 and/or
CSF1 to recruit and develop TAMs, which interact with cancer cells and promote
cancer cell migration, intravasation, and outgrowth in the metastatic sites. TAMs
contribute to adaptive resistance to targeted therapy in cancer (Smith et al., 2014).
TAMs are also important determinants of response to immunotherapy (DeNardo
et al., 2019). Since the TAMs are one of the most dominant innate immune cells in
tumors, the mutual interactions between TAMs and cancer cells outline the tumor
immune landscape (Xiao et al., 2021).
1.3.1.1.5 Neut rophils
The myeloid precursor derived neutrophils are the most abundant white blood cells
in peripheral blood and the pioneer responders of innate immunity. Tumor-associated
neutrophils (TANs) form an important part of the TME and are actively involved in
tumor progression and metastasis. TANs exhibit an N1 (tumor-suppressive) or N2
(tumor-promoting) phenotype. The phenotype of neutrophils in the TME varies with
the type of tumor and the condition of disease progression. Neutrophils are inam-
matory in early stages of tumor, but with tumor progression, they adopt an immuno-
suppressive phenotype (Fridlender et al., 2012).
Antitumor properties of TANs include direct cytotoxicity toward tumor cells and
metastasis inhibition (Granot et al., 2011). Parallelly, TANs can support tumor pro-
gression by promoting the angiogenic switch, stimulating motility, migration and
invasion of tumor cell, and modulating other immune cells as part of the “immu-
nosuppressive switch” (Coffelt et al., 2016). Neutrophils related to cancer (both
tumor-associated and circulating) maintain functional plasticity and can undergo
“alternative activation” when exposed to various cues found in the TME just like the
presence of transforming growth factor-β (TGFβ) promote a protumor phenotype
(N2 TANs), whereas the presence of interferon-β (IFNβ) or the inhibition of TGFβ
signaling results in TANs of an antitumor (or N1) phenotype (Sionov et al., 2015;
8 The Dynamics of Tumor Microenvironment and Therapeutic Targets
Andzinski et al., 2016). The protumor roles of TANs are achieved moderately by
stimulating the ECM and inammation of the TME. Neutrophil-released granules
consist of various proteases, including matrix metalloprotease 9 (MMP-9), neutro-
phil elastase, and cathepsin G, which can remodel ECM and promote tumor invasion
(Dumitru et al., 2013).
To date, at least three discrete neutrophil populations have been identied in the
circulation of cancer patients which can be roughly divided into mature high-den-
sity neutrophils (HDNs), mature low-density neutrophils (LDNs), and immature
LDNs. Neutrophils of the mature HDN subtype have been shown to have an N1-like
phenotype and to kill tumor cells; however, mature LDNs are not cytotoxic and typi-
cally have impaired functionality and immunosuppressive properties (Ley et al.,
2018, Shaul et al., 2019).
Immunosuppressive factors such as arginase 1 and TGFβ produced by TANs
suppress adaptive immunity and release growth factors, including HGF, sup-
porting tumor progression. Apart from TANS in the TME, neutrophils in the
peripheral blood facilitate tumor progression and metastasis. (Grecian et al., 2018;
Szczerba et al., 2019) and stimulate tumor cell extravasation (Huh et al., 2010;
Xiao et al., 2021). The specic location of TANs in the TME is associated with
prognosis. The presence of intratumoral neutrophils have the strongest connection
with detrimental prognosis in comparison to peritumoral or stromal neutrophils
(Wikberg et al., 2017).
1.3.1.1.6 Dendritic Cells
The dendritic cells (DCs) are the connecting link between the adaptive and innate
immune systems. In addition to other antigen-presenting cells (APCs), they tutor T
cell responses and are therefore important for boosting protective immunity. DCs are
functionally grouped into different subtypes, namely, classical DCs (cDCs), plasma-
cytoid DCs (pDCs), and monocyte-derived inammatory DCs (moDCs). While the
cDCs and pDCs are active during steady state conditions, the moDCs arise during
inammation (Hinshaw et al., 2019).
The presence of antigen-presenting DCs has also been detected in a differ-
ent TME. Often referred to as the tumor-inltrating dendritic cells (TIDC), their
location plays crucial role in the presentation of tumor antigen to T cells (Chaux
et al., 1993). These DCs exhibit both antitumorigenic and protumorigenic func-
tions. As is evident, the interaction of DCs with different immune effector cells
support innate antitumor immunity and humoral responses which inhibits tumor
development. TME-derived signals can drive conventional antigen-presenting DCs
to protumorigenic, regulatory ones. DCs are drafted to the tumor site by explicit
tumor derived and stroma-derived factors, which may impair DC maturation, dif-
ferentiation, and function, thus resulting in the decient formation of antitumor
immune response or development of DC-mediated tolerance and immune suppres-
sion (Zong et al., 2016).
The tumor-associated DCs are faulty in their differentiation and activation and
are poor stimulators of immune responses. Diminished pH, hypoxia, accumulation
of adenosine, and increased levels of lactate impair the normal function of DCs. In
breast cancer, IL-10 has been shown to inhibit IL-12 production by tumor-inltrating
9Tumor Microenvironment
DCs, altering their ability to launch antigen specic T cell responses (Ruffell
et al., 2014). Accumulation of abnormal amount of lipids in DCs is one of the major
mechanisms contributing to DC dysfunction leading to an impaired antigen cross-
presentation, thereby supporting tumor progression (Herber et al., 2010). The TME
can convert tumor-inltrating DCs into immunosuppressive regulatory cells, which
produce tumor promoting IL-6 and immunosuppressive galectin-1 (Tesone et al.,
2016). In the TME, the pDCs are immature and defective in the production of type
IIFN and can induce Treg production. These pDCs tend to be tolerogenic, favoring
tumor progression and is associated with poor prognosis (Veglia et al., 2017). Thus,
the DCs play unique and diverse roles in the tumor occurrence, development, pro-
gression, and response to therapy (Zong et al., 2016; Balkwill et al., 2012).
1.3.1.2 Stromal Cells
The TME comprises a range of stromal cells including vascular endothelial cells,
pericytes, adipocytes, broblasts, and mesenchymal stromal cells (MSCs). In healthy
condition, the local stromal cells modify their phenotype to become reactive stromal
cells during normal wound healing and inammation. Under specied conditions,
such as tumor development and progression; tumor cells recruit these reactive stro-
mal cells and transform them into tumor-associated stromal cells (TASCs) (Kidd
et al., 2012). Within the TME, there is substantial evidence of cellular transdiffer-
entiation, from stromal cell to stromal cell and from tumor cell to stromal cell. The
most cited example is that of broblast transdifferentiation into activated myobro-
blast during formation of the reactive stroma (Midgley et al., 2013).
As compared to their normal counterpart, the TASCs express higher levels of
proteins, including broblast-activating protein, alpha-smooth muscle actin, and
matrix metalloproteinases. TASCs also secrete many protumorigenic factors, such
as IL-6, IL-8, stromal-derived factor-1 alpha, VEGF, and tenascin-C which recruit
supplementary tumor and protumorigenic cells to the emerging microenvironment.
TASCs promote tumor growth in the TME by secreting various cytokines and che-
mokines. IL-6, specically, is a pro-inammatory cytokine which alters stromal
cell function, migration, and epithelial to mesenchymal transition (EMT) in the
TME. The TASCs, recruited from the local host stroma, promote remodeling of
ECM, cellular migration, neo-angiogenesis, invasion, drug resistance, and evasion
of immunosurveillance (Hanahan et al., 2012; Bussard et al., 2016). TASCs pro-
duce reactive oxygen species (ROS), which enhances tumorigenicity (Capparelli
et al., 2012).
microRNAs (miRs) are a group of small, single-stranded, noncoding RNAs
involved in gene expression, stem cell maintenance, cell fate determination, and
developmental processes. Dysregulation of miR expression has been implicated in
tumor cell promotion, migration, and invasion. Activation of TASCs is found to be
regulated by miR-21/miR-221 (Ali et al., 2015). The presence of TASCs is a prereq-
uisite for invasion of tumor cell and metastasis (Bussard et al., 2016). Within the
TME, β-adrenergic receptors on stromal cells are activated by catecholamines from
local sympathetic nerve bers (norepinephrine) and circulating blood (epinephrine).
The β-adrenergic signaling aids in may cancer promoting function of the TASCs
(Cole et al., 2012).
10 The Dynamics of Tumor Microenvironment and Therapeutic Targets
1.3.1.2.1 Endothelial Cells
The cancer-associated endothelial cells (CAECs) are a major cell type of the TME,
mostly developing from the transdifferentiation of pericytes. Glioblastoma stem-
like cells are capable of transdifferentiation into mural-like endothelial cells to
promote vascular mimicry. Twist 1 promotes transdifferentiation of endothelial
cell head and neck through Jagged1/KLF4 axis to boost tumor angiogenesis (Chen
et al., 2014).
The endothelial cell derived TASC subtype play important role in tumor growth
and invasion. It is seen that proliferating endothelial cells derived from the BM
undergo an endothelial to mesenchymal transition (EndMT) in the presence of
tumor growth factor-beta (TGFβ), converting the endothelial cells into broblast-
like cells. These newly derived CAECs display downregulation of endothelial
cell markers CD31 and upregulation of the markers FSP1 and alpha-SMA. Breast
cancer treatment with chemotherapeutic agents increases CAEC-derived produc-
tion of TNFα, causing an enhanced production of CXCL1/2 via NFκβB by the
cancer cells. Increased CXCL1/2 production increase breast cancer cell survival
and chemoresistance by attracting myeloid cells and stimulating them to produce
S100A8/9 proteins (Acharyya et al., 2012). These cells also are directly involved
in activation of DCs (Podgrabinska et al., 2009). CAECs also promote tumor cell
metastasis and protect tumor cells in circulation from targeted therapeutics via
supervising cancer cells to distant sites and providing a temporary substratum to
protect them from anoikis. Thus, CAECs are strategic players in cancer cell eva-
sion of immunosurveillance and enhanced chemoresistance (Yadav et al., 2015;
Bussard et al., 2016).
1.3.1.2.2 Cancer-Associated Fibroblasts (CAFs)
Fibroblasts are essential in standard homeostasis process and wound healing
(Bellusci et al., 1997). Throughout wound healing, macrophages produce TGF-β and
platelet-derived growth factor (PDGF), which activates broblasts to secure a myo-
broblast state (Wahl et al., 1990; Bonner et al., 1991). In wound healing, angiogen-
esis, remodeling of the ECM and epithelial proliferation are noted while in the TME,
these benet in tumor development (Denton et al., 2018).
The broblasts associated with TME are often referred to as the cancer-associated
broblasts (CAFs). CAFs are derivatives of tissue-resident broblasts, which are acti-
vated in the milieu of the TME (Quante et al., 2011). CAFs can also originate from
stellate cells, adipose or BM-derived stromal cells, and endothelial and epithelial
cells, through EndMT or EMT in the TME (Denton et al., 2018).
CAFs produce CXCL12, which drives cancer cell growth through CXCR4
expressed on the cancer cells (Orimo et al., 2005). In addition, CAFs also modu-
late their phenotype rendering them more carcinogenic (Wang et al., 2001). Cells
with higher levels of Wnt signaling exhibit enhanced clonogenicity with the ability
of recreating a tumor and are called “cancer stem cells.” The CAFs are responsible
for maintaining of the cancer “stemness” (Vermeulen et al., 2010). CAFs can also
promote angiogenesis by releasing active growth factors from the ECM due to their
expression of MMPs, MMP9, and MMP13, which release VEGF from the ECM
promoting angiogenesis (Bergers et al., 2000; Lederle et al., 2010). CAFs exert
11Tumor Microenvironment
their effects on invasion and metastasis through modulation of ECM composition
by expressing lysyl oxidase, leading to cross-linking of collagen and intensied tis-
sue stiffness, which is associated integrin signaling (Levental et al., 2009). CAFs
especially the broblast-derived exosomes have been linked in driving resistance
to chemotherapy in cancer. It has been elucidated that exosomes carrying plentiful
RNAs stimulated breast cancer cells which along with NOTCH3 signaling by the
CAFs converged on STAT1 signaling leading to resistance of the tumor cells to
chemotherapy and radiotherapy (Boelens et al., 2014). CAFs producing CXCL1,
CXCL2, IL-1β, and IL-6 (among others) are important players in carcinogene-
sis. IL-6 protect tumor cells from apoptosis in a STAT3-dependent mechanism
(Naugler et al., 2008) and can drive angiogenesis (Nilsson et al., 2005), while
IL-1β promotes carcinogenesis (Langowski et al., 2006). CD8+T cell inltration
into cancer nests within the TME has good prognosis (Zhang et al., 2003), but
CAFs directly limit T cell inltration (Cardone et al., 1997). Additionally, CAFs
exert a directly immunosuppressive mechanism of action which suppresses T cell
function (Kraman et al., 2010).
Modication of CAFs by the cancer cells alter the immune cell components
within the TME. For example, induction of expression of lymph node chemoattrac-
tant chemokine CCL21 in cancer cells, in invasive cancer cells [125], leads to stromal
organization reminiscent of broblastic reticular cells (FRCs) of the lymph node.
This FRC-like stromal organization recruits CCR7-expressing DCs, naïve T cells,
and Treg cells to the TME, promoting tumor growth (Shields et al., 2007; 2010).
Thus, the CAFs are responsible for the promotion and maintenance of cancers.
CAFs have several effects on the growth and maintenance of cancer, including inhi-
bition of immune cell access to the TME, thereby restricting the host immune sur-
veillance (Denton et al., 2018).
1.3.1.2.3 Adipocytes
Adipocytes are a kind of stromal cell found in many tissues playing an active role in
the TME. When peritumoral adipocytes exhibit a change in phenotype and some bio-
logical features like decrease in the expression of differentiation markers on mature
adipocytes, production of a many fat-derived factors, and promotion of metabolic
reprogramming of cancer cells), they are labeled the cancer-associated adipocytes
(CAA s) (Wu et al., 2019).
CAAs demonstrate a malignant phenotype and are found at the TME, mediating
a crosstalk between adipocytes (the precursor cells that will become CAAs) and the
cancer cells (Yao et al., 2021). The CAAs express factors concerned with matrix
remodeling, invasion, and survival of cancer cells, as well as EMT (Xiong et al.,
2015). They produce amplied amounts of insulin-like growth factor binding pro-
tein-2 (IGFBP-2) compared to normal adipocyte and this CAA-derived IGFBP-2 is
involved in greater migration and metastasis of cancer cells both (Wang et al., 2015).
CAAs enhance their expression of MMP-11, pro-inammatory cytokines IL-6,
IL-1β, and IL-8, and fatty-acid-binding proteins that promote the homing, migra-
tion, and invasion of cancer cells (Xiong et al., 2015). Moreover, CAAs may addi-
tionally be an energy source for the cancer cells by lipolysis. CAAs contribute to a
highly complex inammatory cycle that is regulated by the TME to promote tumor
12 The Dynamics of Tumor Microenvironment and Therapeutic Targets
development. The malignant functions of CAAs may amplify this cycle, and there-
fore, CAAs may serve as an obstacle to tumor treatment (Hoxhaj et al., 2020). Thus,
the crosstalk between CAAs and cancer cells promote development of the TME as
well as the homing and metastasis of cancer cells (Bussard et al., 2016).
1.3.1.2.4 Stellate Cells
Stellate cells are inactive broblasts residing in several organs being the primary
ECM-producing cells and help in recovering from injury (Yin et al., 2013).
Activated pancreatic stellate cells (PSCs) in the stroma, present as a quiescent
form in normal pancreatic tissue, are the sprouted seed of cancer cell progression and
metastasis. This star-shaped lipid containing cells was initially identied in the liver
in 1876 (Aterman, 1986). They were reported from pancreas around 1982 (Watari
etal., 1982). In the parenchyma of normal pancreas, PSCs are found in inactivated
form containing ample vitamin Aand fat droplets in the cytoplasm. Loss of these
lipid droplets by any pathological or physiological reactions leads to their activa-
tion with increased expression of α-smooth muscle actin (α-SMA) and desmin and
broblast-like features. PSCs aberrantly secrete matrix proteins, such as collagen,
laminin, and bronectin, in the ECM that induces desmoplastic reactions in the pan-
creas (Berna et al., 2010). Tumorigenesis causes conformational change in PSCs,
which exhibit myobroblast-like characteristics and have a strong effect upon tumor
progression and metastasis (Thomas et al., 2019). Pancreatic stellate cells secrete
excess TGF-β that results in leads to dysregulated turnover of ECM and unusual
accumulation of matrix proteins and immune cells, which accelerate the cancer cell
metastasis in the stromal region (Vonlaufen et al., 2008). Activated pancreatic stel-
late cells activate cell proliferation by undergoing EMT, a mechanism which further
links brosis and cancer metastasis (Kikuta et al., 2010).
1.3.2 NoNCellular CompoNeNts
1.3.2.1 Extracellular Matrix (ECM)
The tumor microenvironment (TME) also includes various acellular components
derived from both tumor and stromal cells. Among these, the extracellular matrix
(ECM) is regarded as a key factor due to its signicant roles in inuencing nutrient
availability, directing immune cell migration toward tumor cells, inducing metabolic
stress, acting as a physical barrier to drugs and growth factors, and contributing to
poor prognosis. The ECM consists of diverse biomolecules, such as collagens, pro-
teoglycans, hyaluronic acid, and laminins, which become increasingly complex and
disorganized, leading to altered properties. Moreover, ECM determines the morpho-
logical appearance, growth pattern, and migratory behavior of human cells. Laminin
and bronectin components of the ECM participate in the adhesion of tumor cells
(Vlodavsky et al., 1980; 1981). Laminin, a glycoprotein is a major tumor promoter
but also has many active domains that reduce tumor growth and metastasis (Jun et
al., 1994; Yamamura et al., 1993). Other ECM components like osteopontin and the
3D context of the ECM control tumor progression. Gene expression of the adjoining
cells is regulated by the ECM through transmembrane receptors that collaborate with
13Tumor Microenvironment
the cytoskeleton and change its alliance with mRNA. This inuences the ECM in a
model of “dynamic reciprocity.” Hence, the interactions between ECM and cells are
dynamic and reciprocal. (Bissell et al., 1982).
ECM components have the ability to inuence the relationship between an organ-
ism’s genotype and phenotype. This inuence can potentially regulate the manifesta-
tion of cancer-related traits. The interactions between cancer cells and the ECM were
revealed, when the cell-transforming Rous sarcoma virus could generate tumors in
chicks only at sites where there was a wound and the ECM had been remodeled
(Dolberg et al., 1985).
ECM remodeling is a key contributor to tumor progression. It was demon-
strated that the stroma is widely modied and linked with enhanced vascularity and
increased ECM production by broblasts in breast carcinoma (Rønnov-Jessen et al.,
1996). The formation of a dense ECM, termed desmoplasia, is correlated with vari-
ous cancers. It is illustrated by massive proliferation of myobroblasts expressing
smooth muscle actin in the ECM and by an increase in bronectin, brillar collagen,
proteoglycans, and tenascin (Liu et al., 2012; Ren et al., 2018). MMPs produced
primarily by non-malignant cells of the TME are the foremost drivers and mediators
of ECM remodeling, which in turn accelerates tumor growth and progression. This
is facilitated by MMP-mediated destruction of the basement membrane, leading to
cancer cell invasion and release of angiogenic-stimulating factors from the ECM,
which support tumor growth (Bergers et al., 2000).
Angiogenesis promoted by the ECM recruits new blood vessels in the TME form-
ing an irregular, highly permeable microvasculature, causing an inux of uid and
macromolecules into the tumor. This lifts the interstitial uid pressure. Additionally,
the tumor causes an increase in the number of peritumoral lymphatics, which con-
tributes to the uid ux into the surrounding TME (Boucher et al., 1992). As tumor
cells proliferate in an unrestrained way within a conned tissue, radial and circum-
ferential stresses are induced in the surrounding tissue and in the tumor mass itself.
Such solid stress applies forces and tensile stress on the surrounding cells like bro-
blasts, altering their behavior (Tomasek et al., 2002). Cells are highly reactive to the
matrix stiffness around them, which promotes a malignant phenotype (Paszek et al.,
2005; Maman et al., 2018).
1.3.2.2 Exosomes
Exosomes are extracellular vesicles with an average diameter of ~100 nm and an
endosomal origin. They contain many constituents of a cell like lipids, proteins,
nucleic acids, and metabolites. One speculated role is that exosomes likely remove
excess and unnecessary constituents from cells to maintain cellular homeostasis
(Kalluri et al., 2020).
Initially considered as “garbage bins,” the exosomes are now elucidated to perform
many functions that involve interactions within the TME. Exosome-mediated continu-
ous interference between cancer cells and stroma are believed to regulate hypoxia-
adaptation and to rebuild the microenvironment in return (Meng et al., 2019).
The tumor-derived exosomes (TDEs) are augmented in the TME, delivering
tumoral signaling to both tumor cells and stromal cells and playing fundamental func-
tions in a wide array of pathological scenarios, viz. tumor invasiveness, angiogenesis,
14 The Dynamics of Tumor Microenvironment and Therapeutic Targets
cell proliferation (Xue et al., 2017), chemotherapy and radiation resistance, immune
evasion, metabolism, and cancer stemness (Ramteke et al., 2015). The proteins associ-
ated with ECM degradation activity like MMP-13 and MMP14 found in exosomes are
involved in tumor migration and invasiveness (Shan et al., 2018). The TDEs are also
enriched in pro-angiogenic proteins that stimulate tubule formation by endothelial
cells, not even under hypoxic condition, promoting angiogenesis (Skog et al., 2008).
An alternative set of exosomal cargos that play strategic role in hypoxia regulation is
non-coding RNA, micro RNAs, and long non-coding RNAs (Meng et al., 2019).
1.3.2.3 Cytokines and Chemokines
Small signaling proteins, cytokines, and chemokines orchestrate complex interac-
tions between tumor cells, immune cells, and stromal components, affecting various
aspects of tumor biology, particularly in shaping the TME and inuencing cancer
prognosis. (Yi et al., 2024). Each chemokine (e.g., CXCL/CXCR and CCL/CCR
axes) orchestrates the migration and positioning of immune cells within the TME.
These soluble, secreted proteins can directly bind to their respective receptors on
tumor cells, blocking apoptosis by regulating the expression and function of pro-
and anti-apoptotic molecules. Simultaneously, they induce tumor cell proliferation
and survival. Cytokines and chemokines also activate multiple oncogenic signaling
pathways, such as PI3K/mTOR/AKT/NF-κB and MAPK/ERK/NF-κB, promoting
angiogenesis, metastasis, and cancer stem-like cell properties. Studies, including
clinical trials, have begun to explore combinations of cytokine- and chemokine-
targeted therapies with other treatment modalities to overcome resistance and
improve patient outcomes. (“Harnessing cytokines and chemokines for cancer ther-
apy, David J. Propper& Frances R. Balkwill; Nature Reviews Clinical Oncology
volume 19, pages 237–253). Therefore, understanding the intricate network of cyto-
kines and chemokines in the TME is crucial for developing more effective cancer
treatments and addressing therapy resistance.
1.3.2.4 Circulating Tumor Cells (CTCs) and
Circulating Nucleic Acids (CNAs)
The signicant genetic and phenotypic heterogeneity in tumors underscores the
urgent need for personalized care and the development of robust tools to monitor
treatment responses, evaluate antitumor treatment efcacy, and prevent recurrence.
Tumors can shed cells and nucleic acids into the TME and circulation. These nucleic
acids, collectively known as circulating tumor nucleic acids (ctNAs), include cell-
free DNA and RNA molecules that are released passively or actively by tumor cells.
Interestingly, some tumors shed substantial amounts of ctNAs, while others pro-
duce levels that are barely detectable. The relationships between tumor evolution,
ctNA characteristics, shedding dynamics, and their overall clinical utility remain
underexplored. Recent studies have emphasized the potential of non-invasive liquid
biopsy-based biomarkers as real-time indicators of tumor burden, offering diagnos-
tic, prognostic, and predictive insights to guide cancer management.
Among the circulating components of the TME, circulating tumor cells (CTCs)
and circulating tumor DNA (ctDNA) are regarded as the two primary elements
of liquid biopsy. However, detecting CTCs is challenging due to their rarity, and
Tumor Microenvironment 15
ctDNA assays often suffer from high false-negative rates. Additionally, circulating
tumor RNA (ctRNA) is emerging as a promising biomarker that may provide unique
insights not available through CTCs or ctDNA (Stejskal et al., 2023, Khatami et al.,
2018, Osumi et al., 2019, Alix-Panabieres et al., 2021).
1.4 DISCUSSION
Altogether, a deeper understanding of the complex biology of the TME could enhance
the application of liquid biopsies, biomarker identication and detection, immuno-
therapy, chemotherapy, radiation, and molecularly targeted therapies—whether used
independently or in combination—in personalized medicine, ultimately improving
outcomes for cancer patients.
REFERENCES
Acharyya S, Oskarsson T, Vanharanta S, Malladi S, Kim J, Morris PG, Manova-Todorova
K, Leversha M, Hogg N, Seshan VE, Norton L, Brogi E, Massagué J. A CXCL1 para-
crine network links cancer chemoresistance and metastasis. Cell. 2012 Jul 6;150(1):
165–178. https://doi.org/10.1016/j.cell.2012.04.042. PMID: 22770218; PMCID:
PMC3528019.
Ali S, Suresh R, Banerjee S, Bao B, Xu Z, Wilson J, Philip PA, Apte M, Sarkar FH. Contribution
of microRNAs in understanding the pancreatic tumor microenvironment involving can-
cer associated stellate and broblast cells. Am J Cancer Res. 2015 Feb 15;5(3):1251–
1264. PMID: 26046003; PMCID: PMC4449452.
Alix-Panabieres C, Pantel K. Liquid biopsy: From discovery to clinical application. Cancer
Discov. 2021;11:858–873.
Andzinski L, Kasnitz N, Stahnke S, Wu CF, Gereke M, von Köckritz-Blickwede M, Schilling
B, Brandau S, Weiss S, Jablonska J. Type IIFNs induce anti-tumor polarization of tumor
associated neutrophils in mice and human. Int J Cancer. 2016 Apr 15;138(8):1982–1993.
https://doi.org/10.1002/ijc.29945. Epub 2015 Dec 17. PMID: 26619320.
Arneth B. Tumor microenvironment. Med. (Kaunas). 2019 Dec 30;56(1):15. https://doi.
org/10.3390/medicina56010015. PMID: 31906017; PMCID: PMC7023392.
Aterman K. The parasinusoidal cells of the liver: A historical account. Histochem J.
1986;18(6):279–305.
Balkwill FR, Capasso M, Hagemann T. The tumor microenvironment at a glance. J Cell
Sci. 2012 Dec 1;125(Pt 23):5591–5596. https://doi.org/10.1242/jcs.116392. PMID:
23420197.
Bellusci S, Grindley J, Emoto H, Itoh N, Hogan BL. Fibroblast growth factor 10 (FGF10)
and branching morphogenesis in the embryonic mouse lung. Development. 1997
Dec;124(23):4867–4678. https://doi.org/10.1242/dev.124.23.4867. PMID: 9428423.
Benish M, Bartal I, Goldfarb Y, Levi B, Avraham R, Raz A, Ben-Eliyahu S. Perioperative
use of beta-blockers and COX-2 inhibitors may improve immune competence and
reduce the risk of tumor metastasis. Ann Surg Oncol. 2008 Jul;15(7):2042–2052. https://
doi.org/10.1245/s10434-008-9890-5. Epub 2008 Apr 9. PMID: 18398660; PMCID:
PMC3872002.
Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003
Jun;3(6):401–410. https://doi.org/10.1038/nrc1093. PMID: 12778130.
Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P,
Itohara S, Werb Z, Hanahan D. Matrix metalloproteinase-9 triggers the angiogenic
switch during carcinogenesis. Nat Cell Biol. 2000 Oct;2(10):737–744. https://doi.
org/10.1038/35036374. PMID: 11025665; PMCID: PMC2852586.